N

R

O

SQ1

LGa

b

c

d

e

f

g

h

i

j

a

ARRA

KDBOIAA

C

2dhIidspaRn

3

h0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

ARTICLE IN PRESSG ModelBR 1953 1–17

Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rn al h om epage: www.elsev ier .com/ locate /neubiorev

eview

xidative & nitrosative stress in depression: Why so much stress?

teve Moylana,h,∗, Michael Berka,b,c,d,h,j, Olivia M. Deana,b,d, Yuval Samunia,ana Williamsa,d, Adrienne O’Neil a,c, Amie C. Hayleya, Julie A. Pascoa,e,eorge Andersonf, Felice Jackaa, Michael Maesa,g,i

IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, AustraliaFlorey Institute for Neuroscience and Mental Health University of Melbourne, Parkville, Victoria, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Prahran, Victoria, AustraliaUniversity of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville 3052, AustraliaNorthwest Academic Centre, University of Melbourne, St. Albans, Victoria, AustraliaCRC Scotland & London, London, United KingdomDepartment of Psychiatry, Chulalongkorn University, Faculty of Medicine, Bangkok, ThailandBarwon Health, Geelong, Victoria, AustraliaDepartment of Psychiatry, State University of Londrina, Londrina, BrazilOrygen Youth Health Research Centre, University of Melbourne, Parkville, Victoria, Australia

r t i c l e i n f o

rticle history:eceived 3 February 2014eceived in revised form 17 April 2014ccepted 13 May 2014

a b s t r a c t

Many studies support a crucial role for oxidative & nitrosative stress (O&NS) in the pathophysiologyof unipolar and bipolar depression. These disorders are characterized inter alia by lowered antioxidantdefenses, including: lower levels of zinc, coenzyme Q10, vitamin E and glutathione; increased lipid perox-idation; damage to proteins, DNA and mitochondria; secondary autoimmune responses directed againstredox modified nitrosylated proteins and oxidative specific epitopes. This review examines and details a

eywords:epressionipolar disorderxidative & nitrosative stress

nflammation

model through which a complex series of environmental factors and biological pathways contribute toincreased redox signaling and consequently increased O&NS in mood disorders. This multi-step processhighlights the potential for future interventions that encompass a diverse range of environmental andmolecular targets in the treatment of depression.

ntioxidantsutoimmune

© 2014 Published by Elsevier Ltd.

ontents

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2. Depression-related pathways causing O&NS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Activated immune-inflammatory pathways . . . . . . . . . . . . . . . . . . . . . . .2.2. Leaking gut and the microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: 5-HT, 5-hydroxytryptophan; 5-HTTLPR, serotonin transporter lin′-deoxyguanosine; ATP, adenosine triphosphate; BH4, 5,6,7,8-tetrahydrobiopterin;

amage-associated molecular pattern; DNA, eeoxyribonucleic acid; GPX, glutathypothalamic–pituitary–adrenal axis; IDO, indoleamine 2,3-dioxygenase; IFN�, interfer

gM, immunoglobulin M; IL-1, interleukin-1; IL-10, interleukin-10; IL-12, interleukin-12NOS, inducible nitric oxide synthase; KYNA, kynurenic acid; LDL, low-density lipoproteinialdehyde; NAC, N-acetylcysteine; NDMA, N-methyl-d-aspartate; NF-�B, nuclear factorynthase; NOX, NADPH oxidase complex.; Nrf2, nuclear factor erythroid 2-related factoreroxynitrite; OSA, obstructive sleep apnoea; OSE, oxidation specific epitope; Ox-LDL, oxssociated molecular pattern; PIC, pro-inflammatory cytokine; PON1, paraxonase 1; PRR,

OS, reactive oxygen species; SOD, Superoxide dismutase; SSRI, selective serotonin reupecrosis factor-alpha; TRYCAT, tryptophan catabolite.∗ Corresponding author at: C/o IMPACT Strategic Research Centre, School of Medicine,220, Australia. Tel.: +61 342153306; fax: +61 342153491.

E-mail address: steven.moylan@deakin.edu.au (S. Moylan).

ttp://dx.doi.org/10.1016/j.neubiorev.2014.05.007149-7634/© 2014 Published by Elsevier Ltd.

ive stress in depression: Why so much stress? Neurosci. Biobehav.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

ked polymorphic region; 8-iso, 8-iso-prostaglandin F2; 8-OHdG, 8-hydroxy-CMI, cell mediated immune; CRH, corticotrophin releasing hormone; DAMP,ione peroxidase; GSH, glutathione; HDL, high density lipoprotein; HPA,

on-alpha; IFN�, interferon-gamma; Ig, immunoglobulin; IgG, immunoglobulin G;; IL-1�, interleukin-1�; IL-2, interleukin-2; IL-4, interleukin-4; IL-6, interleukin-6;; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; MDA, malon-

(NF)-�B; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NOS, nitric oxide; NSE, nitrosative specific epitopes; O&NS, oxidative & nitrosative stress; ONOO-,idized low density lipoprotein; Ox-PLP, oxidized phospholipids; PAMP, pathogen-pattern recognition receptor; QUIN, quinolinic acid; RNS, reactive nitrogen species;take inhibitor; TCA, trycyclic antidepressant; TLR, Toll-like receptor; TNF-�, tumor

Deakin University, Kitchener House, Geelong Hospital, Ryrie St., Geelong, Victoria

ARTICLE IN PRESSG ModelNBR 1953 1–17

2 S. Moylan et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx

2.3. Activation of the Toll-like receptor radical cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.4. The tryptophan catabolite (TRYCAT) pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.5. The glutamate–cystine cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.6. Mitochondrial dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. Depression-related factors causing dysregulated O&NS pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Genetic polymorphisms in O&NS genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. Psychological stressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3. Medical comorbid disorders and conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.4. Obesity and metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.5. Sleep disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.6. Cigarette smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.7. Dietary factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.8. Vitamin D status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.9. Sedentary lifestyle and exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . .

1

cmgpiaWataptooif

leaw((eed2os2

toofp2Hge2b

Q2

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Many studies support dysregulated redox signaling as beingrucial in the pathophysiology and neuroprogressive nature ofajor depression (Maes et al., 2011a). Reactive oxygen and nitro-

en species (ROS and RNS), including peroxynitrite, superoxides,eroxides and nitric oxide (NO), are produced during normal phys-

ologic processes and, through interacting with proteins, fatty acidsnd DNA, perform numerous roles in regulation of cellular function.hen present in excess however, ROS/RNS can lead to structural

nd functional changes that produce cellular injury. These poten-ially toxic effects are offset under normal conditions by intrinsicntioxidant mechanisms that participate in the physiologic and/orathologic metabolism of ROS/RNS (Maes et al.). Increased oxida-ive and nitrosative stress (O&NS), which can arise as a consequencef raised production of ROS and RNS and/or decreased availabilityf antioxidant defenses, may cause damage to cellular components,nduce harmful autoimmune responses, and ultimately facilitateailure of normal cellular processes.

People with unipolar and bipolar depression display dysregu-ated redox signaling (Lee et al., 2013; Maes et al., 2011a; Moylant al., 2013c; Scapagnini et al., 2012). Studies using clinical andnimal models have demonstrated that depression is associatedith increased levels of redox products such as malondialdehyde

MDA, a marker for lipid peroxidation) and 8-iso-prostaglandin F28-iso) (a marker of arachidonic acid peroxidation) (Dimopoulost al., 2008; Forlenza and Miller, 2006; Galecki et al., 2009; Yagert al., 2010). Additionally, other studies have reported oxidativeamage to DNA, as measured by increased levels of 8-hydroxy-′-deoxyguanosine (8-OHdG) in serum (Forlenza and Miller, 2006)xidative damage to RNA in post-mortem hippocampus in depres-ion (Che et al., 2010) and telomere shortening (Shalev et al.,014).

Studies conducted in depressed populations demonstrate sus-ained increases in O&NS. These effects result in depleted levelsf n-3 fatty acid concentrations (Peet et al., 1998), a loweredxidative potential index of serum (Maes et al., 1999), reducedunctioning of antioxidant systems represented by lower levels oflasma concentrations of vitamin E (Maes et al., 2000; Owen et al.,005) and C (Khanzode et al., 2003), decreased albumin levels (Vanunsel et al., 1996), lowered levels of antioxidants including zinc,

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

lutathione (GSH) and coenzyme Q10 (Maes et al.), and lower lev-ls of amino acids, such as tryptophan and tyrosine (Maes et al.,000). Similarly, alterations of antioxidant-enzyme levels haveeen reported. For example, levels of superoxide dismutase (SOD)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

and glutathione peroxidase (GpX) are lower in depressed patients(Maes et al., 2011a). Paraoxonase 1 (PON1), an antioxidant enzymebound to high-density lipoprotein (HDL), was significantly reducedin unipolar, but not bipolar, depression (Vargas et al., submitted for

publication). Impairment of these aforementioned antioxidant sys-tems contributes to the pathophysiology of depression via loweredprotection to ROS and RNS, which may result in increased risk ofsustained O&NS damage (Forlenza and Miller, 2006; Maes et al.,2011a).

NO is an important mediator in many neural processes. Rodentssubjected to acute and chronic immobilization stress exhibitincreased levels of inducible nitric oxide synthase (iNOS). AlthoughNO levels, iNOS and neuronal NOS (nNOS) expression are increasedin depression, recent studies have indicated that NOS participates inthe mechanisms underlying antidepressant efficacy (Galecki et al.,2012; Maes et al., 2008b). This suggests that NO may have differ-ential effects at different sites during the course and treatment ofdepression. Persistently increased levels of NO and O2

− may leadto the formation of peroxynitrite (ONOO ) and subsequent oxida-tion, nitration and nitrosylation of proteins, thereby contributingto cellular injury (Maes et al., 2008b, 2011d).

Major depression and bipolar depression are also accompaniedby increased autoimmune responses against newly formed oxida-tion specific epitopes (OSEs), following structural damage by O&NS(Maes et al., 2007, 2011d, 2013b). Immunoglobulin (Ig)G and IgM-mediated immune responses against OSEs of membrane fatty acids,like oxidized low density lipoprotein (LDL), oleic acid, MDA and aze-laic acid, and anchorage molecules, such as phosphatidyl inositol,palmitic acid, myristic acid and farnesyl-l-cysteine, can be seen indepression (Maes et al., 2007, 2011d, 2013b). This may have pro-found functional consequences as oxidative damage to membranes,especially to the major anchorage molecules, may affect the opera-tion of hundreds of functionally “anchored” proteins that regulatebasic cellular processes, including cell survival, growth, apoptosis,cell-signaling, neuroplasticity and neurotransmission (Maes et al.,2011a).

Chronically increased NO, following iNOS activation, can nitro-sylate (NSO or NO) proteins and amino acids yielding newNO-adducts (NO-neoepitopes) like NO-tyrosine, NO-tryptophan,NO-arginine, NSO-cysteine and NO-albumin. The consequenthyper-nitrosylation may cause dysfunction to intracellular signal-

ive stress in depression: Why so much stress? Neurosci. Biobehav.

ing, as well as competitively inhibit the palmitoylation of anchoredproteins to the membrane (Maes et al., 2008b, 2011d, 2012a).Moreover, some of these NO adducts can be immunogenic andtherefore contribute to further autoimmune responses directed

122

123

124

125

ING ModelN

iobeh

aMdi

aeaas

otaGitoifi

2

2

eDvaIwcs2acesaiitiTtoecrnMaimtaoniuiif2

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

gainst “nitrosative specific epitopes” (NSEs) (Boullerne et al., 2002;aes et al., 2011d, 2012a). Finally, the autoimmune response

irected against some of these NSEs (e.g. NSO-cysteine) may resultn serious neurotoxic effects (Boullerne et al., 2002).

Animal studies have demonstrated that various classes ofntidepressants can reduce levels of oxidative stress markers (Erent al., 2007a,b; Maes et al., 2011a) and increase some endogenousntioxidants (Maes et al., 2011d). Further, some redox modulatorsppear to have some promise as adjunctive treatments for depres-ion (Maes et al., 2012a; Scapagnini et al., 2012).

The above observations provide greater insight into the pathol-gy of depression, but also raise a pertinent question: what arehe underlying pathways and factors that contribute to the onsetnd maintenance of the increased O&NS state in depression?reater understanding of the pathways and factors that precip-

tate a state of subchronic O&NS in depression may inform newherapeutic and preventative strategies. Here, we review numer-us pathways and factors that may contribute to increased O&NSn major depression, and discuss the potential implications of thesendings.

. Depression-related pathways causing O&NS

.1. Activated immune-inflammatory pathways

Considerable evidence supports the role of central and periph-ral immune-inflammatory processes in depression pathogenesis.epression is associated with cell-mediated immune (CMI) acti-ation, increased monocytic activation and a T helper (Th)-1-nd Th-17-like cytokine response (Leonard and Maes, 2012).n addition, recent meta-analyses demonstrate that patients

ith depression have higher serum levels of pro-inflammatoryytokines (PICs) such interleukin (IL)-1, IL-6 and tumor necro-is factor alpha (TNF�) (Dowlati et al., 2010; Howren et al.,009). Depression is also associated with increased levels ofcute phase proteins, including C-reactive protein and haptoglobin,hemokines, adhesions molecules and complement factors (Berkt al., 1997; Maes et al., 1997a; Pasco et al., 2010). An eventronger association between pro-inflammatory cytokines and LPSnd depressive-like behaviors has been reported in rodent stud-es where administration of IL-6, IL-1�, TNF� or LPS resultedn depressive-like and anxiety-like-behaviors. Similar manifesta-ions of depressive symptoms are also seen in patients undergoingmmunotherapy with IL-2 and INF-� (Dutcher et al., 2000).he reader is referred to three recent reviews demonstratinghat in depression and bipolar disorder peripheral activationf immune-inflammatory pathways coupled with elevated lev-ls of circulating LPS may contribute to neuroinflammation andonsequent neuroprogressive changes including decreased neu-oplasticity, neurogenesis, and increased neurodegeneration andeuronal apoptosis (Berk et al., 2011b; Leonard and Maes, 2012;oylan et al., 2013c). In addition, immune-inflammatory pathways

ffect the expression of key neurotransmitters thought involvedn depression pathogenesis (e.g. serotonin, noradrenaline) through

ultiple pathways. One example is through effects on 5,6,7,8-etrahydrobiopterin (Bh4). (BH4) is a critical co-factor of numerousmino acid converting enzymes responsible for the productionf neurotransmitters including NO, tryptophan, dopamine andoradrenaline (Sperner-Unterweger et al., 2014). Under acute

nflammatory conditions these BH4 related enzymes are upreg-lated, leading to increased biosynthesis of neurotransmitters

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

n the short term. However, chronic low-grade inflammations associated with “oxidative loss of BH4”, reducing capacityor neurotransmitter biosynthesis (Sperner-Unterweger et al.,014).

PRESSavioral Reviews xxx (2014) xxx–xxx 3

Studies assessing the effect of antidepressants on immune-inflammatory markers in depression provide further corroborationfor the role of immune-inflammatory processes in depression.Administration of tricyclic antidepressants (TCAs) and selectiveserotonin inhibitors (SSRI) has been shown to suppress CMI, whilstattenuating inflammatory biomarkers and acute phase protein lev-els in animal models (Leonard and Maes, 2012). Not surprisingly,the relationship between the immune-inflammatory response anddepression may be driven, or modulated, by underlying geneticvulnerability. A recent review of genetic variants in neurobiolog-ical pathways associated with immune activation and depressiondemonstrates that allelic variants of IL-1�, TNF-� and CRP mayincrease depression risk. SNPs in the IL-1�, IL-6 and IL-11 genes mayalso be associated with reduced responsiveness to antidepressants(Bufalino et al., 2013).

Mutual inductions between immune-inflammatory and O&NSpathways may be key in depression pathogenesis (Maes et al.,2011a, 2012a). Activation of immune-inflammatory pathways,O&NS processes and lowered antioxidant defenses are insepara-bly interrelated (Maes et al., 2012a). Activated phagocytes and M1macrophages produce large quantities of ROS and RNS. Increasedlevels of TNF� can upregulate the expression of iNOS via transloca-tion of nuclear factor kappa B (NF-�B), while interferon-gamma(IFN�) may activate the production of iNOS and thus NO bymacrophages. In different cell types, such as macrophages, neu-trophils, epithelial cells and microglia, cytokines such as IL-1, TNF�and IFN� activate ROS production (superoxide) via the NADPH oxi-dase complex (NOX). Neopterin, a surrogate marker of the Th-1-likeresponse, activates iNOS and NO production and the productionof hydrogen peroxide. On the other hand, activated O&NS path-ways may increase nuclear factor (NF)-�B, activator protein-1and mitogen-activated protein kinases (MAPK) thereby increas-ing the production of inflammatory mediators, such as PICs andchemokines.

Inflammatory and O&NS processes may also affect antioxidantdefenses. For example, the inflammatory processes in depressionare associated with lowered levels of zinc and vitamin E (Maeset al., 2011e). ROS produced in physiological conditions and duringinflammation upregulate antioxidant defense systems. In responseto O&NS, cells increase their antioxidant defenses through activa-tion of nuclear factor erythroid 2-related factor (Nrf2) (Maes et al.,2012a). Once activated, Nrf2 increases the expression of multipleendogenous antioxidants. On the other hand, severe inflamma-tion accompanied by increased ROS, as observed in inflammatorybowel disease, causes an increased consumption of tissue antioxi-dant defenses masking increased antioxidant levels due to the mildO&NS (Blau et al., 2000).

Since antioxidants, such as coenzyme Q10, zinc and glutathione,have anti-inflammatory effects, the lowered levels of those antiox-idants in depression increase the inflammatory and O&NS burden(Maes et al.). Moreover, reduced glutathione (GSH) and the regula-tion of pro-inflammatory cytokines are intimately interlinked. Forexample, the transcription of IL-1�, IL-6, and TNF� are regulatedby the redox state of the cell and depletion of GSH enhances thetranscription of these cytokines (Haddad, 2000).

Fig. 1 shows the associations between activated immune-inflammatory pathways, lowered antioxidant defenses andincreased damage by O&NS in depression. Factors that are knownto activate immune-inflammatory pathways (review: (Berk et al.,2013)) may therefore lead to downstream activation of ROS/RNSproduction and O&NS. It may be concluded that in depression, low-ered levels of antioxidants and activation of immune-inflammatory

ive stress in depression: Why so much stress? Neurosci. Biobehav.

and O&NS pathways are complex processes that exacerbate eachother via multiple feedback loops. Interactions of these seem-ingly enmeshed pathways further contribute to the complexity ofdepression pathogenesis.

250

251

252

ARTICLE ING ModelNBR 1953 1–17

4 S. Moylan et al. / Neuroscience and Biobeh

Fig. 1. Depression is characterized by multiple associations between activatedimmune-inflammatory pathways, lowered levels of key antioxidants and increasedreactive nitrogen species (RNS) and reactive oxygen species (ROS), which activatenuclear factor erythroid 2-related factor (Nrf2) increasing the expression of endoge-nous antioxidants. ROS, on the other hand, increases the consumption of antioxidantdefenses. The consequences of activated oxidative and nitrosative stress (O&NS)pathways comprise the following: (a) formation of oxidative (OSEs) and nitrosative(NSEs) specific epitopes, which may be immunogenic thereby causing autoimmuner(s

2

rrtnMrgWtcaitpbl12carm

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

esponses; (b) oxidative and nitrosative damage to various cellular components; andc) hyper-nitrosylation. These consequences of activated oxidative and nitrosativetress pathways ultimately cause a wide variety of cellular dysfunctions.

.2. Leaking gut and the microbiome

Clinically depressed patients display higher IgM and IgAesponses to lipopolysaccharides (LPS) from gram-negative bacte-ia, potentially as consequence of bacterial translocation secondaryo increased gut permeability (Maes et al., 2008a, 2012b). Gram-egative bacteria including Hafnia alvei, Pseudomonas aeruginosa,organella morganii, Proteus mirabilis, Pseudomonas putida, Cit-

obacter koseri and Klebsiella pneumoniae belong to the normalut flora and are termed commensal gut bacteria (Todar, 2006;iest, 2005). Under normal conditions the immune system is func-

ionally and geographically separated from these poorly invasiveommensal gut bacteria by an intact gut tight junction barrier (Bergnd Garlington, 1979; Wiest and Garcia-Tsao, 2005). Due to this,mmune cells are not normally primed against commensal gut bac-eria. However, when the gut wall is weakened by increased gutermeability, gram-negative bacteria can exploit the loosened gutarrier, thereby translocating from the gut into the mesenteric

ymph nodes (MLNs) or the blood stream (Berg and Garlington,979; Chavez et al., 1999; Clark et al., 2005; Wiest and Garcia-Tsao,005; Yang et al., 2003). Once bacteria are translocated, immuno-

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

ytes can mount an IgA or IgM-mediated immune response directedgainst the LPS of gut commensal bacteria. Measuring IgA and IgMesponses against LPS of commensal bacteria is a more sensitiveethod to detect bacterial translocation than the assay of serum

PRESSavioral Reviews xxx (2014) xxx–xxx

LPS, because it also detects bacterial LPS when bacteria have notspread into the blood circulation but when the bacteria are translo-cated into the MLNs (Maes et al., 2013a). The finding that clinicaldepression is associated with increased IgM/IgA responses to LPStherefore indicates that immune cells are activated by LPS fromgram-negative bacteria, which is translocated into the MLNs, theblood stream, or both. Because if their particular role in mucosaldefence, Th17 cells, a subset of T helper cells have a particular roleagainst gut infections and are associated with atopic, inflammatory,and autoimmune disorders. Th17 cells may disrupt the blood–brainbarrier leading to infiltration of the central nervous system, anddrive neuroprogression (Debnath and Berk, 2014).

Through binding with the Toll-like receptor (TLR)2 andTLR4 complexes, LPS activates different intracellular signalingmolecules, including NF-�� and MAPK, thereby increasing expres-sion of PIC and O&NS genes (Tsukamoto et al., 2010; Wiest andGarcia-Tsao, 2005). For example, NF-�� induces the production ofIL-1, IL-6, TNF� and iNOS (Brasier, 2006). LPS additionally activatesNOX, which in turn increases production of iNOS, NO, superox-ide and peroxides (Chan and Riches, 2001; Check et al., 2010;Peng et al., 2005). Previously, it has been shown that increasedgut permeability is accompanied by elevated plasma LPS and signsof inflammation and O&NS, with these processes being attenu-ated or reversed upon successful treatment of the leaky gut (Quanet al., 2004; Zhou et al., 2003). This is relevant to depression, asLPS administration increases nitrite, nitrate and MDA levels whilstdecreasing brain GSH levels (Tyagi et al., 2010). LPS also reduces thelevels of CC16 or uteroglobin, an endogenous anti-inflammatorysubstance, thereby increasing inflammatory potential (Franssonet al., 2007). CC16 is significantly lowered in depressed subjects; inpart explaining the immune-inflammatory responses in that illness(Rief et al., 2001).

In patients with depression there are significant and positivecorrelations between bacterial translocation (increased IgA andIgM responses to LPS) and signs of increased O&NS (Maes et al.,2012b) including increased plasma oxidized LDL antibodies, IgMresponses to NSEs, such as NO-tryptophan and NO-tyrosine, aswell as IgM responses directed against OSEs, including azelaic acid,MDA and phosphatidyl inositol (Maes et al., 2012b). These find-ings indicate that increased bacterial translocation in depressiondrives chronically activated O&NS pathways (damage to fatty acidsand proteins) and autoimmune responses directed against OSEsand NSEs (Maes et al., 2012b). Gut bacteria produce a plethora ofcompounds that influence redox signaling, with different popula-tions producing different compounds. One example is molecularhydrogen which has wide-ranging biological effects, includinganti-oxidative, anti-apoptotic and anti-inflammatory properties(Ghanizadeh and Berk, 2013).

Recently a review of the bidirectional connections between thegut and the brain summarized the evidence that gastrointestinalhomeostasis may modulate emotion, affect, neurocognitive func-tions and motivation (Mayer, 2011). Most importantly, animalsexposed to repeated restraint and acoustic stressors demonstratedincreased gut permeability, TLR4 activation and neuroinflam-mation (Garate et al., 2013). Moreover, attenuation of bacterialtranslocation through antibiotic induced intestinal decontamina-tion reduces stress-induced neuroinflammation, suggesting thatstress-induced neuroinflammation is at least partially caused byincreased bacterial translocation. For these reasons, increased bac-terial translocation may be a promising drug target in stress-relateddisorders, such as depression (Garate et al., 2013).

ive stress in depression: Why so much stress? Neurosci. Biobehav.

2.3. Activation of the Toll-like receptor radical cycle

Pattern recognition receptors (PRRs), which include TLR2 andTLR4, are an important part of the host defense system (Lucas

338

339

340

ING ModelN

iobeh

al(iTcadtc

p(siedo(t1dacs(aRw

tcoeDoi

2

dttmdlc

iIrcfuAtcaie(hap

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

nd Maes, 2013). PRRs recognize pathogen-associated molecu-ar patterns (PAMPs) and damage-associated molecular patternsDAMPs), which consequently activate MAPK and/or NF-�B lead-ng to activation of immune-inflammatory and O&NS pathways.he TLRs recognize mycoplasma, fungus, viruses and LPS, a typi-al PAMP derived from gram-negative bacteria. Since depression isccompanied by increased IgM/IgA-mediated immune responsesirected against LPS of gut commensals, it may be concluded thathe TLR2/TLR4 complexes are activated by PAMP-mediated pro-esses.

Typically DAMPs, including �-defensin, high mobility grouprotein 1 (HMGB1), heat shock proteins (HSPs), extracellular matrixECM), cathelicidin (LL37), hyaluronic acid, heparin sulfate, sub-tance P and redox-derived DAMPs, appear following injury andnflammation (Carta et al., 2009; Kaczmarek et al., 2013; Lotzet al., 2007; Rubartelli and Lotze, 2007; Uchida, 2013). Redox-erived DAMPs are produced during lipid peroxidation and consistf oxidatively modified molecules, such as oxidized phospholipidsOx-PLP), oxidized LDL (Ox-LDL), 4-HNE and MDA modified pro-eins (Carta et al., 2009; Uchida, 2013). As reviewed in Section, depression is accompanied by increased levels of some redox-erived DAMPS, including oxidized LDL, oxidized phospholipidsnd MDA-derived adducts (Maes et al., 2011d). These moleculesan activate the TLR2/TLR4 complex and play a role in the down-tream activation of immune-inflammatory and O&NS pathwaysLucas and Maes, 2013). As a consequence, depression may beccompanied by a vicious cycle between TLR2/TLR4 activation andOS production causing increased levels of redox-derived DAMPs,hich further stimulate the TLRs.

Exposure to TLR agonists has been shown to sensitize and primehe TLR response to subsequent stimulation by other agonists. Psy-hosocial stressors may additionally upregulate TLR4 expressionr activation (Lucas and Maes, 2013). Thus, in depression differ-nt TLR2/TLR4 agonists, including bacterial LPS and redox-derivedAMPs, and psychosocial stressors may cause hypersensitivityf the TLR complexes, thereby activating downstream immune-nflammatory and O&NS pathways.

.4. The tryptophan catabolite (TRYCAT) pathway

Interactions between inflammation, O&NS, lowered antioxi-ant levels and bacterial translocation may occur via changes inhe tryptophan catabolite (TRYCAT) pathway. By diverting tryp-ophan metabolism away from serotonin, N-acetylserotonin and

elatonin production, increased activation of indoleamine 2,3-ioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) have

ong been identified as being associated with depression and asso-iated conditions (Maes et al., 1993, 2011c).

IDO, a heme-centered enzyme, is upregulated in pro-nflammatory states in particular by INF�, but also IL-1, IL-6,L-18, TNF� and LPS (Maes et al., 2011a). When IDO is in its fer-ous form and in the presence of molecular oxygen, it acts toleave tryptophan to N-formylkynurenine, initiating induction ofurther TRYCATs. Alternatively, when IDO is in its ferric form ittilizes O2

− as a reducing agent to trigger the TRYCAT pathway.s such, the inflammatory state and redox status regulates how

ryptophan is utilized, with significant consequences for processeslassically associated with depression (Maes et al., 2011c; Wernernd Werner-Felmayer, 2007). In addition, lowered tryptophan andncreased levels of most TRYCATs have negative immunoregulatoryffects that suppress primary immune-inflammatory responses

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

Maes et al., 2011c). Thus, induction of the TRYCAT pathway mayave a protective function, but the longer-term consequence ofctivation can be crucial to alterations in neuronal activity andatterning in depression.

PRESSavioral Reviews xxx (2014) xxx–xxx 5

IDO is predominantly expressed in microglia within the CNS(Alberati-Giani and Cesura, 1998). Microglia are important reg-ulators and coordinators of central changes in depression anddepression-associated neurodegenerative disorders (Maes et al.,2011c). The activation of IDO leads to production of neuroregu-latory TRYCATs including kynurenic acid (KYNA) and quinolinicacid (QUIN). KYNA is inhibitory at the �7 nicotinic receptor, whilstQUIN is excitotoxic at N-methyl d-aspartate (NMDA) receptors byincreasing NO-mediated damage to neurons and astrocytes (Braidyet al., 2009).

Moreover, TRYCATs have anti-oxidant and pro-oxidant effects.For example, 3-hydroxykynurenine, 3-hydroxyanthranilic acid andxanthurenic acid perform antioxidant functions including scaveng-ing free radicals, reducing lipid peroxidation, and preventing thespontaneous oxidation of glutathione and damage to 2-deoxy-d-ribose (Christen et al., 1990; Goda et al., 1999; Leipnitz et al., 2007).However, 3-hydroxykynurenine, 3-hydroxyanthranilic and quino-linic acid also display pro-oxidant effects by generating ROS (e.g.superoxide and hydrogen peroxide) and causing lipid peroxidationand oxidative cell damage (Dykens et al., 1987; Goldstein et al.,2000; Guidetti and Schwarcz, 1999; Murakami et al., 2006; Okudaet al., 1998; Rios and Santamaria, 1991; Santamaria et al., 2001;Smith et al., 2009).

Genetic variants of IDO genes may influence inflammatorystatus, thereby regulating the etiology, course and outcome ofdepression (Bufalino et al., 2013). Another important regulatorof the TRYCAT pathways is TDO, which in the CNS is predom-inantly expressed in astrocytes, although also in some neurons(Funakoshi et al., 2011). The activation of TDO is primarily mediatedby cortisol (Ren and Correia, 2000). Therefore, increased immune-inflammatory pathway activation and O&NS, through drivingincreases in hypothalamic pituitary adrenal (HPA) axis activitycommonly found in depression (Carroll, 1980), will also contributeto increased TDO, further depleting serotonin, N-acetylserotoninand melatonin, whilst changing neuroregulation by the inductionof KYNA, which is the TRYCAT predominantly produced follow-ing TDO induction. Overall, immune-inflammatory processes andO&NS, including via the regulation of IDO and TDO, are intimatelylinked to processes altered in depression.

2.5. The glutamate–cystine cycle

Prolonged oxidative stress reduces the capacity of astrocytesto import glutamate facilitating an increase in extracellular gluta-mate levels (Dallas et al., 2007). Higher extrasynaptic and lowersynaptic glutamate may play a role in depression (Sanacora et al.,2003), and depression is associated with glutamate supersensi-tivity (Berk et al., 2001). A genome-wide association study indepression demonstrated involvement of glutamatergic synapticneurotransmission genes in depression (Lee et al., 2012). Oxidative-stress increased glutamate levels can inhibit cystine uptake by thexc-antiporter system thereby causing intracellular GSH depletionand consequently oxidative-stress-induced neurotoxicity throughexcitotoxic effects, a process called “oxidative glutamate toxicity”(Murphy et al., 1989; Schubert and Piasecki, 2001) that is at leastin part mediated by increased calcium signaling.

2.6. Mitochondrial dysfunction

The mitochondrial electron transport chain (ETC) is responsi-ble for cellular energy generation via adenosine-5-triphosphate(ATP) production (Adam-Vizi and Starkov, 2010). ATP is gener-

ive stress in depression: Why so much stress? Neurosci. Biobehav.

ated by transferring electrons through complexes I–V (Green andKroemer, 2004; Lenaz, 2001). During this process electrons canescape, resulting in the reduction of molecular oxygen, whichleads to the generation of the superoxide anion (O2

−) (Green and

462

463

464

465

IN PRESSG ModelN

6 iobehavioral Reviews xxx (2014) xxx–xxx

Ki

hivcttd

astdtMpmt2ttfimisgaald

D(dlp1aecm

matdIbrmchim

oto

2

c

Fig. 2. Different pathways may play a role in the increased oxidative and nitrosativestress (O&NS) in depression: (a) activated immune-inflammatory pathways; (b)lowered levels of key antioxidants. Increased oxidative stress increases the con-sumption of antioxidant defenses and activates nuclear factor erythroid 2-relatedfactor (Nrf2), which increases the expression of endogenous antioxidants; (c) oxida-tive stress induced activation of the tryptophan catabolite (TRYCAT) pathway withquinolinic acid (Quin)-induced increases in nitric oxide (NO)-mediated cell dam-age; (d) oxidative stress induced glutamate levels depleting intracellular glutathione(GSH) and facilitating consequent “oxidative glutamate toxicity”; (e) oxidativestress-induced mitochondrial dysfunctions leading to increased production of reac-tive oxygen species (ROS); (f) formation of oxidative (OSEs) and nitrosative (NSEs)specific epitopes which may be immunogenic and mount autoimmune responsesfurther driving O&NS processes; (g) formation of redox-derived damage associ-ated molecular patterns (DAMPs) activating the Toll-like receptor (TLR) radical

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

roemer, 2004). Mitochondria are therefore an endogenous phys-ological source of ROS.

As a consequence of high ROS production, mitochondria areeavily reliant on local antioxidants and antioxidant enzymes,

ncluding GSH, coenzyme Q10, zinc, SOD, selenium, vitamin C anditamin E, to maintain their function. The coordination of mito-hondrial oxidant induction with antioxidant response is crucialo normal cellular plasticity, with alterations in this balance con-ributing to the etiology and course of multiple disorders includingepression (Gardner and Boles, 2011; Maes et al., 2011a).

Mitochondrial dysfunction in depression, including reducedctivity of the ETC and its enzymes, decreased production of adeno-ine triphosphate (ATP), changes in mitochondrial structures inhe brain (e.g. prefrontal and frontal cortex), mitochondrial DNAeletions and decreased expression of mitochondrial DNA-encodedranscripts, have recently been reviewed (Gardner and Boles, 2011;

aes et al., 2012a). Increased activity of immune-inflammatoryathways in depression, such as increased levels of IL-1� and TNF�,ay cause lowered ATP production and concomitant disorders in

he ETC and thus impaired oxidative phosphorylation (Maes et al.,011a, 2012a). The depleted levels of the aforementioned impor-ant mitochondrial antioxidants in depression likely contribute tohe impact of immune-inflammatory stressors on mitochondrialunctions and structures. The consequent lipid peroxidation andncreased MDA and 4-HNE production can cause mitochondrial

embrane dysfunction, including increased membrane permeabil-ty; ultimately leading to mitochondrial dysfunction. Increased NOignaling additionally inhibits mitochondrial respiration and mayenerate peroxynitrite, which may further reduce ETC functioning,nd damage mitochondrial DNA and functional proteins (Morrisnd Maes, 2013). These mitochondrial dysfunctions, in turn, mayead to an increased production of superoxide, which causes furtheramage to mitochondria and leads to lowered ATP production.

Some of the key processes altered by O&NS include damage toNA, which results in an increase in poly(ADP-ribose) polymerase

PARP), which, in turn, depletes nicotinamide (NAD+), leading toecreased sirtuins. Both sirtuin-1 and sirtuin-3 are crucial regu-

ators of mitochondrial function. Sirtuin-1 increases peroxisomeroliferator-activated receptor gamma coactivator-1alpha (PGC-�), the master mitochondria regulator, whilst sirtuin-3 is locatedt mitochondria where it is crucial to optimal functioning (D’Aquilat al., 2012). As such increased O&NS, including when produced asonsequence of mitochondrial function, may in fact contribute toitochondrial dysfunction via the consequences of DNA damage.Another new putative pathway that plays a key role in

itochondria-related oxidative stress and mitochondria-mediatedpoptosis is p66shc (Galimov et al., 2014). p66shc is an adaptor pro-ein that activates the mitochondrial apoptosis pathway and mayownregulate cellular antioxidant defenses (Galimov et al., 2014).

mportantly, p66 gene deletion reduces emotionality and increasesrain plasticity in association with increased brain derived neu-otrophic factor (BDNF) levels, suggesting strong links betweenitochondrial-generated oxidative stress, emotional behavior and

entral BDNF (Berry and Cirulli, 2013). Sirtuins and the p66shc geneave been under-investigated in the course of depression; top-

cs requiring further attention given their potential importance initochondrial functioning.These data suggest the potential for development of a new class

f antidepressant medications that prevent mitochondrial dysfunc-ion, especially the consequent oxidative damage to DNA, proteinsr lipids (Maes et al., 2012a).

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

.7. Conclusions

Fig. 2 shows the different pathways in depression that mayause activation of O&NS pathways. The TLR2/TLR4 complexes

cycle thereby inducing immune-inflammatory and O&NS pathways; (h) increasedpathogen associated molecular patterns, such as lipopolysaccharide (LPS), and psy-chosocial stressors may activate or sensitize TLRs.

may be activated or upregulated by LPS and psychosocial stressorsleading to downstream production of proinflammtory cytokinesand activation of O&NS pathways. Due to this, new redox-derivedDAMPs are formed which further activate the TLR radical cycle.Prolonged oxidative stress may cause activation of the TRYCATpathway leading to NMDA receptor-associated excitotoxicity byincreasing NO-mediated cell damage, and increased glutamate lev-els that deplete intracellular GSH and facilitate oxidative glutamatetoxicity.

3. Depression-related factors causing dysregulated O&NSpathways

3.1. Genetic polymorphisms in O&NS genes

Depression is associated with single nucleotide polymorphisms(SNP) in pro-oxidant and antioxidant enzyme genes (Maes et al.,2011a). Polymorphisms in the myeloperoxidase gene, in particularGG homozygote and the G allele, increase the risk of depression(Galecki et al., 2010). This is important, as myeloperoxidase is apro-oxidant and pro-inflammatory enzyme that is increased ininflammatory disorders. The G/A SNP of the iNOS gene signifi-cantly increases susceptibility to recurrent depression, while A/Ahomozygous carriers demonstrate a lower risk of recurrent depres-sion (Galecki et al., 2011). There is also a significant associationbetween SNPs in MnSOD and depression, which may lead to aslower uptake of MnSOD in the mitochondria and to mRNA insta-bility (Galecki et al., 2010). Variation on the GpX1 gene is associated

ive stress in depression: Why so much stress? Neurosci. Biobehav.

with increased depression risk (Johnson et al., 2013), and addi-tionally modulates the effects of antioxidants, such as selenium(Johnson et al., 2013). Some, but not all, studies have demonstratedthat a functional polymorphism in the PON1 gene (Q → R at the

555

556

557

558

ING ModelN

iobeh

1(bastaappe

mmc

3

OcfStlh(pI(saaoaeccri2suloK

lwPac(ieersabe

3

a

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

92 position) increases the odds of unipolar and bipolar depressionVargas et al., 2013). In addition, gene by environmental effects maye involved. For example, an interaction between PON1 gene SNPnd smoking is associated with bipolar depression (Vargas et al.,ubmitted for publication). While polymorphisms of glutamate cys-eine ligase, a key synthetic enzyme in the glutathione pathwaysre associated with disorders such as schizophrenia, this does notppear to be the case in depression (Berk et al., 2011a). SNPs ofro-inflammatory cytokine genes, including IL-1 and IL-6, may alsoredict responsiveness to treatment with antidepressants (Baunet al., 2010; Uher et al., 2010).

Therefore, underlying genetic vulnerabilities produced by poly-orphisms in pro-oxidant, antioxidant and inflammatory genesay contribute to the O&NS processes in depression especially in

onditions of increased ROS/RNS production.

.2. Psychological stressors

A vast literature suggests psychosocial stressors may induce&NS pathways and reduce antioxidant defenses. Psychologi-al stress causes a pro-oxidant state and oxidative damage toatty acids (Aleksandrovskii Iu et al., 1988; Pertsov et al., 1995;osnovskii and Kozlov, 1992). Morimoto et al. (2008) reportedhat in postmenopausal women, mental stress induces increasedipid peroxidation as measured by plasma 4-HNE. In nurses withigh job stress, significantly decreased levels of alpha-tocopherolvitamin E) and a significant relationship between MDA levels anderceived stress ratings have been detected (Tsuboi et al., 2006).

n workers from a pre-hospital emergency service, Casado et al.2006) observed a significant association between occupationaltress and erythrocyte MDA levels. In females, stress variables, suchs perceived stress and workload and less coping with stress, weressociated with increased levels of 8-OHdG (Irie et al., 2001). Stress-rs such as examination stress decrease plasma antioxidant activitynd increases oxidative stress-induced damage to DNA (Sivonovat al., 2004). Conversely, lifestyle-modifying programs may signifi-antly improve antioxidant defenses. For example, in patients withoronary artery disease an intensive lifestyle modification programesulted in statistically significant increases in plasma total antiox-dant capacity, vitamin E and erythrocyte GSH (Jatuporn et al.,003). In animal models, many different types of psychophysicaltressors, including immobilization stress, restraint stress, chronicnpredictable stress and chronic mild stress, were shown to cause

owered levels of antioxidants, such as GSH, and increased lipid per-xidation, as measured with MDA and 4-HNE (Ahmad et al., 2010;ubera et al., 2011; Moretti et al., 2012; Wang et al., 2012).

As psychological stressors may cause O&NS, the role of psycho-ogical trauma has been examined in animal models and individuals

ith post-traumatic stress disorder (PTSD). An animal model ofTSD demonstrated that increased expression of oxidative stressnd pro-inflammatory cytokine mRNA in the brain and systemicirculation are associated with the onset and exacerbation of PTSDWilson et al., 2013). In patients with PTSD, however, no changesn urinary 8-OHdG could be detected, while protein carbonyl lev-ls were lower in the PTSD group (Ceprnja et al., 2011). Millert al. (2013) identified a variant in the gene retinoid-related orphaneceptor alpha (RORA) as being protective against the effects oftress on the brain, and subsequent development of PTSD. Theuthors concluded that this gene plays a crucial role in guardingrain cells from the detrimental effects of oxidative stress (Loguet al., 2013).

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

.3. Medical comorbid disorders and conditions

Depression is highly comorbid with many systemic immunend O&NS-related disorders (e.g. Chronic Obstructive Pulmonary

PRESSavioral Reviews xxx (2014) xxx–xxx 7

Disorder; COPD, atherosclerosis, rheumatoid arthritis, inflam-matory bowel disease, psoriasis, diabetes type 1 and type 2,HIV-infection), neuroinflammatory and O&NS-related brain disor-ders (e.g. Parkinson’s disease, Alzheimer’s disease, stroke, multiplesclerosis) and conditions accompanied by increased inflammatorypotential and O&NS (hemodialysis, IFN�-based immunotherapy)(Maes et al., 2011b). Depression may be triggered by these disor-ders or conditions, or worsen outcomes for those in whom thesedisorders are present (Maes et al., 2011b).

Increased O&NS and immune-inflammatory pathways mayunderpin the comorbidity and interaction between depression andthese related conditions (Maes et al., 2011a; Wolkowitz et al.,2011). Recently, it has been proposed that the underlying biologicalprocesses driving depression intimately overlap with neurodegen-erative processes, suggesting that depression may be more than acomorbidity but rather is intertwined with degenerative processes(Anderson and Maes, 2013b). Oxidative stress drives telomereshortening, a key mechanism underlying the aging process (Phillipset al., 2013), and therapies that reduce oxidative stress such aslithium are associated with longer telomeres (Martinsson et al.,2013). There may be additional effects of aging on O&NS pathwaysand a number of ‘age-related’ disorders such as cardiovascular dis-ease (CVD) (Maes et al., 2011e), stroke (El Kossi and Zakhary, 2000),diabetes (Maritim et al., 2003), metabolic syndrome (Hansel et al.,2004), and sleep apnea (Jelic et al., 2008); all of which are recog-nized to share common origins of increased O&NS (Forlenza andMiller, 2006).

3.4. Obesity and metabolic syndrome

Accumulating clinical and epidemiological evidence suggeststhat obesity contributes to the pathogenesis of depression (Atlantiset al., 2009). Cross-sectional studies have linked obesity withdepression (Atlantis and Baker, 2008; de Wit et al., 2010) and neg-ative affect (Pasco et al., 2013), and a series of longitudinal studieshave demonstrated this association is bi-directional (Luppino et al.,2010; Pan et al., 2012). Traditionally regarded as an energy storagedepot, adipose tissue is now recognized as having a role in bothphysical and mental health.

Excessive accumulation of adipose tissue in obesity perturbs theregulatory network of neural circuits and circulatory messengersthat has evolved to maintain energy homeostasis. As one of thecell types in adipose tissue, adipocytes (fat cells) serve as depotsfor energy storage and mobilization. Adipocytes produce biolog-ically active molecules known as adipokines (or adipocytokines)that have pro-inflammatory or anti-inflammatory activities, andthese include leptin, TNF� and adiponectin. Leptin is a pro-inflammatory cytokine that plays a key role in regulating energyintake and expenditure and signals the brain when adipocytesbecome enlarged to modify appetite and behavior (Jequier, 2002).TNF� is a pro-inflammatory cytokine that stimulates the acutephase reaction and adiponectin is an anti-inflammatory factor. Cir-culating levels of leptin (Pasco et al., 2008a; Solin et al., 1997) andTNF� (Kern et al., 1995) are elevated in obesity and raised levels ofboth factors have been reported in depression (Halaris et al., 2012;Pasco et al., 2008a). By contrast, adiponectin levels are reduced inobesity (Ryo et al., 2004) and depression (Leo et al., 2006).

In the obese state, enlarged mature adipocytes become stressedand macrophages accumulate in the expanded adipose tissue,releasing a host of pro-inflammatory cytokines and establishinga low-grade inflammatory state. Such adipose tissue dysregulationalso impairs the differentiation of pre-adipocytes and favors the

ive stress in depression: Why so much stress? Neurosci. Biobehav.

storage of excess lipid in other tissues (ectopic depots) (Gustafsonet al., 2009), which is metabolically toxic.

Adipose tissue dysregulation induces oxidative stress and adi-pose tissue itself is considered an important source of ROS

681

682

683

684

ING ModelN

8 iobeh

(tEpasics

atlyn

hnsepas

pssi

3

sab1tes(coIadtbrma

wio2dplhmoMrdas

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

Furukawa et al., 2004; Houstis et al., 2006; Lee et al., 2009), poten-ially through the stimulation of NOX (Furukawa et al., 2004).vidence from mouse models suggests that oxidative stress in adi-ose tissue hampers adipogenesis through Wnt signaling (Funatond Miki, 2010), thereby promoting undesirable ectopic fat depo-ition and further aggravating health. It is even hypothesized thatmbalances in immune-inflammatory and O&NS pathways are theommon soil from which insulin resistance, dyslipidemia and obe-ity may develop (Bryan et al., 2013).

Metabolic syndrome, a clustering of conditions includingbdominal (central) obesity, high blood pressure, plasma glucose,riglycerides, and low HDL levels), is accompanied by increasedevels of MDA, advanced oxidation protein products, lipid hydrox-peroxides and nitric oxide metabolites (plasma concentrations ofitrite and nitrate) (Bortolasci et al., 2014; Sankhla et al., 2012).

Patients with metabolic syndrome have higher MDA levels, lipidydroxyperoxides and advanced oxidation protein products, butot NO metabolites, when compared with controls; however thetatus of serum total antioxidants in metabolic syndrome remainsquivocal (Vargas et al., submitted for publication). Interestingly,araoxonase Q192R functional genotypes or activity phenotypesre associated not only with depression, but also with the metabolicyndrome (Bortolasci et al., 2014).

These findings suggest that activation of immune-inflammatoryathways and oxidative stress balance may underpin both depres-ion and the metabolic syndrome. Therefore, the metabolicyndrome when comorbid with depression may increase themmune-inflammatory and oxidative burden.

.5. Sleep disorders

Numerous studies have indicated a bidirectional link betweenleep disturbances and depression (Tsuno et al., 2005). Prospectivend longitudinal studies have demonstrated that sleep distur-ances predict later episodes of major depression (Breslau et al.,996; Perlis et al., 1997), and symptomatic depression is recognizedo act as a proxy for the later development of insomnia (Breslaut al., 1996; LeBlanc et al., 2009). These findings have further beenustained after accounting for possible lifestyle factors such as ageChang et al., 1997), gender (Taylor et al., 2005), general medicalonditions (Taylor et al., 2005) and prior history of a depressiver sleep disorder (Buysse et al., 2008; Neckelmann et al., 2007).n addition, numerous studies have demonstrated that individu-ls with obstructive sleep apnea (OSA) often exhibit high rates ofepression (Harris et al., 2009; Schroder and O’Hara, 2005), withhe degree of depressive symptoms thought to reflect nocturnaliomarkers such as the hypoxemia nadir (McCall et al., 2006) andelative disease severity (Millman et al., 1989). Despite this, theechanisms that underlie the association between disturbed sleep

nd depression have not yet been fully elucidated.Sleep has a number of restorative functions. Sleep disruption,

hether acute or chronic, endogenously or exogenously mediated,s associated with increased risk for later development of seri-us medical illnesses to which O&NS contributes (Foster et al.,007; Ozkan et al., 2008). Individuals with primary sleep disor-ers and OSA typically exhibit activation of immune-inflammatoryathways, including increased IL-6, IL-8 and prostaglandin E2

evels and lowered plasma tryptophan (Song et al., 1998) andigher 8-isoprostane (Alonso-Fernandez et al., 2009) but lower NOetabolites (Ozkan et al., 2008). Patients with primary sleep dis-

rders also show significantly lower activity of GpX and higherDA concentrations than controls (Gulec et al., 2012), compa-

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

able to research investigating individuals diagnosed with majorepression (Bilici et al., 2001). Volna et al. (2011) found a strongssociation between OSA symptomology and markers of oxidativetress, and significant inverse correlations between mean blood

PRESSavioral Reviews xxx (2014) xxx–xxx

hemoglobin oxygen saturation and matrix metalloproteinase 9, C-reactive protein and fibrinogen. The oxygen desaturation indexwas additionally correlated with advanced glycation end products.Sleep fragmentation and intermittent hypoxia largely determinethe molecular signature of OSA, including oxidative stress andinflammation, although comorbid obesity may play a role due toits impact on shared molecular pathways (Arnardottir et al., 2009,2012). Mitigation of nocturnal symptoms via night-time therapyalso appears to neutralize the degree of O&NS damage in OSApatients (Alonso-Fernandez et al., 2009).

Preliminary findings derived from animal studies have high-lighted the potential of melatonin administration as an effectivetherapeutic agent in regard to its O&NS effects (Manda and Bhatia,2003). Although the possible therapeutic benefits of this hormonein the treatment of a range O&NS specific disorders has been previ-ously described (see review (Reiter et al., 2009)), and independentreports have profiteered the usefulness of melatonin in a rangeof sleep-disordered populations (Reiter et al., 2007), there is lit-tle information integrating this knowledge regarding the possibleefficacy of this hormone in targeting sleep-disorder specific O&NS.Moreover, the availability of a unified model describing the impactof O&NS damage in sleep disorders is currently lacking, and thuscurrently available treatment options are unable to effectively tar-get underlying mechanisms associated with O&NS. Future researchwill therefore benefit from both further exploring the relationshipbetween insomnia and O&NS, as well as systematically assessingthe efficacy of melatonin as a possible therapeutic option.

3.6. Cigarette smoking

The prevalence of cigarette smoking is significantly higherin individuals suffering from depressive and anxiety disorders(Moylan et al., 2012; Pasco et al., 2008b) than those without. Thismay be linked, at least in part, to the inter-relationship betweencigarette smoking and precipitated oxidative stress (Moylan et al.,2013b). Cigarette smoke contains many chemicals that increaselevels of O&NS and is a substantial source of exogenous free radi-cals (Stedman, 1968). Multiple animal models have demonstratedthat exposure to cigarette smoke can lead to increases in levelsof brain O&NS, as demonstrated by increased levels of reactiveoxygen species, including superoxide, thiobarbituric acid reactivesubstances (TBARS), carbonylated proteins and markers of lipidperoxidation (Anbarasi et al., 2005; Luchese et al., 2009; Stangherlinet al., 2009; Thome et al., 2011; Tuon et al., 2010). In additions tothese changes, exposure to cigarette smoke appears to be associ-ated with lowered levels of antioxidant enzymes, such as catalase,vitamins (A, C, E), GpX, glutathione reductase, PON1, glutathioneand SOD (Anbarasi et al., 2005; Luchese et al., 2009).

As with other factors that stimulate production of O&NS, acuteexposure to cigarette smoke appears to provoke a protectiveincrease in antioxidant enzymes. However, more chronic exposureoverwhelms these defences and leaves the system vulnerable tocellular damage. This is important, as factors which can assist theadaptive protective mechanisms, such as augmentation with vita-min E or active exercise (Thome et al., 2011; Tuon et al., 2010),appear to assist by limiting the increase in O&NS provoked byexposure to cigarette smoke. Investigations also reveal that themajor addictive component of cigarette smoke, nicotine, may beresponsible for the major proportion of increased O&NS attributedto cigarette smoke exposure. For example, studies utilizing exoge-nous administration of nicotine to isolate cell lines in culture leadto reduced production of antioxidant enzymes and increased mark-

ive stress in depression: Why so much stress? Neurosci. Biobehav.

ers of lipid peroxidation, lactate dehydrogenase activity and TBARS(Bhagwat et al., 1998; Yildiz et al., 1998). Given the interactionbetween cigarette smoking and O&NS balance, coupled with theassociative findings between O&NS and depressive and anxiety

809

810

811

812

ING ModelN

iobeh

dudigdi2

etivriedtrwestei

2aairNindTi(tetadcimoafoi2cesp

3

cowefr

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

isorders, it is possible that exposure to cigarette smoke, partic-larly in vulnerable individuals, plays a contributing role in theevelopment of depression through modulation of O&NS. Indeed,

t was recently demonstrated that interactions between PON1enotypes and smoking significantly increased the odds of bipolarepression, while decreased PON1 activity levels, but not smok-

ng, significantly predicted unipolar major depression (Vargas et al.,013).

However, it should be noted that nicotine has some anti-stressffects, with its activation of nicotinic receptors affording protec-ion in a number of neurodegenerative and psychiatric conditions,ncluding Parkinson’s disease (Anderson and Maes, 2013a), in partia improvements in arousal-associated cognition. Alpha7 nicotiniceceptor activation in murine regulatory T cells potentiates theirmmuno-suppressive capacity (Wang et al., 2010), exacerbating theffects of nicotine via immune system regulation in different CNSisorders (Quik et al., 2012). Given the role of gut permeability inhe modulation of depression, it is of note that nicotine amelio-ates ulcerative colitis, partly by increasing regulatory T cells, butorsens Crohn’s disease, where it increases Th17 cells (Galitovskiy

t al., 2011). Cigarette smokers also show a decreased incidence ofome inflammatory and allergic disorders, partly mediated by nico-ine effects on mast cells (Linneberg et al., 2001). As such, nicotineffects on O&NS in isolated cells require balance with its effects onmmune system regulation.

Some of the effects of cigarette smoke are mediated by,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which activates theryl hydrocarbon receptor, which, as well as inducing oxidantsnd antioxidants also increases IDO, contributing to TRYCATnduction and serotonin depletion. TCDD-inducible poly (ADP-ibose) polymerase (TiPARP/ARTD14) (Opitz et al., 2011) decreasesAD+, in turn lowering sirtuins and PGC-1� and thereby inhibit-

ng mitochondrial function (Diani-Moore et al., 2010). However,icotine may have some direct protective effects at mitochon-ria, suggesting that nicotine effects will interact with those ofCDD in the regulation of mitochondrial function. Other factorsn cigarette smoke including 2,3,6-trimethyl-1,4-naphthoquinoneTMN), a MAO-A/B inhibitor, also provide protection, partly viahe decreased metabolism of serotonin and dopamine (Castagnolit al., 2003). Taking these diverse effects together, it is possiblehat the level of stimulated oxidative stress induced by nicotinend cigarette smoke may alter the balance between protective andamaging effects to cellular structures. Nicotine stimulates acetyl-holine receptors in a more sustained fashion than normally occursn acetylcholine transmission. Depending upon the conditions, this

ay lead to production of a small, but still regulated amountf oxidative stress that can potentially even augment importantspects of cell signaling that may exert protective effects to cellularunction. However, persistent exposure to increased signaling mayverwhelm intrinsic protective mechanisms, leading to chronicallyncreased oxidative stress leading to cellular damage (Moylan et al.,013b; Newman et al., 2002). As such, depending on the individualonditions present, nicotine and cigarette smoke may have diverseffects on processes driving the biological underpinnings of depres-ion, including via the regulation of O&NS, immune-inflammatoryrocesses and their interaction.

.7. Dietary factors

Levels of ROS/RNS and an individual’s endogenous antioxidantapacity are influenced by dietary factors. Fruits, vegetables, oliveil, nuts and other plant foods are all potent sources of antioxidants,

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

hile a range of dietary derived amino acids, found in meats, veg-tables, whole grains, eggs and yoghurt, are important precursorsor the body’s endogenous antioxidant, GpX. In contrast, high satu-ated fat diets (Morrison et al., 2010) and hyperglycaemia (Yu et al.,

PRESSavioral Reviews xxx (2014) xxx–xxx 9

2006) increase ROS. The effects of dietary factors on the incidenceof depression are exemplified in the PREDIMED randomized trial(Sanchez-Villegas et al., 2013). In patients with comorbid type 2diabetes, 3-year exposure to a Mediterranean diet (rich in olive oil,fruit, vegetables, legumes, tomato, garlic, onion and fish, but low inmeat, cream, butter, fast foods and sugar) supplemented with nutswas significantly and inversely associated with a lower incidenceof depression.

The dietary minerals selenium, copper, manganese and zinc arerequired as cofactors by oxidative enzymes (Parletta et al., 2013).Selenium is also a co-factor in the synthesis of GSH and its relatedenzymes. Selenium appears to play a role in modulating moodand has been shown to be inversely associated with an increasedlikelihood of de novo major depressive disorder (Pasco et al.,2012). In West Texas, residential selenium levels in groundwaterhave been significantly and negatively associated with depressivesymptoms, explaining up 17% of their variance (Johnson et al.,2013).

Reduced dietary intakes of zinc-rich foods have been associatedwith increased odds for depression (Jacka et al., 2012). Decreasedserum zinc is commonly described in individuals with depres-sion (Maes et al., 1994, 1997b; McLoughlin and Hodge, 1990) andis negatively correlated with illness severity (Maes et al., 1994).A meta-analysis showed that zinc supplementation has clinicalefficacy in treatment-resistant depression as an adjunct to antide-pressants as well as a stand-alone intervention (Lai et al., 2012).Zinc’s antidepressant activity can be explained by its anti-oxidativeand anti-inflammatory effects, and also by its neuroprotectiveeffects related to the modulation of neurogenesis, n-3 metabolism,NMDA receptor and glutamate levels (Szewczyk et al., 2011). Forexample, zinc administration mitigated apoptosis and behavioralchanges in rats exposed to malathion, a toxic insecticide knownto induce depressive behaviors and oxidative damage to the brain(Brocardo et al., 2007).

Vitamins A, C and E, present in fruits, vegetables and nuts,(Bolling et al., 2011), are antioxidants that scavenge free rad-icals, protect against cell damage, and upregulate antioxidantcapacity (Parletta et al., 2013). As noted previously, vitaminsE and C are significantly lowered in depressed patients. Thereare few intervention studies examining vitamins in relation todepression, although one randomized, double-blinded, placebocontrolled trial did demonstrate improvements in subjective moodin healthy middle-aged men using a high-dose B vitamin com-plex with vitamin C and minerals (Kennedy et al., 2010). In animalmodels of depression, administration of vitamin E yields a signif-icant antidepressant-like effect, while long-term treatment alsoimproves the antioxidant defenses in the prefrontal cortex andhippocampus (Lobato et al., 2010).

Another vitamin that appears important in depression patho-genesis is vitamin B6. The active form of vitamin B6, pyridoxol-5-phosphate, can influence synthesis of key neurotransmitters dueto its role in tryptophan metabolism. Deficiency in pyridoxol-5-phosphate is associated with depression expression (Hvas et al.,2004) and higher intakes of vitamin B6 appear to be protectiveagainst depression expression (Skarupski et al., 2010).

Reduced folate intake (Tolmunen et al., 2004) and folate status(Nanri et al., 2012) is associated with an increased risk for depres-sion. A Cochrane review supports the use of folate as an adjunctivetreatment in major depression, although it is still unclear as towhether supplementation will benefit both those with low and nor-mal levels of folate (Taylor et al., 2004). At this time however thereis no evidence that folate is useful as a monotherapy (Luberto et al.,

ive stress in depression: Why so much stress? Neurosci. Biobehav.

2013). Recent reviews concluded that folic acid levels should bemeasured and corrected in treatment-resistant depression and insubjects with increased risk for deficiencies in folic acid (Lazarouand Kapsou, 2010).

939

940

941

942

IN PRESSG ModelN

1 iobehavioral Reviews xxx (2014) xxx–xxx

dantm

bpodntrnrcnbei(

tmwlldmcsaoiio2aBodtat

3

a2ucC(anaDDgi

hoe

Fig. 3. This figure shows the wide array of factors that may contribute to increasedoxidative and nitrosative stress (O&NS) in depression. Increased O&NS, in turn,activates the Toll-like receptor (TLR) radical cycle through formation of redox-derived damage associated molecular patters (DAMPs), including malondialdehyde(MDA) and oxidized low density lipoprotein (ox-LDL) and phospholipids (ox-PLP),which further activate immune-inflammatory and O&NS pathways by stimulatingTLRs. The TLR radical cycle is further activated or sensitized by increased levels oflipopolysaccharide (LPS) from gram-negative bacteria, psychosocial stressors and

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

ARTICLEBR 1953 1–17

0 S. Moylan et al. / Neuroscience and B

In elderly (>70 years of age) Japanese individuals, a tomato-richiet, which contains high levels of lycopene, was inversely associ-ted with depressive symptoms (Niu et al., 2013). In the same studyo significant association was detected between depressive symp-oms and the intake of other vegetables, suggesting that lycopenes

ay have the potential to prevent depressive symptoms.Polyphenols, found in particular abundance in herbs and spices,

erries, green tea, nuts, red wine and other plant foods, also haveotent antioxidant properties. In elderly subjects, the higher intakef green tea polyphenols is accompanied by a reduced incidence ofepressive symptoms, while in animal models green tea polyphe-ols show antidepressant-like effects, which are in part relatedo their antioxidant effects (Liu et al., 2013; Zhu et al., 2012). Aecent paper reviewed the antidepressant potential of polyphe-ols, such as curcumin, ferulic acid, hesperidin, rutin, quercetin andesveratrol (Pathak et al., 2013). Resveratrol, one of the phenolicompounds abundant in berries, grapes, red wine, and peanuts, isot only a strong antioxidant and anti-inflammatory compound,ut also is neuroprotectant (Joseph et al., 1999). Polyphenols maynhance brain plasticity by modulating signaling pathways tonduce the activation of key molecules and proteins, such as BDNFWilliams et al., 2008).

The brain is particularly vulnerable to oxidative damage dueo the high content of polyunsaturated fatty acids in erythrocyte

embranes. The activated immune-inflammatory and O&NS path-ays that commonly accompany depression result in increased

ipid peroxidation, which may account for the decreased levels ofong chain fatty acids regularly observed in those with depressiveisorders (Berk and Jacka, 2012). Such peroxidation decreases cellembrane fluidity and can damage membrane proteins. While long

hain n-3 fatty acids help to mitigate the impact of these processes,upplementation with nutritional antioxidants, such as vitamins And E, polyphenols, lycopenes and zinc might prevent lipid per-xidation. Pre-treatment with antioxidants can prevent cell lossn animal models of acute stress (Lee et al., 2006), while studiesn rodents demonstrate that the adverse effects of high fat dietsn BDNF expression are ameliorated by antioxidants (Wu et al.,004b). Similarly, adverse effects of induced traumatic brain injuryre ameliorated by n-3 PUFAs (Wu et al., 2004a). Moreover vitamins6, B12 and folate can reduce levels of homocysteine, increasesxidative stress in endothelial cells (Parletta et al., 2013). Theseata indicate that nutrient sufficiency is likely to play an impor-ant role in reducing the impact of O&NS on the brain via increasedntioxidant and anti-inflammatory effects and related neuropro-ection.

.8. Vitamin D status

Vitamin D is a secosteroid that has a primary role in bonend muscle health. Widespread vitamin D deficiency, particularly5-hydroxyvitamin D, has been identified among western pop-lations at higher latitudes and cultures with restrictive dressodes (Pasco et al., 2001). Many adverse health outcomes includingVD, osteoporosis and cancer are linked to vitamin D insufficiencyNowson et al., 2012). Additionally, Vitamin D has many less well-ppreciated roles in neural physiology and immune regulation thatotably overlap with the pathophysiology of depression. Vitamin Dlso impacts on sleep and circadian rhythms. Receptors for vitamin

are found in brain regions important in mood regulation. Vitamin influences cell proliferation in the developing brain and embryo-enesis as well as influencing neuronal growth. It also plays a rolen glucocorticoid physiology (Eyles et al., 2011).

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

Cross-sectional and prospective data suggest that serum 25-ydroxyvitamin D insufficiency is associated with an increased riskf developing depression (Kjaergaard et al., 2012). There is, how-ver, inconsistent clinical trial data of the antidepressant effects of

1041

autoimmune responses directed against oxidative (OSEs) and nitrosative (NSEs)specific epitopes.

supplementation with vitamin D, with both positive and null trialsreported (Lansdowne and Provost, 1998; Sanders et al., 2011).

Vitamin D also has roles in preventing DNA damage and regu-lating cell growth. Preclinical data suggest that vitamin D reducesoxidative stress mediated damage, particularly to DNA, evidencedby reduced 8-OHdg, reduced chromosomal aberrations, the pre-vention of telomere shortening and the inhibition of telomeraseactivity. It also regulates the cell cycle, preventing propagation ofdamaged DNA, and regulates cell death pathways and apoptosis(Nair-Shalliker et al., 2012). Vitamin D3 can reverse the inductionof diabetes by streptozotocin in animal models; a state which isassociated with reduced antioxidant defenses including superox-ide dismutase and GpX (George et al., 2012). In elderly subjects withglucose intolerance, a significant association has been observedbetween oxidative stress markers, particularly advanced glycationend products, advanced oxidation protein products, LDL suscep-tibility to oxidation and NO metabolic pathway products with25(OH)D levels. This effect was more marked in hyperglycemic sub-jects, a state known to be linked to oxidative stress (Gradinaru et al.,2012).

Early life vitamin D deficiency is associated with increasedblood pressure and vascular oxidative stress (Argacha et al., 2011).Calcitriol can reduce expression of inflammation and oxidativestress markers in patients receiving hemodialysis with secondaryhyperparathyroidism (Wu et al., 2011). Calcitriol increases brainglutathione levels, and is a catalyst for GSH production, a find-ing concordant with both the role of GSH as a principal redoxdefense, and in the modulation of depression (Garcion et al., 2002).Some of the efficacy of valproate in bipolar disorder is mediated byan increase in bcl-2 associated anthanogen-1 (BAG-1), which pre-vents the nuclear translocation of cortisol’s glucocorticoid receptor,thereby preventing many of the effects of this stress hormone,including in neuroinflammatory disorders such as multiple sclero-sis (Anderson and Rodriguez, 2011). BAG-1 also transports vitaminD3 to the nuclear vitamin D receptor, suggesting that stress and

ive stress in depression: Why so much stress? Neurosci. Biobehav.

depression associated O&NS may be intimately involved in the reg-ulation of vitamin D3 effects, partly via BAG-1 regulation. Togetherthese findings suggest that oxidative stress may play a modulatory

1042

1043

1044

ARTICLE IN PRESSG ModelNBR 1953 1–17

S. Moylan et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx 11

Fig. 4. This figure demonstrates a model depicting the interrelationship between (neuro)inflammation, oxidative and nitrosative stress (O&NS), mood disorders and theprocess of neuroprogression. Multiple medical, environmental and genetic factors predispose to (neuro)inflammation and increased O&NS. (Neuro)inflammation and O&NSproducts contribute to expression of mood disorder symptoms and to neuroprogressive processes. These products also lead to direct cell damage and dysfunction thatcontribute to disorder expression, neuroprogression, and to development of autoimmune responses that reinforce a (neuro)inflammatory and O&NS state. This reinforcingc n chac

r2

3

t(tiaiaerehdeaheiacLw

dcH

Q3

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

1085

1086

1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

1097

1098

ycle contributes to further neuroprogression, and subsequent staging of depressiohronicity. LPS – lipopolysaccharide.

ole in the interaction between vitamin D and mood (Autier et al.,013).

.9. Sedentary lifestyle and exercise

Despite the known health benefits of exercise it is estimatedhat more than 30% of the global population are physically inactiveOrganisation, 2002). With increasing sedentary behavior comeshe risk of many diseases, including depression. Physical inactiv-ty across the lifespan has been cross-sectionally and prospectivelyssociated with depression (Teychenne et al., 2008). In a studynvestigating self-reported levels of physical activity in childhoodnd adult depression, low physical activity levels throughout thearly years was associated with up to a 35% increased risk of self-eported depression in adulthood (Jacka et al., 2010). Furthermore,pidemiological studies of younger, middle aged and older adults,ave shown habitual physical activity to reduce the likelihood ofe novo depression (Brown et al., 2005; Pasco et al., 2011; Sagatunt al., 2007; Strawbridge et al., 2002). These observational findingsre somewhat supported by intervention studies where exerciseas been demonstrated to be effective in treating depression (Rimert al., 2012). For example, older patients with depression random-zed to a twice-weekly exercise group for 10 weeks demonstrated

modest reduction in depression scores compared to non-exerciseontrols (weekly health education talks) (Mather et al., 2002).arger effect sizes are reported when comparison is made to aaiting list or placebo treatment (Rimer et al., 2012).

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

Exercise is likely to influence the rate of depression and relatedisorders through numerous biochemical, physiological and psy-hological pathways (Eyre and Baune, 2012; Moylan et al., 2013a).owever, O&NS is likely to act as a prominent mechanism by which

racterized by increasing sensitivity to relapse, treatment resistance and symptom

this occurs. O&NS has been shown to be increased in those whoare physically inactive as well as in individuals following acuteexercise, whereas chronic or habitual exercise has been shownto be associated with a reduction in O&NS via an up regulationof antioxidant defenses (Gomes et al., 2012). For example, in asmall group of physical inactive medical students, levels of MDAwere shown to be increased when compared with age-matchedfootball players under regular training (Metin et al., 2003). Antioxi-dant enzyme levels are increased in response to exercise, indicatingthat physical activity has the ability to diminish lipid peroxidation(Djordjevic et al., 2012; Evelson et al., 2002; Fisher-Wellman andBloomer, 2009; Metin et al., 2003). Exercise, like antidepressants,is a significant inducer of neurogenesis, with melatonin furtherpotentiating the effects of exercise on rodent neurogenesis (Liu

et al., in press). Given the role of O&NS in both depression andexercise, these data highlight the possibility of O&NS modulatingexercise-induced mood improvements. However, further researchinto the optimal type, duration and intensity of the exercise isrequired.

4. Conclusions

Fig. 3 summarizes the pathways and factors that may contributeto O&NS in depression. A vicious cycle of activated immune-inflammatory pathways, lowered antioxidant levels, redox-derivedDAMPs and activation of the TLR4 complex with downstreamproduction of immune-inflammatory mediators and ROS/RNS

ive stress in depression: Why so much stress? Neurosci. Biobehav.

characterizes depression. Psychosocial stressors, metabolic syn-drome and obesity, sleep disorders, smoking, lowered vitaminD status, a diet low in antioxidants, such as selenium, folate,zinc, lycopenes and polyphenols, and a sedentary lifestyle may

1099

1100

1101

1102

ING ModelN

1 iobeh

crOa

ecseOnadpttTrTNatbHmbtoib2

rpadcttOpOFtkinadairarairpvatpiaip

Q4

Q5

Q6

1103

1104

1105

1106

1107

1108

1109

1110

1111

1112

1113

1114

1115

1116

1117

1118

1119

1120

1121

1122

1123

1124

1125

1126

1127

1128

1129

1130

1131

1132

1133

1134

1135

1136

1137

1138

1139

1140

1141

1142

1143

1144

1145

1146

1147

1148

1149

1150

1151

1152

1153

1154

1155

1156

1157

1158

1159

1160

1161

1162

1163

1164

1165

1166

1167

1168

1169

1170

1171

1172

1173

1174

1175

1176

1177

1178

1179

1180

1181

1182

1183

1184

1185

1186

1187

1188

1189

1190

1191

1192

1193

1194

1195

1196

1197

1198

1199

1200

1201

1202

1203

1204

1205

1206

1207

1208

1209

1210

1211

1212

1213

1214

1215

1216

1217

1218

1219

1220

1221

1222

1223

1224

1225

1226

1227

1228

1229

1230

1231

1232

1233

1234

ARTICLEBR 1953 1–17

2 S. Moylan et al. / Neuroscience and B

ontribute to activated O&NS pathways in depression. Neu-oinflammatory brain disorders and systemic immune- and&NS-related disorders and conditions characterized by O&NS aredditionally associated with the onset of depression.

Activated peripheral immune-inflammatory pathways and low-red peripheral antioxidant defenses may have consequences forentral immune-inflammatory and O&NS pathways. As previouslyummarized (Leonard and Maes, 2012), peripherally increased lev-ls of LPS and pro-inflammatory cytokines, driven by activated&NS pathways and lowered antioxidant defenses, may cause braineuroinflammation. The latter involves not only inflammation butlso O&NS processes fueled by a systemic loss of antioxidantefenses and increased gut permeability. Activated central O&NSathways may cause lipid peroxidation, and result in new forma-ion of redox-derived DAMPs that in turn may further activatehe TLR radical cycle in the brain. Increased levels of peripheralRYCATs, such as kynurenine, may pass the blood brain bar-ier to exert depressogenic and neurotoxic activities in the brain.he peripheral autoimmune processes directed against OSEs andSEs may have grave consequences for CNS functions. In patientsnd animals with autoimmune conditions, including lupus ery-hematosus, associations have been detected between serum andrain autoantibodies and neuropsychiatric symptoms (Zameer andoffman, 2001). These behavioral changes accompanying autoim-une diseases are centrally mediated through increased blood

rain barrier permeability and infiltration of white blood cellshrough the choroid plexus (Zameer and Hoffman, 2001). More-ver, some of the IgM autoantibodies directed against NSEs that arencreased in depressed patients (e.g. S–NO–cysteine) are known toe highly neurotoxic and to cause demyelination (Boullerne et al.,002).

Fig. 4 depicts the wide-angle lens picture emerging from theeviewed research literature, demonstrating that activation oferipheral and central immune-inflammatory and O&NS pathwaysre linked to expression of mood disorder symptoms, staging ofepression and to neuroprogressive processes. A series of medi-al, environmental and genetic factors predispose and contributeo development of increased levels of peripheral inflammationhat can precipitate development of neuroinflammation. Activated&NS pathways and lowered antioxidant defenses also drive thisrocess. Increased neuroinflammation and central activation of&NS pathways have two broad, non-mutually exclusive, effects.irst, they can influence development of depressive symptomshrough effects on cellular functioning and through influencingey factors underpinning depression effects (e.g. through impair-ng normal neurotransmitter synthesis and metabolism). Second,euroinflammatory and O&NS products cause direct cellular dam-ge (e.g. lipid peroxidation) and dysfunction. Cellular damage andysfunction contributes to expression of depressive symptoms (asbove) and to processes underlying neuroprogression, includingncreased neuronal apoptosis and decreased neurogenesis and neu-oplasticity. The cell damage in addition can further stimulateutoimmune pathways, leading to further increases in central neu-oinflammation and O&NS and reinforcing further depressogenicnd neuroprogressive effects. These effects contribute to the stag-ng of depression, increasing the likelihood of recurrence, treatmentesistance and a chronic depressive state. The delineation of theseathways highlights multiple opportunities for therapeutic inter-ention in preventing and/or reducing levels of neuroinflammationnd O&NS in depression. Future research should delineate whetherhe pathways involved in the immune-inflammatory and O&NSathophysiology of depression are useful as state, trait or stag-

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

ng biomarkers for depression. Lastly, understanding of the processnd its constituents offers both molecular targets for pharmacolog-cal intervention and environmental targets for public health andreventive approaches.

PRESSavioral Reviews xxx (2014) xxx–xxx

Funding

MB has received Grant/Research Support from the NIH, Cooper-

ative Research Centre, Simons Autism Foundation, Cancer Councilof Victoria, Stanley Medical Research Foundation, MBF, NHMRC,Beyond Blue, Rotary Health, Geelong Medical Research Foundation,Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novar-tis, Mayne Pharma, Servier and Woolworths, has been a speakerfor Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithK-line, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo,Servier, Solvay and Wyeth, and served as a consultant to AstraZeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, JanssenCilag, Lundbeck Merck and Servier. MB, AO, FNJ have receivedfunding from Meat and Livestock, Australia. JAP has receivedGrant/Research support from the NHMRC, Perpetual, Amgen, BUPAFoundation and Arthritis Australia and has received speaker feesfrom Amgen and Sanofi Aventis. OMD has received Grant supportfrom the Brain and Behavior Foundation, Simons Autism Founda-tion, Stanley Medical Research Institute, Lilly, NHMRC, an AlfredDeakin Postdoctoral Research Fellowship and an ASBD/Serviergrant. LW has received Grant/Research support from Eli Lilly, Pfizer,The University of Melbourne, Deakin University and the NHMRC.

Acknowledgements

MB is supported by a NHMRC Senior Principal Research Fellow-ship. AO is supported by a NHMRC ECR Fellowship (1052865).

References

Adam-Vizi, V., Starkov, A.A., 2010. Calcium and mitochondrial reactive oxygenspecies generation: how to read the facts. J. Alzheimer’s Dis. 20 (Suppl. 2),S413–S426.

Ahmad, A., Rasheed, N., Banu, N., Palit, G., 2010. Alterations in monoamine levelsand oxidative systems in frontal cortex, striatum, and hippocampus of the ratbrain during chronic unpredictable stress. Stress 13, 355–364.

Alberati-Giani, D., Cesura, A.M., 1998. Expression of the kynurenine enzymes inmacrophages and microglial cells: regulation by immune modulators. AminoAcids 14, 251–255.

Aleksandrovskii Iu, A., Poiurovskii, M.V., Neznamov, G.G., Seredeniia, S.B., Krasova,E.A., 1988. Lipid peroxidation in emotional stress and neurotic disorders. Zh.Nevropatol. Psikhiatr. Im. S.S. Korsakova 88, 95–101.

Alonso-Fernandez, A., Garcia-Rio, F., Arias, M.A., Hernanz, A., de la Pena, M., Pierola, J.,Barcelo, A., Lopez-Collazo, E., Agusti, A., 2009. Effects of CPAP on oxidative stressand nitrate efficiency in sleep apnoea: a randomised trial. Thorax 64, 581–586.

Anbarasi, K., Vani, G., Balakrishna, K., Devi, C.S., 2005. Effect of bacoside A onmembrane-bound ATPases in the brain of rats exposed to cigarette smoke. J.Biochem. Mol. Toxicol. 19, 59–65.

Anderson, G., Maes, M., 2013a. Neurodegeneration in Parkinson’s disease: inter-actions of oxidative stress, tryptophan catabolites and depression withmitochondria and sirtuins. Mol. Neurobiol..

Anderson, G., Maes, M., 2013b. Oxidative/nitrosative stress and immuno-inflammatory pathways in depression: treatment implications. Curr. Pharm.Des..

Anderson, G., Rodriguez, M., 2011. Multiple sclerosis, seizures, and antiepileptics:role of IL-18, IDO, and melatonin. Eur. J. Neurol. 18, 680–685.

Argacha, J.F., Egrise, D., Pochet, S., Fontaine, D., Lefort, A., Libert, F., Goldman, S., vande Borne, P., Berkenboom, G., Moreno-Reyes, R., 2011. Vitamin D deficiency-induced hypertension is associated with vascular oxidative stress and alteredheart gene expression. J. Cardiovasc. Pharmacol. 58, 65–71.

Arnardottir, E.S., Mackiewicz, M., Gislason, T., Teff, K.L., Pack, A.I., 2009. Molecularsignatures of obstructive sleep apnea in adults: a review and perspective. Sleep32, 447–470.

Arnardottir, E.S., Maislin, G., Schwab, R.J., Staley, B., Benediktsdottir, B., Olafsson, I.,Juliusson, S., Romer, M., Gislason, T., Pack, A.I., 2012. The interaction of obstruc-tive sleep apnea and obesity on the inflammatory markers C-reactive proteinand interleukin-6: the Icelandic Sleep Apnea Cohort. Sleep 35, 921–932.

Atlantis, E., Baker, M., 2008. Obesity effects on depression: systematic review ofepidemiological studies. Int. J. Obes. 32, 881–891.

Atlantis, E., Goldney, R.D., Wittert, G.A., 2009. Obesity and depression or anxiety.BMJ 339, b3868.

Autier, P., Boniol, M., Pizot, C., Mullie, P., 2013. Vitamin D status and ill health: a

ive stress in depression: Why so much stress? Neurosci. Biobehav.

systematic review. Lancet Diabetes Endocrinol..Baune, B.T., Dannlowski, U., Domschke, K., Janssen, D.G., Jordan, M.A., Ohrmann, P.,

Bauer, J., Biros, E., Arolt, V., Kugel, H., Baxter, A.G., Suslow, T., 2010. The inter-leukin 1 beta (IL1B) gene is associated with failure to achieve remission andimpaired emotion processing in major depression. Biol. Psychiatry 67, 543–549.

1235

1236

1237

1238

1239

ING ModelN

iobeh

B

B

B

B

B

B

B

B

B

B

B

B

B

Q7B

B

B

B

B

B

B

B

B

CC

C

C

C

C

1240

1241

1242

1243

1244

1245

1246

1247

1248

1249

1250

1251

1252

1253

1254

1255

1256

1257

1258

1259

1260

1261

1262

1263

1264

1265

1266

1267

1268

1269

1270

1271

1272

1273

1274

1275

1276

1277

1278

1279

1280

1281

1282

1283

1284

1285

1286

1287

1288

1289

1290

1291

1292

1293

1294

1295

1296

1297

1298

1299

1300

1301

1302

1303

1304

1305

1306

1307

1308

1309

1310

1311

1312

1313

1314

1315

1316

1317

1318

1319

1320

1321

1322

1323

1324

1325

1326

1327

1328

1329

1330

1331

1332

1333

1334

1335

1336

1337

1338

1339

1340

1341

1342

1343

1344

1345

1346

1347

1348

1349

1350

1351

1352

1353

1354

1355

1356

1357

1358

1359

1360

1361

1362

1363

1364

1365

1366

1367

1368

1369

1370

1371

1372

1373

1374

1375

1376

1377

1378

1379

1380

1381

1382

1383

1384

1385

1386

1387

1388

1389

1390

1391

1392

1393

1394

1395

1396

1397

1398

1399

1400

1401

1402

1403

1404

1405

1406

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

erg, R.D., Garlington, A.W., 1979. Translocation of certain indigenous bacteria fromthe gastrointestinal tract to the mesenteric lymph nodes and other organs in agnotobiotic mouse model. Infect. Immun. 23, 403–411.

erk, M., Jacka, F., 2012. Preventive strategies in depression: gathering evidence forrisk factors and potential interventions. Br. J. Psychiatry 201, 339–341.

erk, M., Johansson, S., Wray, N.R., Williams, L., Olsson, C., Haavik, J., Bjerkeset, O.,2011a. Glutamate cysteine ligase (GCL) and self reported depression: an associ-ation study from the HUNT. J. Affect. Disord. 131, 207–213.

erk, M., Kapczinski, F., Andreazza, A.C., Dean, O.M., Giorlando, F., Maes, M., Yucel, M.,Gama, C.S., Dodd, S., Dean, B., Magalhaes, P.V., Amminger, P., McGorry, P., Malhi,G.S., 2011b. Pathways underlying neuroprogression in bipolar disorder: focuson inflammation, oxidative stress and neurotrophic factors. Neurosci. Biobehav.Rev. 35, 804–817.

erk, M., Plein, H., Ferreira, D., 2001. Platelet glutamate receptor supersensitivity inmajor depressive disorder. Clin. Neuropharmacol. 24, 129–132.

erk, M., Wadee, A.A., Kuschke, R.H., O’Neill-Kerr, A., 1997. Acute phase proteins inmajor depression. J. Psychosom. Res. 43, 529–534.

erk, M., Williams, L.J., Jacka, F.N., O’Neil, A., Pasco, J.A., Moylan, S., Allen, N.B., Stuart,A.L., Hayley, A.C., Byrne, M.L., Maes, M., 2013. So depression is an inflammatorydisease, but where does the inflammation come from? BMC Med. 11, 200.

erry, A., Cirulli, F., 2013. The p66(Shc) gene paves the way for healthspan:evolutionary and mechanistic perspectives. Neurosci. Biobehav. Rev. 37,790–802.

hagwat, S.V., Vijayasarathy, C., Raza, H., Mullick, J., Avadhani, N.G., 1998.Preferential effects of nicotine and 4-(N-methyl-N-nitrosamine)-1-(3-pyridyl)-1-butanone on mitochondrial glutathione S-transferase A4-4 induction andincreased oxidative stress in the rat brain. Biochem. Pharmacol. 56, 831–839.

ilici, M., Efe, H., Koroglu, M.A., Uydu, H.A., Bekaroglu, M., Deger, O., 2001. Antioxida-tive enzyme activities and lipid peroxidation in major depression: alterationsby antidepressant treatments. J. Affect. Disord. 64, 43–51.

lau, S., Kohen, R., Bass, P., Rubinstein, A., 2000. Relation between colonicinflammation severity and total low-molecular-weight antioxidant profiles inexperimental colitis. Dig. Dis. Sci. 45, 1180–1187.

olling, B.W., Chen, C.Y., McKay, D.L., Blumberg, J.B., 2011. Tree nut phytochemi-cals: composition, antioxidant capacity, bioactivity, impact factors. A systematicreview of almonds, Brazils, cashews, hazelnuts, macadamias, pecans, pine nuts,pistachios and walnuts. Nutr. Res. Rev. 24, 244–275.

ortolasci, C.C., Vargas, H.O., Souza-Nogueira, A., Moreira, E.G., Nunes, S.O., Berk, M.,Dodd, S., Barbosa, D.S., Maes, M., 2014. Paraoxonase (PON)1 Q192R functionalgenotypes and PON1 Q192R genotype by smoking interactions are risk factorsfor the metabolic syndrome, but not overweight or obesity. Redox Rep. (in press).

oullerne, A.I., Rodriguez, J.J., Touil, T., Brochet, B., Schmidt, S., Abrous, N.D., LeMoal, M., Pua, J.R., Jensen, M.A., Mayo, W., Arnason, B.G., Petry, K.G., 2002.Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination inexperimental autoimmune encephalomyelitis: implications for multiple sclero-sis. J. Neurosci. 22, 123–132.

raidy, N., Grant, R., Adams, S., Brew, B.J., Guillemin, G.J., 2009. Mechanism forquinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox. Res.16, 77–86.

rasier, A.R., 2006. The NF-kappaB regulatory network. Cardiovasc. Toxicol. 6,111–130.

reslau, N., Roth, T., Rosenthal, L., Andreski, P., 1996. Sleep disturbance and psy-chiatric disorders: a longitudinal epidemiological study of young adults. Biol.Psychiatry 39, 411–418.

rocardo, P.S., Assini, F., Franco, J.L., Pandolfo, P., Muller, Y.M., Takahashi, R.N.,Dafre, A.L., Rodrigues, A.L., 2007. Zinc attenuates malathion-induced depressant-like behavior and confers neuroprotection in the rat brain. Toxicol. Sci. 97,140–148.

rown, W.J., Ford, J.H., Burton, N.W., Marshall, A.L., Dobson, A.J., 2005. Prospectivestudy of physical activity and depressive symptoms in middle-aged women. Am.J. Prev. Med. 29, 265–272.

ryan, S., Baregzay, B., Spicer, D., Singal, P.K., Khaper, N., 2013. Redox-inflammatorysynergy in the metabolic syndrome. Can. J. Physiol. Pharmacol. 91, 22–30.

ufalino, C., Hepgul, N., Aguglia, E., Pariante, C.M., 2013. The role of immune genesin the association between depression and inflammation: a review of recentclinical studies. Brain Behav. Immun. 31, 31–47.

uysse, D.J., Angst, J., Gamma, A., Ajdacic, V., Eich, D., Rossler, W., 2008. Prevalence,course, and comorbidity of insomnia and depression in young adults. Sleep 31,473–480.

arroll, B.J., 1980. Dexamethasone suppression test in depression. Lancet 2, 1249.arta, S., Castellani, P., Delfino, L., Tassi, S., Vene, R., Rubartelli, A., 2009. DAMPs and

inflammatory processes: the role of redox in the different outcomes. J. Leukoc.Biol. 86, 549–555.

asado, A., De Lucas, N., Lopez-Fernandez, E., Sanchez, A., Jimenez, J.A., 2006. Lipidperoxidation, occupational stress and aging in workers of a prehospital emer-gency service. Eur. J. Emerg. Med. 13, 165–171.

astagnoli, K., Petzer, J.B., Steyn, S.J., van der Schyf, C.J., Castagnoli Jr., N., 2003. Inhi-bition of human MAO-A and MAO-B by a compound isolated from flue-curedtobacco leaves and its neuroprotective properties in the MPTP mouse model ofneurodegeneration. Inflammopharmacology 11, 183–188.

eprnja, M., Derek, L., Unic, A., Blazev, M., Fistonic, M., Kozaric-Kovacic, D., Franic,

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

M., Romic, Z., 2011. Oxidative stress markers in patients with post-traumaticstress disorder. Coll. Antropol. 35, 1155–1160.

han, E.D., Riches, D.W., 2001. IFN-gamma + LPS induction of iNOS is modulated byERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am. J. Physiol.Cell Physiol. 280, C441–C450.

PRESSavioral Reviews xxx (2014) xxx–xxx 13

Chang, P.P., Ford, D.E., Mead, L.A., Cooper-Patrick, L., Klag, M.J., 1997. Insomnia inyoung men and subsequent depression. The Johns Hopkins Precursors Study.Am. J. Epidemiol. 146, 105–114.

Chavez, A.M., Menconi, M.J., Hodin, R.A., Fink, M.P., 1999. Cytokine-induced intesti-nal epithelial hyperpermeability: role of nitric oxide. Crit. Care Med. 27,2246–2251.

Che, Y., Wang, J.F., Shao, L., Young, T., 2010. Oxidative damage to RNA but not DNA inthe hippocampus of patients with major mental illness. J. Psychiatry Neurosci.35, 296–302.

Check, J., Byrd, C.L., Menio, J., Rippe, R.A., Hines, I.N., Wheeler, M.D., 2010. Src kinaseparticipates in LPS-induced activation of NADPH oxidase. Mol. Immunol. 47,756–762.

Christen, S., Peterhans, E., Stocker, R., 1990. Antioxidant activities of some trypto-phan metabolites: possible implication for inflammatory diseases. Proc. Natl.Acad. Sci. U.S.A. 87, 2506–2510.

Clark, E., Hoare, C., Tanianis-Hughes, J., Carlson, G.L., Warhurst, G., 2005. Interferongamma induces translocation of commensal Escherichia coli across gut epithelialcells via a lipid raft-mediated process. Gastroenterology 128, 1258–1267.

D’Aquila, P., Rose, G., Panno, M.L., Passarino, G., Bellizzi, D., 2012. SIRT3 gene expres-sion: a link between inherited mitochondrial DNA variants and oxidative stress.Gene 497, 323–329.

Dallas, M., Boycott, H.E., Atkinson, L., Miller, A., Boyle, J.P., Pearson, H.A., Peers, C.,2007. Hypoxia suppresses glutamate transport in astrocytes. J. Neurosci. 27,3946–3955.

de Wit, L., Luppino, F., van Straten, A., Penninx, B., Zitman, F., Cuijpers, P., 2010.Depression and obesity: a meta-analysis of community-based studies. Psychia-try Res. 178, 230–235.

Debnath, M., Berk, M., 2014. Th17 pathway-mediated immunopathogenesis ofschizophrenia: mechanisms and implications. Schizophr. Bull..

Diani-Moore, S., Ram, P., Li, X., Mondal, P., Youn, D.Y., Sauve, A.A., Rifkind, A.B., 2010.Identification of the aryl hydrocarbon receptor target gene TiPARP as a mediatorof suppression of hepatic gluconeogenesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin and of nicotinamide as a corrective agent for this effect. J. Biol. Chem.285, 38801–38810.

Dimopoulos, N., Piperi, C., Psarra, V., Lea, R.W., Kalofoutis, A., 2008. Increased plasmalevels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression.Psychiatry Res. 161, 59–66.

Djordjevic, D.Z., Cubrilo, D.G., Barudzic, N.S., Vuletic, M.S., Zivkovic, V.I., Nesic,M., Radovanovic, D., Djuric, D.M., Jakovljevic, V., 2012. Comparison of bloodpro/antioxidant levels before and after acute exercise in athletes and non-athletes. Gen. Physiol. Biophys. 31, 211–219.

Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., Lanctot,K.L., 2010. A meta-analysis of cytokines in major depression. Biol. Psychiatry67, 446–457.

Dutcher, J.P., Logan, T., Gordon, M., Sosman, J., Weiss, G., Margolin, K., Plasse, T., Mier,J., Lotze, M., Clark, J., Atkins, M., 2000. Phase II trial of interleukin 2, interferonalpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine workinggroup study. Clin. Cancer Res. 6, 3442–3450.

Dykens, J.A., Sullivan, S.G., Stern, A., 1987. Oxidative reactivity of the tryptophanmetabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate.Biochem. Pharmacol. 36, 211–217.

El Kossi, M.M., Zakhary, M.M., 2000. Oxidative stress in the context of acute cere-brovascular stroke. Stroke 31, 1889–1892.

Eren, I., Naziroglu, M., Demirdas, A., 2007a. Protective effects of lamotrigine, arip-iprazole and escitalopram on depression-induced oxidative stress in rat brain.Neurochem. Res. 32, 1188–1195.

Eren, I., Naziroglu, M., Demirdas, A., Celik, O., Uguz, A.C., Altunbasak, A., Ozmen, I., Uz,E., 2007b. Venlafaxine modulates depression-induced oxidative stress in brainand medulla of rat. Neurochem. Res. 32, 497–505.

Evelson, P., Gambino, G., Travacio, M., Jaita, G., Verona, J., Maroncelli, C., Wikinski,R., Llesuy, S., Brites, F., 2002. Higher antioxidant defences in plasma and lowdensity lipoproteins from rugby players. Eur. J. Clin. Invest. 32, 818–825.

Eyles, D., Burne, T., McGrath, J., 2011. Vitamin D in fetal brain development. Semin.Cell Dev. Biol. 22, 629–636.

Eyre, H., Baune, B.T., 2012. Neuroimmunological effects of physical exercise indepression. Brain Behav. Immun. 26, 251–266.

Fisher-Wellman, K., Bloomer, R.J., 2009. Acute exercise and oxidative stress: a 30year history. Dynam. Med. 8, 1.

Forlenza, M.J., Miller, G.E., 2006. Increased serum levels of 8-hydroxy-2’-deoxyguanosine in clinical depression. Psychosom. Med. 68, 1–7.

Foster, G.E., Poulin, M.J., Hanly, P.J., 2007. Intermittent hypoxia and vascular func-tion: implications for obstructive sleep apnoea. Exp. Physiol. 92, 51–65.

Fransson, M., Adner, M., Uddman, R., Cardell, L.O., 2007. Lipopolysaccharide-induceddown-regulation of uteroglobin in the human nose. Acta Otolaryngol. (Stockh.)127, 285–291.

Funakoshi, H., Kanai, M., Nakamura, T., 2011. Modulation of tryptophan metabolism,pomotion of neurogenesis and alteration of anxiety-related behavior in trypto-phan 2, 3-dioxygenase-deficient mice. Int. J. Tryptophan Res. 4, 7.

Funato, Y., Miki, H., 2010. Redox regulation of Wnt signalling via nucleoredoxin. FreeRadic. Res. 44, 379–388.

Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y.,

ive stress in depression: Why so much stress? Neurosci. Biobehav.

Nakayama, O., Makishima, M., Matsuda, M., Shimomura, I., 2004. Increasedoxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest.114, 1752–1761.

Galecki, P., Galecka, E., Maes, M., Chamielec, M., Orzechowska, A., Bobinska, K.,Lewinski, A., Szemraj, J., 2012. The expression of genes encoding for COX-2, MPO,

1407

1408

1409

1410

1411

ING ModelN

1 iobeh

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

G

H

H

H

H

H

H

H

I

J

J

1412

1413

1414

1415

1416

1417

1418

1419

1420

1421

1422

1423

1424

1425

1426

1427

1428

1429

1430

1431

1432

1433

1434

1435

1436

1437

1438

1439

1440

1441

1442

1443

1444

1445

1446

1447

1448

1449

1450

1451

1452

1453

1454

1455

1456

1457

1458

1459

1460

1461

1462

1463

1464

1465

1466

1467

1468

1469

1470

1471

1472

1473

1474

1475

1476

1477

1478

1479

1480

1481

1482

1483

1484

1485

1486

1487

1488

1489

1490

1491

1492

1493

1494

1495

1496

1497

1498

1499

1500

1501

1502

1503

1504

1505

1506

1507

1508

1509

1510

1511

1512

1513

1514

1515

1516

1517

1518

1519

1520

1521

1522

1523

1524

1525

1526

1527

1528

1529

1530

1531

1532

1533

1534

1535

1536

1537

1538

1539

1540

1541

1542

1543

1544

1545

1546

1547

1548

1549

1550

1551

1552

1553

1554

1555

1556

1557

1558

1559

1560

1561

1562

1563

1564

1565

1566

1567

1568

1569

1570

1571

1572

1573

1574

1575

1576

1577

1578

ARTICLEBR 1953 1–17

4 S. Moylan et al. / Neuroscience and B

iNOS, and sPLA2-IIA in patients with recurrent depressive disorder. J. Affect.Disord. 138, 360–366.

alecki, P., Maes, M., Florkowski, A., Lewinski, A., Galecka, E., Bienkiewicz, M.,Szemraj, J., 2011. Association between inducible and neuronal nitric oxide syn-thase polymorphisms and recurrent depressive disorder. J. Affect. Disord. 129,175–182.

alecki, P., Smigielski, J., Florkowski, A., Bobinska, K., Pietras, T., Szemraj, J., 2010.Analysis of two polymorphisms of the manganese superoxide dismutase gene(Ile-58Thr and Ala-9Val) in patients with recurrent depressive disorder. Psychi-atry Res. 179, 43–46.

alecki, P., Szemraj, J., Bienkiewicz, M., Florkowski, A., Galecka, E., 2009. Lipid perox-idation and antioxidant protection in patients during acute depressive episodesand in remission after fluoxetine treatment. Pharmacol. Rep. 61, 436–447.

alimov, E.R., Chernyak, B.V., Sidorenko, A.S., Tereshkova, A.V., Chumakov, P.M.,2014. Prooxidant properties of p66shc are mediated by mitochondria in humancells. PLoS ONE 9, e86521.

alitovskiy, V., Qian, J., Chernyavsky, A.I., Marchenko, S., Gindi, V., Edwards, R.A.,Grando, S.A., 2011. Cytokine-induced alterations of alpha7 nicotinic receptor incolonic CD4 T cells mediate dichotomous response to nicotine in murine modelsof Th1/Th17- versus Th2-mediated colitis. J. Immunol. 187, 2677–2687.

arate, I., Garcia-Bueno, B., Madrigal, J.L., Caso, J.R., Alou, L., Gomez-Lus, M.L., Mico,J.A., Leza, J.C., 2013. Stress-induced neuroinflammation: role of the Toll-likereceptor-4 pathway. Biol. Psychiatry 73, 32–43.

arcion, E., Wion-Barbot, N., Montero-Menei, C.N., Berger, F., Wion, D., 2002. Newclues about vitamin D functions in the nervous system. Trends Endocrinol.Metab. 13, 100–105.

ardner, A., Boles, R.G., 2011. Beyond the serotonin hypothesis: mitochondria,inflammation and neurodegeneration in major depression and affective spec-trum disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 730–743.

eorge, N., Kumar, T.P., Antony, S., Jayanarayanan, S., Paulose, C.S., 2012. Effectof vitamin D3 in reducing metabolic and oxidative stress in the liver ofstreptozotocin-induced diabetic rats. Br. J. Nutr. 108, 1410–1418.

hanizadeh, A., Berk, M., 2013. Molecular hydrogen: an overview of its neurobio-logical effects and therapeutic potential for bipolar disorder and schizophrenia.Med. Gas Res. 3, 11.

oda, K., Hamane, Y., Kishimoto, R., Ogishi, Y., 1999. Radical scavenging propertiesof tryptophan metabolites. Estimation of their radical reactivity. Adv. Exp. Med.Biol. 467, 397–402.

oldstein, L.E., Leopold, M.C., Huang, X., Atwood, C.S., Saunders, A.J., Hartshorn, M.,Lim, J.T., Faget, K.Y., Muffat, J.A., Scarpa, R.C., Chylack Jr., L.T., Bowden, E.F., Tanzi,R.E., Bush, A.I., 2000. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid gen-erate hydrogen peroxide and promote alpha-crystallin cross-linking by metalion reduction. Biochemistry 39, 7266–7275.

omes, E.C., Silva, A.N., de Oliveira, M.R., 2012. Oxidants, antioxidants, and the ben-eficial roles of exercise-induced production of reactive species. Oxid. Med. Cell.Longevity 2012, 756132.

radinaru, D., Borsa, C., Ionescu, C., Margina, D., Prada, G.I., Jansen, E., 2012. Vitamin Dstatus and oxidative stress markers in the elderly with impaired fasting glucoseand type 2 diabetes mellitus. Aging Clin. Exp. Res. 24, 595–602.

reen, D.R., Kroemer, G., 2004. The pathophysiology of mitochondrial cell death.Science 305, 626–629.

uidetti, P., Schwarcz, R., 1999. 3-Hydroxykynurenine potentiates quinolinate butnot NMDA toxicity in the rat striatum. Eur. J. Neurosci. 11, 3857–3863.

ulec, M., Ozkol, H., Selvi, Y., Tuluce, Y., Aydin, A., Besiroglu, L., Ozdemir, P.G., 2012.Oxidative stress in patients with primary insomnia. Prog. Neuropsychopharma-col. Biol. Psychiatry 37, 247–251.

ustafson, B., Gogg, S., Hedjazifar, S., Jenndahl, L., Hammarstedt, A., Smith, U., 2009.Inflammation and impaired adipogenesis in hypertrophic obesity in man. Am. J.Physiol. Endocrinol. Metab. 297, E999–E1003.

addad, J.J., 2000. Glutathione depletion is associated with augmenting aproinflammatory signal: evidence for an antioxidant/pro-oxidant mechanismregulating cytokines in the alveolar epithelium. Cytokines Cell. Mol. Ther. 6,177–187.

alaris, A., Meresh, E., Fareed, J., Hoppensteadt, D., Kimmons, S., Sinacore, J., 2012. 2.Tumor necrosis factor alpha as a biomarker in major depressive disorder. BrainBehav. Immun. 26 (Suppl. 1), S1.

ansel, B., Giral, P., Nobecourt, E., Chantepie, S., Bruckert, E., Chapman, M.J., Kon-tush, A., 2004. Metabolic syndrome is associated with elevated oxidative stressand dysfunctional dense high-density lipoprotein particles displaying impairedantioxidative activity. J. Clin. Endocrinol. Metab. 89, 4963–4971.

arris, M., Glozier, N., Ratnavadivel, R., Grunstein, R.R., 2009. Obstructive sleep apneaand depression. Sleep Med. Rev. 13, 437–444.

oustis, N., Rosen, E.D., Lander, E.S., 2006. Reactive oxygen species have a causal rolein multiple forms of insulin resistance. Nature 440, 944–948.

owren, M.B., Lamkin, D.M., Suls, J., 2009. Associations of depression with C-reactiveprotein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186.

vas, A.M., Juul, S., Bech, P., Nexo, E., 2004. Vitamin B6 level is associated withsymptoms of depression. Psychother. Psychosom. 73, 340–343.

rie, M., Asami, S., Nagata, S., Miyata, M., Kasai, H., 2001. Relationships betweenperceived workload, stress and oxidative DNA damage. Int. Arch. Occup. Environ.Health 74, 153–157.

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

acka, F.N., Maes, M., Pasco, J.A., Williams, L.J., Berk, M., 2012. Nutrient intakes andthe common mental disorders in women. J. Affect. Disord. 141, 79–85.

acka, F.N., Pasco, J.A., Williams, L.J., Leslie, E.R., Dodd, S., Nicholson, G.C., Kotowicz,M.A., Berk, M., 2010. Lower levels of physical activity in childhood associatedwith adult depression. J. Sci. Med. Sport 14, 222–226.

PRESSavioral Reviews xxx (2014) xxx–xxx

Jatuporn, S., Sangwatanaroj, S., Saengsiri, A.O., Rattanapruks, S., Srimahachota,S., Uthayachalerm, W., Kuanoon, W., Panpakdee, O., Tangkijvanich, P.,Tosukhowong, P., 2003. Short-term effects of an intensive lifestyle modifica-tion program on lipid peroxidation and antioxidant systems in patients withcoronary artery disease. Clin. Hemorheol. Microcirc. 29, 429–436.

Jelic, S., Padeletti, M., Kawut, S.M., Higgins, C., Canfield, S.M., Onat, D., Colombo,P.C., Basner, R.C., Factor, P., LeJemtel, T.H., 2008. Inflammation, oxidative stress,and repair capacity of the vascular endothelium in obstructive sleep apnea.Circulation 117, 2270–2278.

Jequier, E., 2002. Leptin signaling, adiposity, and energy balance. Ann. N.Y. Acad. Sci.967, 379–388.

Johnson, L.A., Phillips, J.A., Mauer, C., Edwards, M., Balldin, V.H., Hall, J.R., Barber, R.,Conger, T.L., Ho, E.J., O’Bryant, S.E., 2013. The impact of GPX1 on the associa-tion of groundwater selenium and depression: a Project FRONTIER study. BMCPsychiatry 13, 7.

Joseph, J.A., Shukitt-Hale, B., Denisova, N.A., Bielinski, D., Martin, A., McEwen, J.J.,Bickford, P.C., 1999. Reversals of age-related declines in neuronal signal trans-duction, cognitive, and motor behavioral deficits with blueberry, spinach, orstrawberry dietary supplementation. J. Neurosci. 19, 8114–8121.

Kaczmarek, A., Vandenabeele, P., Krysko, D.V., 2013. Necroptosis: the release ofdamage-associated molecular patterns and its physiological relevance. Immu-nity 38, 209–223.

Kennedy, D.O., Veasey, R., Watson, A., Dodd, F., Jones, E., Maggini, S., Haskell, C.F.,2010. Effects of high-dose B vitamin complex with vitamin C and minerals onsubjective mood and performance in healthy males. Psychopharmacology (Berl.)211, 55–68.

Kern, P.A., Saghizadeh, M., Ong, J.M., Bosch, R.J., Deem, R., Simsolo, R.B., 1995. Theexpression of tumor necrosis factor in human adipose tissue. Regulation byobesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95,2111–2119.

Khanzode, S.D., Dakhale, G.N., Khanzode, S.S., Saoji, A., Palasodkar, R., 2003. Oxida-tive damage and major depression: the potential antioxidant action of selectiveserotonin re-uptake inhibitors. Redox Rep. 8, 365–370.

Kjaergaard, M., Waterloo, K., Wang, C.E., Almas, B., Figenschau, Y., Hutchinson, M.S.,Svartberg, J., Jorde, R., 2012. Effect of vitamin D supplement on depression scoresin people with low levels of serum 25-hydroxyvitamin D: nested case-controlstudy and randomised clinical trial. Br. J. Psychiatry 201, 360–368.

Kubera, M., Obuchowicz, E., Goehler, L., Brzeszcz, J., Maes, M., 2011. In animal mod-els, psychosocial stress-induced (neuro)inflammation, apoptosis and reducedneurogenesis are associated to the onset of depression. Prog. Neuropsychophar-macol. Biol. Psychiatry 35, 744–759.

Lai, J., Moxey, A., Nowak, G., Vashum, K., Bailey, K., McEvoy, M., 2012. The effi-cacy of zinc supplementation in depression: systematic review of randomisedcontrolled trials. J. Affect. Disord. 136, e31–e39.

Lansdowne, A.T., Provost, S.C., 1998. Vitamin D3 enhances mood in healthy subjectsduring winter. Psychopharmacology (Berl.) 135, 319–323.

Lazarou, C., Kapsou, M., 2010. The role of folic acid in prevention and treatmentof depression: an overview of existing evidence and implications for practice.Complement. Ther. Clin. Pract. 16, 161–166.

LeBlanc, M., Merette, C., Savard, J., Ivers, H., Baillargeon, L., Morin, C.M., 2009. Inci-dence and risk factors of insomnia in a population-based sample. Sleep 32,1027–1037.

Lee, H., Lee, Y.J., Choi, H., Ko, E.H., Kim, J.W., 2009. Reactive oxygen species facilitateadipocyte differentiation by accelerating mitotic clonal expansion. J. Biol. Chem.284, 10601–10609.

Lee, P.H., Perlis, R.H., Jung, J.Y., Byrne, E.M., Rueckert, E., Siburian, R., Haddad, S.,Mayerfeld, C.E., Heath, A.C., Pergadia, M.L., Madden, P.A., Boomsma, D.I., Pen-ninx, B.W., Sklar, P., Martin, N.G., Wray, N.R., Purcell, S.M., Smoller, J.W., 2012.Multi-locus genome-wide association analysis supports the role of glutamater-gic synaptic transmission in the etiology of major depressive disorder. Transl.Psychiatry 2, e184.

Lee, S.Y., Lee, S.J., Han, C., Patkar, A.A., Masand, P.S., Pae, C.U., 2013. Oxida-tive/nitrosative stress and antidepressants: targets for novel antidepressants.Prog. Neuropsychopharmacol. Biol. Psychiatry 46, 224–235.

Lee, Y.J., Choi, B., Lee, E.H., Choi, K.S., Sohn, S., 2006. Immobilization stress inducescell death through production of reactive oxygen species in the mouse cerebralcortex. Neurosci. Lett. 392, 27–31.

Leipnitz, G., Schumacher, C., Dalcin, K.B., Scussiato, K., Solano, A., Funchal, C.,Dutra-Filho, C.S., Wyse, A.T., Wannmacher, C.M., Latini, A., Wajner, M., 2007.In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain. Neurochem. Int. 50, 83–94.

Lenaz, G., 2001. The mitochondrial production of reactive oxygen species: mecha-nisms and implications in human pathology. IUBMB Life 52, 159–164.

Leo, R., Di Lorenzo, G., Tesauro, M., Cola, C., Fortuna, E., Zanasi, M., Troisi, A., Siracu-sano, A., Lauro, R., Romeo, F., 2006. Decreased plasma adiponectin concentrationin major depression. Neurosci. Lett. 407, 211–213.

Leonard, B., Maes, M., 2012. Mechanistic explanations how cell-mediated immuneactivation, inflammation and oxidative and nitrosative stress pathways and theirsequels and concomitants play a role in the pathophysiology of unipolar depres-sion. Neurosci. Biobehav. Rev. 36, 764–785.

Linneberg, A., Nielsen, N.H., Madsen, F., Frolund, L., Dirksen, A., Jorgensen, T., 2001.

ive stress in depression: Why so much stress? Neurosci. Biobehav.

Factors related to allergic sensitization to aeroallergens in a cross-sectionalstudy in adults: The Copenhagen Allergy Study. Clin. Exp. Allergy 31, 1409–1417.

Liu, J., Somera-Molina, K.C., Hudson, R.L., Dubocovich, M.L., 2013. Melatonin potenti-ates running wheel-induced neurogenesis in the dentate gyrus of adult C3H/HeNmice hippocampus. J. Pineal Res. 54, 222–231.

1579

1580

1581

1582

1583

ING ModelN

iobeh

L

L

L

L

L

L

L

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

M

Q8

1584

1585

1586

1587

1588

1589

1590

1591

1592

1593

1594

1595

1596

1597

1598

1599

1600

1601

1602

1603

1604

1605

1606

1607

1608

1609

1610

1611

1612

1613

1614

1615

1616

1617

1618

1619

1620

1621

1622

1623

1624

1625

1626

1627

1628

1629

1630

1631

1632

1633

1634

1635

1636

1637

1638

1639

1640

1641

1642

1643

1644

1645

1646

1647

1648

1649

1650

1651

1652

1653

1654

1655

1656

1657

1658

1659

1660

1661

1662

1663

1664

1665

1666

1667

1668

1669

1670

1671

1672

1673

1674

1675

1676

1677

1678

1679

1680

1681

1682

1683

1684

1685

1686

1687

1688

1689

1690

1691

1692

1693

1694

1695

1696

1697

1698

1699

1700

1701

1702

1703

1704

1705

1706

1707

1708

1709

1710

1711

1712

1713

1714

1715

1716

1717

1718

1719

1720

1721

1722

1723

1724

1725

1726

1727

1728

1729

1730

1731

1732

1733

1734

1735

1736

1737

1738

1739

1740

1741

1742

1743

1744

1745

1746

1747

1748

1749

1750

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

obato, K.R., Cardoso, C.C., Binfare, R.W., Budni, J., Wagner, C.L., Brocardo, P.S., deSouza, L.F., Brocardo, C., Flesch, S., Freitas, A.E., Dafre, A.L., Rodrigues, A.L., 2010.Alpha-tocopherol administration produces an antidepressant-like effect in pre-dictive animal models of depression. Behav. Brain Res. 209, 249–259.

ogue, M.W., Baldwin, C., Guffanti, G., Melista, E., Wolf, E.J., Reardon, A.F., Uddin, M.,Wildman, D., Galea, S., Koenen, K.C., Miller, M.W., 2013. A genome-wide asso-ciation study of post-traumatic stress disorder identifies the retinoid-relatedorphan receptor alpha (RORA) gene as a significant risk locus. Mol. Psychiatry18, 937–942.

otze, M.T., Zeh, H.J., Rubartelli, A., Sparvero, L.J., Amoscato, A.A., Washburn,N.R., Devera, M.E., Liang, X., Tor, M., Billiar, T., 2007. The grateful dead:damage-associated molecular pattern molecules and reduction/oxidation reg-ulate immunity. Immunol. Rev. 220, 60–81.

uberto, C.M., White, C., Sears, R.W., Cotton, S., 2013. Integrative medicine for treat-ing depression: an update on the latest evidence. Curr. Psychiatry Rep. 15, 391.

ucas, K., Maes, M., 2013. Role of the Toll like receptor (TLR) radical cycle in chronicinflammation: possible treatments targeting the TLR4 pathway. Mol. Neurobiol.48, 190–204.

uchese, C., Pinton, S., Nogueira, C.W., 2009. Brain and lungs of rats are differentlyaffected by cigarette smoke exposure: antioxidant effect of an organoseleniumcompound. Pharmacol. Res. 59, 194–201.

uppino, F.S., de Wit, L.M., Bouvy, P.F., Stijnen, T., Cuijpers, P., Penninx, B.W., Zitman,F.G., 2010. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch. Gen. Psychiatry 67, 220–229.

aes, M., Christophe, A., Delanghe, J., Altamura, C., Neels, H., Meltzer, H.Y., 1999.Lowered omega3 polyunsaturated fatty acids in serum phospholipids andcholesteryl esters of depressed patients. Psychiatry Res. 85, 275–291.

aes, M., D’Haese, P.C., Scharpe, S., D’Hondt, P., Cosyns, P., De Broe, M.E., 1994.Hypozincemia in depression. J. Affect. Disord. 31, 135–140.

aes, M., De Vos, N., Pioli, R., Demedts, P., Wauters, A., Neels, H., Christophe, A., 2000.Lower serum vitamin E concentrations in major depression. Another marker oflowered antioxidant defenses in that illness. J. Affect. Disord. 58, 241–246.

aes, M., Delange, J., Ranjan, R., Meltzer, H.Y., Desnyder, R., Cooremans, W., Scharpe,S., 1997a. Acute phase proteins in schizophrenia, mania and major depression:modulation by psychotropic drugs. Psychiatry Res. 66, 1–11.

aes, M., Fisar, Z., Medina, M., Scapagnini, G., Nowak, G., Berk, M., 2012a. Newdrug targets in depression: inflammatory, cell-mediated immune, oxidative andnitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways.And new drug candidates–Nrf2 activators and GSK-3 inhibitors. Inflammophar-macology 20, 127–150.

aes, M., Galecki, P., Chang, Y.S., Berk, M., 2011a. A review on the oxidative andnitrosative stress (O&NS) pathways in major depression and their possiblecontribution to the (neuro)degenerative processes in that illness. Prog. Neu-ropsychopharmacol. Biol. Psychiatry 35, 676–692.

aes, M., Kubera, M., Leunis, J.C., 2008a. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gramnegative enterobacteria (leaky gut) plays a role in the inflammatory pathophys-iology of depression. Neuroendocrinol. Lett. 29, 117–124.

aes, M., Kubera, M., Leunis, J.C., Berk, M., 2012b. Increased IgA and IgM responsesagainst gut commensals in chronic depression: further evidence for increasedbacterial translocation or leaky gut. J. Affect. Disord. 141, 55–62.

aes, M., Kubera, M., Leunis, J.C., Berk, M., Geffard, M., Bosmans, E., 2013a. In depres-sion, bacterial translocation may drive inflammatory responses, oxidative andnitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr. Scand. 127, 344–354.

aes, M., Kubera, M., Mihaylova, I., Geffard, M., Galecki, P., Leunis, J.C., Berk, M.,2013b. Increased autoimmune responses against auto-epitopes modified byoxidative and nitrosative damage in depression: implications for the pathwaysto chronic depression and neuroprogression. J. Affect. Disord. 149, 23–29.

aes, M., Kubera, M., Obuchowiczwa, E., Goehler, L., Brzeszcz, J., 2011b. Depres-sion’s multiple comorbidities explained by (neuro)inflammatory and oxidative& nitrosative stress pathways. Neuroendocrinol. Lett. 32, 7–24.

aes, M., Leonard, B.E., Myint, A.M., Kubera, M., Verkerk, R., 2011c. The new‘5-HT’ hypothesis of depression: cell-mediated immune activation inducesindoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and anincreased synthesis of detrimental tryptophan catabolites (TRYCATs), both ofwhich contribute to the onset of depression. Prog. Neuropsychopharmacol. Biol.Psychiatry 35, 702–721.

aes, M., Meltzer, H.Y., Scharpe, S., Bosmans, E., Suy, E., De Meester, I., Cal-abrese, J., Cosyns, P., 1993. Relationships between lower plasma l-tryptophanlevels and immune-inflammatory variables in depression. Psychiatry Res. 49,151–165.

aes, M., Mihaylova, I., Kubera, M., Leunis, J.C., 2008b. An IgM-mediated immuneresponse directed against nitro-bovine serum albumin (nitro-BSA) in chronicfatigue syndrome (CFS) and major depression: evidence that nitrosative stressis another factor underpinning the comorbidity between major depression andCFS. Neuroendocrinol. Lett. 29, 313–319.

aes, M., Mihaylova, I., Kubera, M., Leunis, J.C., Geffard, M., 2011d. IgM-mediatedautoimmune responses directed against multiple neoepitopes in depression:new pathways that underpin the inflammatory and neuroprogressive patho-physiology. J. Affect. Disord. 135, 414–418.

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

aes, M., Mihaylova, I., Leunis, J.C., 2007. Increased serum IgM antibodies directedagainst phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and majordepression: evidence that an IgM-mediated immune response against Pi is onefactor underpinning the comorbidity between both CFS and depression. Neu-roendocrinol. Lett. 28, 861–867.

PRESSavioral Reviews xxx (2014) xxx–xxx 15

Maes, M., Ruckoanich, P., Chang, Y.S., Mahanonda, N., Berk, M., 2011e. Multipleaberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS)pathways explain the co-association of depression and cardiovascular disorder(CVD), and the increased risk for CVD and due mortality in depressed patients.Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 769–783.

Maes, M., Vandoolaeghe, E., Neels, H., Demedts, P., Wauters, A., Meltzer, H.Y., Alta-mura, C., Desnyder, R., 1997b. Lower serum zinc in major depression is a sensitivemarker of treatment resistance and of the immune/inflammatory response inthat illness. Biol. Psychiatry 42, 349–358.

Manda, K., Bhatia, A.L., 2003. Prophylactic action of melatonin againstcyclophosphamide-induced oxidative stress in mice. Cell Biol. Toxicol.19, 367–372.

Maritim, A.C., Sanders, R.A., Watkins 3rd., J.B., 2003. Diabetes, oxidative stress, andantioxidants: a review. J. Biochem. Mol. Toxicol. 17, 24–38.

Martinsson, L., Wei, Y., Xu, D., Melas, P.A., Mathe, A.A., Schalling, M., Lavebratt, C.,Backlund, L., 2013. Long-term lithium treatment in bipolar disorder is associatedwith longer leukocyte telomeres. Transl. Psychiatry 3, e261.

Mather, A.S., Rodriguez, C., Guthrie, M.F., McHarg, A.M., Reid, I.C., McMurdo, M.E.,2002. Effects of exercise on depressive symptoms in older adults with poorlyresponsive depressive disorder: randomised controlled trial. Br. J. Psychiatry180, 411–415.

Mayer, E.A., 2011. Gut feelings: the emerging biology of gut-brain communication.Nat. Rev. Neurosci. 12, 453–466.

McCall, W.V., Harding, D., O’Donovan, C., 2006. Correlates of depressive symptomsin patients with obstructive sleep apnea. J. Clin. Sleep Med. 2, 424–426.

McLoughlin, I.J., Hodge, J.S., 1990. Zinc in depressive disorder. Acta Psychiatr. Scand.82, 451–453.

Metin, G., Atukeren, P., Alturfan, A.A., Gulyasar, T., Kaya, M., Gumustas, M.K., 2003.Lipid peroxidation, erythrocyte superoxide-dismutase activity and trace metalsin young male footballers. Yonsei Med. J. 44, 979–986.

Miller, M.W., Wolf, E.J., Logue, M.W., Baldwin, C.T., 2013. The retinoid-related orphanreceptor alpha (RORA) gene and fear-related psychopathology. J. Affect. Disord.151, 702–708.

Millman, R.P., Fogel, B.S., McNamara, M.E., Carlisle, C.C., 1989. Depression as a man-ifestation of obstructive sleep apnea: reversal with nasal continuous positiveairway pressure. J. Clin. Psychiatry 50, 348–351.

Moretti, M., Colla, A., de Oliveira Balen, G., dos Santos, D.B., Budni, J., de Freitas, A.E.,Farina, M., Severo Rodrigues, A.L., 2012. Ascorbic acid treatment, similarly to flu-oxetine, reverses depressive-like behavior and brain oxidative damage inducedby chronic unpredictable stress. J. Psychiatr. Res. 46, 331–340.

Morimoto, K., Morikawa, M., Kimura, H., Ishii, N., Takamata, A., Hara, Y., Uji, M.,Yoshida, K., 2008. Mental stress induces sustained elevation of blood pressureand lipid peroxidation in postmenopausal women. Life Sci. 82, 99–107.

Morris, G., Maes, M., 2013. Mitochondrial dysfunctions in myalgic encephalomyeli-tis/chronic fatigue syndrome explained by activated immuno-inflammatory,oxidative and nitrosative stress pathways. Metab. Brain Dis., 1–18.

Morrison, C.D., Pistell, P.J., Ingram, D.K., Johnson, W.D., Liu, Y., Fernandez-Kim, S.O.,White, C.L., Purpera, M.N., Uranga, R.M., Bruce-Keller, A.J., Keller, J.N., 2010.High fat diet increases hippocampal oxidative stress and cognitive impairmentin aged mice: implications for decreased Nrf2 signaling. J. Neurochem. 114,1581–1589.

Moylan, S., Eyre, H.A., Maes, M., Baune, B.T., Jacka, F.N., Berk, M., 2013a. Exercising theworry away: how inflammation, oxidative and nitrogen stress mediates the ben-eficial effect of physical activity on anxiety disorder symptoms and behaviours.Neurosci. Biobehav. Rev. 37, 573–584.

Moylan, S., Jacka, F.N., Pasco, J.A., Berk, M., 2012. Cigarette smoking, nicotinedependence and anxiety disorders: a systematic review of population-based,epidemiological studies. BMC Med. 10, 123.

Moylan, S., Jacka, F.N., Pasco, J.A., Berk, M., 2013b. How cigarette smoking mayincrease the risk of anxiety symptoms and anxiety disorders: a critical reviewof biological pathways. Brain Behav. 3, 302–326.

Moylan, S., Maes, M., Wray, N.R., Berk, M., 2013c. The neuroprogressive nature ofmajor depressive disorder: pathways to disease evolution and resistance, andtherapeutic implications. Mol. Psychiatry 18, 595–606.

Murakami, K., Haneda, M., Yoshino, M., 2006. Prooxidant action of xanthurenic acidand quinoline compounds: role of transition metals in the generation of reac-tive oxygen species and enhanced formation of 8-hydroxy-2’-deoxyguanosinein DNA. Biometals 19, 429–435.

Murphy, T.H., Miyamoto, M., Sastre, A., Schnaar, R.L., Coyle, J.T., 1989. Glutamatetoxicity in a neuronal cell line involves inhibition of cystine transport leading tooxidative stress. Neuron 2, 1547–1558.

Nair-Shalliker, V., Armstrong, B.K., Fenech, M., 2012. Does vitamin D protect againstDNA damage? Mutat. Res. 733, 50–57.

Nanri, A., Hayabuchi, H., Ohta, M., Sato, M., Mishima, N., Mizoue, T., 2012. Serumfolate and depressive symptoms among Japanese men and women: a cross-sectional and prospective study. Psychiatry Res. 200, 349–353.

Neckelmann, D., Mykletun, A., Dahl, A.A., 2007. Chronic insomnia as a risk factor fordeveloping anxiety and depression. Sleep 30, 873–880.

Newman, M.B., Arendash, G.W., Shytle, R.D., Bickford, P.C., Tighe, T., Sanberg, P.R.,2002. Nicotine’s oxidative and antioxidant properties in CNS. Life Sci. 71,2807–2820.

ive stress in depression: Why so much stress? Neurosci. Biobehav.

Niu, K., Guo, H., Kakizaki, M., Cui, Y., Ohmori-Matsuda, K., Guan, L., Hozawa, A.,Kuriyama, S., Tsuboya, T., Ohrui, T., Furukawa, K., Arai, H., Tsuji, I., Nagatomi, R.,2013. A tomato-rich diet is related to depressive symptoms among an elderlypopulation aged 70 years and over: a population-based, cross-sectional analysis.J. Affect. Disord. 144, 165–170.

1751

1752

1753

1754

1755

ING ModelN

1 iobeh

N

O

O

O

O

O

P

P

P

P

P

P

P

P

P

P

P

P

P

P

P

Q

Q

R

R

R

R

R

R

1756

1757

1758

1759

1760

1761

1762

1763

1764

1765

1766

1767

1768

1769

1770

1771

1772

1773

1774

1775

1776

1777

1778

1779

1780

1781

1782

1783

1784

1785

1786

1787

1788

1789

1790

1791

1792

1793

1794

1795

1796

1797

1798

1799

1800

1801

1802

1803

1804

1805

1806

1807

1808

1809

1810

1811

1812

1813

1814

1815

1816

1817

1818

1819

1820

1821

1822

1823

1824

1825

1826

1827

1828

1829

1830

1831

1832

1833

1834

1835

1836

1837

1838

1839

1840

1841

1842

1843

1844

1845

1846

1847

1848

1849

1850

1851

1852

1853

1854

1855

1856

1857

1858

1859

1860

1861

1862

1863

1864

1865

1866

1867

1868

1869

1870

1871

1872

1873

1874

1875

1876

1877

1878

1879

1880

1881

1882

1883

1884

1885

1886

1887

1888

1889

1890

1891

1892

1893

1894

1895

1896

1897

1898

1899

1900

1901

1902

1903

1904

1905

1906

1907

1908

1909

1910

1911

1912

1913

1914

1915

1916

1917

1918

1919

1920

1921

1922

ARTICLEBR 1953 1–17

6 S. Moylan et al. / Neuroscience and B

owson, C.A., McGrath, J.J., Ebeling, P.R., Haikerwal, A., Daly, R.M., Sanders, K.M.,Seibel, M.J., Mason, R.S., Working Group of: A., New Zealand, B., Mineral Society,E.S.o.A., Osteoporosis, A., 2012. Vitamin D and health in adults in Australia andNew Zealand: a position statement. Med. J. Aust. 196, 686–687.

kuda, S., Nishiyama, N., Saito, H., Katsuki, H., 1998. 3-Hydroxykynurenine, anendogenous oxidative stress generator, causes neuronal cell death with apop-totic features and region selectivity. J. Neurochem. 70, 299–307.

pitz, C.A., Litzenburger, U.M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher,T., Jestaedt, L., Schrenk, D., Weller, M., Jugold, M., Guillemin, G.J., Miller, C.L., Lutz,C., Radlwimmer, B., Lehmann, I., von Deimling, A., Wick, W., Platten, M., 2011. Anendogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.Nature 478, 197–203.

rganisation, W.H., 2002. World Health Report. World Health Organistion Press,Switzerland.

wen, A.J., Batterham, M.J., Probst, Y.C., Grenyer, B.F., Tapsell, L.C., 2005. Low plasmavitamin E levels in major depression: diet or disease? Eur. J. Clin. Nutr. 59,304–306.

zkan, Y., Firat, H., Simsek, B., Torun, M., Yardim-Akaydin, S., 2008. Circulating nitricoxide (NO), asymmetric dimethylarginine (ADMA), homocysteine, and oxidativestatus in obstructive sleep apnea-hypopnea syndrome (OSAHS). Sleep Breath.12, 149–154.

an, A., Sun, Q., Czernichow, S., Kivimaki, M., Okereke, O.I., Lucas, M., Manson, J.E.,Ascherio, A., Hu, F.B., 2012. Bidirectional association between depression andobesity in middle-aged and older women. Int. J. Obes. 36, 595–602.

arletta, N., Milte, C.M., Meyer, B.J., 2013. Nutritional modulation of cognitive func-tion and mental health. J. Nutr. Biochem. 24, 725–743.

asco, J.A., Henry, M.J., Nicholson, G.C., Sanders, K.M., Kotowicz, M.A., 2001. VitaminD status of women in the Geelong Osteoporosis Study: association with diet andcasual exposure to sunlight. Med. J. Aust. 175, 401–405.

asco, J.A., Jacka, F.N., Williams, L.J., Evans-Cleverdon, M., Brennan, S.L., Kotowicz,M.A., Nicholson, G.C., Ball, M.J., Berk, M., 2012. Dietary selenium and majordepression: a nested case–control study. Complement. Ther. Med. 20, 119–123.

asco, J.A., Jacka, F.N., Williams, L.J., Henry, M.J., Nicholson, G.C., Kotowicz, M.A.,Berk, M., 2008a. Leptin in depressed women: cross-sectional and longitudinaldata from an epidemiologic study. J. Affect. Disord. 107, 221–225.

asco, J.A., Nicholson, G.C., Williams, L.J., Jacka, F.N., Henry, M.J., Kotowicz, M.A.,Schneider, H.G., Leonard, B.E., Berk, M., 2010. Association of high-sensitivity C-reactive protein with de novo major depression. Br. J. Psychiatry 197, 372–377.

asco, J.A., Williams, L.J., Jacka, F.N., Brennan, S.L., Berk, M., 2013. Obesity andthe relationship with positive and negative affect. Aust. N.Z. J. Psychiatry 47,477–482.

asco, J.A., Williams, L.J., Jacka, F.N., Henry, M.J., Coulson, C.E., Brennan, S.L., Leslie,E., Nicholson, G.C., Kotowicz, M.A., Berk, M., 2011. Habitual physical activity andthe risk for depressive and anxiety disorders among older men and women. Int.Psychogeriatr. 23, 292–298.

asco, J.A., Williams, L.J., Jacka, F.N., Ng, F., Henry, M.J., Nicholson, G.C., Kotowicz,M.A., Berk, M., 2008b. Tobacco smoking as a risk factor for major depressivedisorder: population-based study. Br. J. Psychiatry 193, 322–326.

athak, L., Agrawal, Y., Dhir, A., 2013. Natural polyphenols in the management ofmajor depression. Expert Opin. Invest. Drugs 22, 863–880.

eet, M., Murphy, B., Shay, J., Horrobin, D., 1998. Depletion of omega-3 fatty acidlevels in red blood cell membranes of depressive patients. Biol. Psychiatry 43,315–319.

eng, T., Lu, X., Feng, Q., 2005. NADH oxidase signaling induces cyclooxygenase-2expression during lipopolysaccharide stimulation in cardiomyocytes. FASEB J.19, 293–295.

erlis, M.L., Giles, D.E., Buysse, D.J., Tu, X., Kupfer, D.J., 1997. Self-reported sleepdisturbance as a prodromal symptom in recurrent depression. J. Affect. Disord.42, 209–212.

ertsov, S.S., Balashova, T.S., Kubatieva, A.A., Sosnovskii, A.S., Pirogova, G.V.,Abramov, V.M., 1995. Lipid peroxidation and antioxidant enzymes in rat brain inacute emotional stress: effect of interleukin-1beta. Biulleten’ eksperimental’noibiologii i meditsiny 120, 244–247.

hillips, A.C., Robertson, T., Carroll, D., Der, G., Shiels, P.G., McGlynn, L., Benzeval, M.,2013. Do symptoms of depression predict telomere length? Evidence from thewest of Scotland twenty-07 study. Psychosom. Med. 75, 288–296.

uan, Z.F., Yang, C., Li, N., Li, J.S., 2004. Effect of glutamine on change in earlypostoperative intestinal permeability and its relation to systemic inflammatoryresponse. World J. Gastroenterol. 10, 1992–1994.

uik, M., Perez, X.A., Bordia, T., 2012. Nicotine as a potential neuroprotective agentfor Parkinson’s disease. Mov. Disord. 27, 947–957.

eiter, R.J., Paredes, S.D., Manchester, L.C., Tan, D.X., 2009. Reducing oxida-tive/nitrosative stress: a newly-discovered genre for melatonin. Crit. Rev.Biochem. Mol. Biol. 44, 175–200.

eiter, R.J., Tan, D.X., Manchester, L.C., Pilar Terron, M., Flores, L.J., Koppisepi, S.,2007. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv. Med. Sci. 52, 11–28.

en, S., Correia, M.A., 2000. Heme: a regulator of rat hepatic tryptophan 2,3-dioxygenase? Arch. Biochem. Biophys. 377, 195–203.

ief, W., Pilger, F., Ihle, D., Bosmans, E., Egyed, B., Maes, M., 2001. Immunological dif-ferences between patients with major depression and somatization syndrome.

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

Psychiatry Res. 105, 165–174.imer, J., Dwan, K., Lawlor, D.A., Greig, C.A., McMurdo, M., Morley, W., Mead, G.E.,

2012. Exercise for depression. Cochrane Database Syst. Rev. 7, CD004366.ios, C., Santamaria, A., 1991. Quinolinic acid is a potent lipid peroxidant in rat brain

homogenates. Neurochem. Res. 16, 1139–1143.

PRESSavioral Reviews xxx (2014) xxx–xxx

Rubartelli, A., Lotze, M.T., 2007. Inside, outside, upside down: damage-associatedmolecular-pattern molecules (DAMPs) and redox. Trends Immunol. 28,429–436.

Ryo, M., Nakamura, T., Kihara, S., Kumada, M., Shibazaki, S., Takahashi, M., Nagai, M.,Matsuzawa, Y., Funahashi, T., 2004. Adiponectin as a biomarker of the metabolicsyndrome. Circ. J. 68, 975–981.

Sagatun, A., Sogaard, A.J., Bjertness, E., Selmer, R., Heyerdahl, S., 2007. The associa-tion between weekly hours of physical activity and mental health: a three-yearfollow-up study of 15–16-year-old students in the city of Oslo, Norway. BMCPublic Health 7, 155.

Sanacora, G., Rothman, D.L., Mason, G., Krystal, J.H., 2003. Clinical studies imple-menting glutamate neurotransmission in mood disorders. Ann. N.Y. Acad. Sci.1003, 292–308.

Sanchez-Villegas, A., Martinez-Gonzalez, M.A., Estruch, R., Salas-Salvado, J., Corella,D., Covas, M.I., Aros, F., Romaguera, D., Gomez-Gracia, E., Lapetra, J., Pinto, X.,Martinez, J.A., Lamuela-Raventos, R.M., Ros, E., Gea, A., Warnberg, J., Serra-Majem, L., 2013. Mediterranean dietary pattern and depression: the PREDIMEDrandomized trial. BMC Med. 11, 208.

Sanders, K.M., Stuart, A.L., Williamson, E.J., Jacka, F.N., Dodd, S., Nicholson, G., Berk,M., 2011. Annual high-dose vitamin D3 and mental well-being: randomisedcontrolled trial. Br. J. Psychiatry 198, 357–364.

Sankhla, M., Sharma, T.K., Mathur, K., Rathor, J.S., Butolia, V., Gadhok, A.K., Vardey,S.K., Sinha, M., Kaushik, G.G., 2012. Relationship of oxidative stress withobesity and its role in obesity induced metabolic syndrome. Clin. Lab. 58,385–392.

Santamaria, A., Galvan-Arzate, S., Lisy, V., Ali, S.F., Duhart, H.M., Osorio-Rico, L.,Rios, C., St’astny, F., 2001. Quinolinic acid induces oxidative stress in rat brainsynaptosomes. Neuroreport 12, 871–874.

Scapagnini, G., Davinelli, S., Drago, F., De Lorenzo, A., Oriani, G., 2012. Antioxidantsas antidepressants: fact or fiction? CNS Drugs 26, 477–490.

Schroder, C.M., O’Hara, R., 2005. Depression and obstructive sleep apnea (OSA). Ann.Gen. Psychiatry 4, 13.

Schubert, D., Piasecki, D., 2001. Oxidative glutamate toxicity can be a component ofthe excitotoxicity cascade. J. Neurosci. 21, 7455–7462.

Shalev, I., Moffitt, T.E., Braithwaite, A.W., Danese, A., Fleming, N.I., Goldman-Mellor,S., Harrington, H.L., Houts, R.M., Israel, S., Poulton, R., Robertson, S.P., Sugden,K., Williams, B., Caspi, A., 2014. Internalizing disorders and leukocyte telomereerosion: a prospective study of depression, generalized anxiety disorder andpost-traumatic stress disorder. Mol. Psychiatry.

Sivonova, M., Zitnanova, I., Hlincikova, L., Skodacek, I., Trebaticka, J., Durackova,Z., 2004. Oxidative stress in university students during examinations. Stress 7,183–188.

Skarupski, K.A., Tangney, C., Li, H., Ouyang, B., Evans, D.A., Morris, M.C., 2010. Lon-gitudinal association of vitamin B-6, folate, and vitamin B-12 with depressivesymptoms among older adults over time. Am. J. Clin. Nutr. 92, 330–335.

Smith, A.J., Smith, R.A., Stone, T.W., 2009. 5-Hydroxyanthranilic acid, a tryptophanmetabolite, generates oxidative stress and neuronal death via p38 activation incultured cerebellar granule neurones. Neurotox. Res. 15, 303–310.

Solin, M.S., Ball, M.J., Robertson, I., de Silva, A., Pasco, J.A., Kotowicz, M.A., Nicholson,G.C., Collier, G.R., 1997. Relationship of serum leptin to total and truncal bodyfat. Clin. Sci. 93, 581–584.

Song, C., Lin, A., Bonaccorso, S., Heide, C., Verkerk, R., Kenis, G., Bosmans, E., Scharpe,S., Whelan, A., Cosyns, P., de Jongh, R., Maes, M., 1998. The inflammatory responsesystem and the availability of plasma tryptophan in patients with primary sleepdisorders and major depression. J. Affect. Disord. 49, 211–219.

Sosnovskii, A.S., Kozlov, A.V., 1992. Increased lipid peroxidation in the rat hypotha-lamus after short-term emotional stress. Biulleten’ eksperimental’noi biologii imeditsiny 113, 486–488.

Sperner-Unterweger, B., Kohl, C., Fuchs, D., 2014. Immune changes and neurotrans-mitters: possible interactions in depression? Prog. Neuropsychopharmacol. Biol.Psychiatry 48, 268–276.

Stangherlin, E.C., Luchese, C., Ardais, A.P., Nogueira, C.W., 2009. Passive smoke expo-sure induces oxidative damage in brains of rat pups: protective role of diphenyldiselenide. Inhal. Toxicol. 21, 868–874.

Stedman, R.L., 1968. The chemical composition of tobacco and tobacco smoke. Chem.Rev. 68, 153–207.

Strawbridge, W.J., Deleger, S., Roberts, R.E., Kaplan, G.A., 2002. Physical activityreduces the risk of subsequent depression for older adults. Am. J. Epidemiol.156, 328–334.

Szewczyk, B., Kubera, M., Nowak, G., 2011. The role of zinc in neurodegenerativeinflammatory pathways in depression. Prog. Neuropsychopharmacol. Biol. Psy-chiatry 35, 693–701.

Taylor, D.J., Lichstein, K.L., Durrence, H.H., Reidel, B.W., Bush, A.J., 2005. Epidemiologyof insomnia, depression, and anxiety. Sleep 28, 1457–1464.

Taylor, M.J., Carney, S.M., Goodwin, G.M., Geddes, J.R., 2004. Folate for depressivedisorders: systematic review and meta-analysis of randomized controlled trials.J. Psychopharmacol. (Oxf.) 18, 251–256.

Teychenne, M., Ball, K., Salmon, J., 2008. Physical activity and likelihood of depressionin adults: a review. Prev. Med. 46, 397–411.

Thome, G.R., Spanevello, R.M., Mazzanti, A., Fiorenza, A.M., Duarte, M.M., da Luz,S.C., Pereira, M.E., Morsch, V.M., Schetinger, M.R., Mazzanti, C.M., 2011. Vitamin

ive stress in depression: Why so much stress? Neurosci. Biobehav.

E decreased the activity of acetylcholinesterase and level of lipid peroxidationin brain of rats exposed to aged and diluted sidestream smoke. Nicotine TobaccoRes. 13, 1210–1219.

Todar, K., 2006. Todar’s Online Textbook of Bacteriology. University of Wisconsin-Madison Department of Bacteriology.

1923

1924

1925

1926

1927

ING ModelN

iobeh

T

T

T

T

T

T

U

U

V

V

V

W

W

W

severe burns: a randomized, double-blind, controlled clinical trial. J. ParenteralEnteral Nutr. 27, 241–245.

Zhu, W.L., Shi, H.S., Wei, Y.M., Wang, S.J., Sun, C.Y., Ding, Z.B., Lu, L., 2012. Green tea

1928

1929

1930

1931

1932

1933

1934

1935

1936

1937

1938

1939

1940

1941

1942

1943

1944

1945

1946

1947

1948

1949

1950

1951

1952

1953

1954

1955

1956

1957

1958

1959

1960

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

ARTICLEBR 1953 1–17

S. Moylan et al. / Neuroscience and B

olmunen, T., Hintikka, J., Ruusunen, A., Voutilainen, S., Tanskanen, A., Valkonen,V.P., Viinamaki, H., Kaplan, G.A., Salonen, J.T., 2004. Dietary folate and the riskof depression in Finnish middle-aged men. A prospective follow-up study. Psy-chother. Psychosom. 73, 334–339.

suboi, H., Tatsumi, A., Yamamoto, K., Kobayashi, F., Shimoi, K., Kinae, N., 2006. Pos-sible connections among job stress, depressive symptoms, lipid modulation andantioxidants. J. Affect. Disord. 91, 63–70.

sukamoto, H., Fukudome, K., Takao, S., Tsuneyoshi, N., Kimoto, M., 2010.Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 dimerizationenables rapid signal transduction against lipopolysaccharide stimulation onmembrane-associated CD14-expressing cells. Int. Immunol. 22, 271–280.

suno, N., Besset, A., Ritchie, K., 2005. Sleep and depression. J. Clin. psychiatry 66,1254–1269.

uon, T., Valvassori, S.S., Lopes-Borges, J., Fries, G.R., Silva, L.A., Kapczinski, F.,Quevedo, J., Pinho, R.A., 2010. Effects of moderate exercise on cigarette smokeexposure-induced hippocampal oxidative stress values and neurological behav-iors in mice. Neurosci. Lett. 475, 16–19.

yagi, E., Agrawal, R., Nath, C., Shukla, R., 2010. Effect of melatonin on neuroin-flammation and acetylcholinesterase activity induced by LPS in rat brain. Eur. J.Pharmacol. 640, 206–210.

chida, K., 2013. Redox-derived damage-associated molecular patterns: ligandfunction of lipid peroxidation adducts. Redox Biol. 1, 94–96.

her, R., Perroud, N., Ng, M.Y., Hauser, J., Henigsberg, N., Maier, W., Mors, O., Pla-centino, A., Rietschel, M., Souery, D., Zagar, T., Czerski, P.M., Jerman, B., Larsen,E.R., Schulze, T.G., Zobel, A., Cohen-Woods, S., Pirlo, K., Butler, A.W., Muglia, P.,Barnes, M.R., Lathrop, M., Farmer, A., Breen, G., Aitchison, K.J., Craig, I., Lewis,C.M., McGuffin, P., 2010. Genome-wide pharmacogenetics of antidepressantresponse in the GENDEP project. Am. J. Psychiatry 167, 555–564.

an Hunsel, F., Wauters, A., Vandoolaeghe, E., Neels, H., Demedts, P., Maes, M., 1996.Lower total serum protein, albumin, and beta- and gamma-globulin in majorand treatment-resistant depression: effects of antidepressant treatments. Psy-chiatry Res. 65, 159–169.

argas, H.O., Nunes, S.O., Pizzo de Castro, M., Cristina Bortolasci, C., Sabbatini Bar-bosa, D., Kaminami Morimoto, H., Venugopal, K., Dodd, S., Maes, M., Berk, M.,2013. Oxidative stress and lowered total antioxidant status are associated witha history of suicide attempts. J. Affect. Disord. 150, 923–930.

olna, J., Kemlink, D., Kalousova, M., Vavrova, J., Majerova, V., Mestek, O., Svar-cova, J., Sonka, K., Zima, T., 2011. Biochemical oxidative stress-related markersin patients with obstructive sleep apnea. Med. Sci. Monitor 17, CR491–CR497.

ang, C., Wu, H.M., Jing, X.R., Meng, Q., Liu, B., Zhang, H., Gao, G.D., 2012. Oxidativeparameters in the rat brain of chronic mild stress model for depression: relationto anhedonia-like responses. J. Membr. Biol. 245, 675–681.

ang, D.W., Zhou, R.B., Yao, Y.M., Zhu, X.M., Yin, Y.M., Zhao, G.J., Dong, N., Sheng,Z.Y., 2010. Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine

Please cite this article in press as: Moylan, S., et al., Oxidative & nitrosatRev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.007

increases suppressive capacity of naturally occurring CD4+CD25+ regulatory Tcells in mice in vitro. J. Pharmacol. Exp. Therapeut. 335, 553–561.

erner, E.R., Werner-Felmayer, G., 2007. Substrate and cofactor requirements ofindoleamine 2,3-dioxygenase in interferon-gamma-treated cells: utilization ofoxygen rather than superoxide. Curr. Drug Metab. 8, 201–203.

PRESSavioral Reviews xxx (2014) xxx–xxx 17

Wiest, R., 2005. Bacterial translocation. Biosci. Microflora 24, 61–90.Wiest, R., Garcia-Tsao, G., 2005. Bacterial translocation (BT) in cirrhosis. Hepatology

41, 422–433.Williams, C.M., El Mohsen, M.A., Vauzour, D., Rendeiro, C., Butler, L.T., Ellis, J.A.,

Whiteman, M., Spencer, J.P., 2008. Blueberry-induced changes in spatial work-ing memory correlate with changes in hippocampal CREB phosphorylationand brain-derived neurotrophic factor (BDNF) levels. Free Radic. Biol. Med. 45,295–305.

Wilson, C.B., McLaughlin, L.D., Nair, A., Ebenezer, P.J., Dange, R., Francis, J., 2013.Inflammation and oxidative stress are elevated in the brain, blood, and adrenalglands during the progression of post-traumatic stress disorder in a predatorexposure animal model. PLoS ONE 8, e76146.

Wolkowitz, O.M., Mellon, S.H., Epel, E.S., Lin, J., Dhabhar, F.S., Su, Y., Reus, V.I.,Rosser, R., Burke, H.M., Kupferman, E., Compagnone, M., Nelson, J.C., Blackburn,E.H., 2011. Leukocyte telomere length in major depression: correlations withchronicity, inflammation and oxidative stress – preliminary findings. PLoS ONE6, e17837.

Wu, A., Ying, Z., Gomez-Pinilla, F., 2004a. Dietary omega-3 fatty acids normalizeBDNF levels, reduce oxidative damage, and counteract learning disability aftertraumatic brain injury in rats. J. Neurotrauma 21, 1457–1467.

Wu, A., Ying, Z., Gomez-Pinilla, F., 2004b. The interplay between oxidative stress andbrain-derived neurotrophic factor modulates the outcome of a saturated fat dieton synaptic plasticity and cognition. Eur. J. Neurosci. 19, 1699–1707.

Wu, C.C., Chang, J.H., Chen, C.C., Su, S.B., Yang, L.K., Ma, W.Y., Zheng, C.M., Diang, L.K.,Lu, K.C., 2011. Calcitriol treatment attenuates inflammation and oxidative stressin hemodialysis patients with secondary hyperparathyroidism. Tohoku J. Exp.Med. 223, 153–159.

Yager, S., Forlenza, M.J., Miller, G.E., 2010. Depression and oxidative damage to lipids.Psychoneuroendocrinology 35, 1356–1362.

Yang, R., Han, X., Uchiyama, T., Watkins, S.K., Yaguchi, A., Delude, R.L., Fink, M.P.,2003. IL-6 is essential for development of gut barrier dysfunction after hemor-rhagic shock and resuscitation in mice. Am. J. Physiol. 285, G621–G629.

Yildiz, D., Ercal, N., Armstrong, D.W., 1998. Nicotine enantiomers and oxidativestress. Toxicology 130, 155–165.

Yu, T., Robotham, J.L., Yoon, Y., 2006. Increased production of reactive oxygen speciesin hyperglycemic conditions requires dynamic change of mitochondrial mor-phology. Proc. Natl. Acad. Sci. U.S.A. 103, 2653–2658.

Zameer, A., Hoffman, S.A., 2001. Immunoglobulin binding to brain in autoimmunemice. J. Neuroimmunol. 120, 10–18.

Zhou, Y.P., Jiang, Z.M., Sun, Y.H., Wang, X.R., Ma, E.L., Wilmore, D., 2003. The effect ofsupplemental enteral glutamine on plasma levels, gut function, and outcome in

ive stress in depression: Why so much stress? Neurosci. Biobehav.

polyphenols produce antidepressant-like effects in adult mice. Pharmacol. Res.65, 74–80.

2020

2021