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Neurobiology of Aging 27 (2006) 1684–1693

DHEA improves symptomatic treatment of moderately andseverely impaired MPTP monkeys

Nancy Belanger a,c,d, Laurent Gregoire a,b,c,d, Paul J. Bedard c,d,Therese Di Paolo a,b,∗

a Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL),2705 Laurier Boulevard, Que., Canada G1V 4G2

b Faculty of Pharmacy, Laval University, Que., Canada G1K 7P4c Neuroscience Research Unit, Laval University Medical Center (CHUL), Que., Canada G1V 4G2

d Department of Medicine, Laval University, Que., Canada G1K 7P4

Received 9 November 2004; received in revised form 26 August 2005; accepted 25 September 2005Available online 25 October 2005

bstract

The steroid dehydroepiandrosterone (DHEA) is abundant in men and women and decreases rapidly during aging. Parkinson’s disease (PD)s the second most common neurodegenerative disorder just behind Alzheimer. l-3,4-Dihydroxyphenylalanine (l-Dopa) therapy remains the

ost effective treatment but many patients develop motor complications. This study investigated the acute effect of DHEA alone and with-Dopa in 12 females monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. DHEA administrationlone improved the mean parkinsonian score at 1, 5 and 15 mg/kg in moderately and severely impaired MPTP monkeys and increased bloodHEA concentrations. DHEA with a low dose of l-Dopa increased the l-Dopa effect in moderately and severely impaired MPTP monkeys.

HEA lengthened duration of the effect of the low dose of l-Dopa by 15–45 min. DHEA at 1, 5 and 15 mg/kg combined with a high dosef l-Dopa did not increase dyskinesias. DHEA could act by reducing inhibitory GABAergic activity in the striatal output pathways. DHEAould also be metabolized into estradiol in the brain and increase acutely dopamine activity.

2005 Elsevier Inc. All rights reserved.

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eywords: Dehydroepiandrosterone; MPTP monkeys; Parkinson’s disease;

. Introduction

Parkinson’s disease (PD) is the second most commoneurodegenerative disorder just behind Alzheimer and itsrevalence is likely to increase due to the aging population60]. PD is caused by the massive destruction of dopaminer-ic neurons of the substantia nigra pars compacta (SNc) thatroject to the striatum thus leading to extensive loss of stri-tal dopamine (DA) concentrations [48]. PD is characterized

ehaviorally by bradykinesia or akinesia, posture instabilitynd tremor [42,43]. There is no cure for PD but the DA pre-ursor L-3,4-dihydroxyphenylalanine (l-Dopa) remains the

∗ Corresponding author. Tel.: +1 418 656 4141x46240;ax: +1 418 654 2761.

E-mail address: therese.dipaolo@crchul.ulaval.ca (T. Di Paolo).

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197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.neurobiolaging.2005.09.028

; Dyskinesia

ost effective symptomatic therapy since its introduction.espite its high efficiency, long-term l-Dopa treatment islagued by motor complications including involuntary move-ents (dyskinesias) and a gradual shortening of the duration

f action of l-Dopa (“wearing-off” phenomenon) that areartly dose related [15]. A recent treatment strategy has beeno add to l-Dopa adjunct pharmacological drugs specifico basal ganglia non-dopaminergic neurotransmitter systems14].

The striatum, the input structure of the basal ganglia,eceives multiple afferent projections, the major one beinghe glutamatergic excitatory input from the cerebral cortex

hereas the internal globus pallidus (GPi) and the substantiaigra pars reticulata (SNr) represent the major outputuclei of the basal ganglia [1]. These structures exert aonic GABAergic inhibitory influence upon the excitatory

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remotor neurons located in the ventral tier thalamic nuclei.etween input and output structures, two major projection

ystems (direct and indirect pathways) have been identified,rising from separate striatal neuronal populations [32,61].he direct pathway originates from striatal neurons thatontain GABA plus the neuroactive peptides substance

or dynorphin and project to the GPi-SNr. The indirectathway arises from striatal neurons that contain GABA andnkephalin and whose influence is conveyed to the GPi-SNria relays in the external globus pallidus (GPe) and theubthalamic nuclei (STN). This sequence of connectionsomprises: (1) a GABAergic inhibitory projection from thetriatum to the GPe; (2) an inhibitory GABAergic projectionrom the GPe to the STN; (3) an excitatory glutamatergicrojection from the STN to the GPi-SNr. At the striatalevel, DA appears to facilitate transmission along the directathway and inhibit transmission along the indirect pathway,hese two opposite effects being proposed to be mediatedy DA, D1 and D2 receptors, respectively [32]. Imbalanceetween the activity in the direct and indirect pathwaysnd the resulting alterations in the GPi-SNr complex arehought to account for the hypo- and hyperkinetic featuresf basal ganglia disorders. Akinesia is postulated to resultrom increased GABAergic inhibition of thalamic premotoreurons, owing to excessive excitatory drive from the STN tohe GPi-SNr. The loss of striatal DA that characterize PD ishought to cause a disinhibition of GABA- and enkephalin-ontaining neurons of the indirect pathway, which leads to aarked hypoactivity of the GPe, followed by a disinhibition

f the STN [15]. GABAA and GABAB receptors are abundantn the striatum and its output structures [70]; we have shownhat GABAA receptors are increased in the GPi of dyskinetic

PTP monkeys [16] and PD patients with dyskinesias17].

Dehydroepiandrosterone (DHEA), a precursor of estra-iol and testosterone, has significant interest because itstrong age-associated decline in humans [44,45]. Thisecline may be linked with different age-associated dis-ases [30,68,71,73]. Lower DHEA levels were associatedith higher ratings of psychopathology, poorer memoryerformance, and more severe parkinsonian movementsn schizophrenic and schizoaffective parkinsonian patients36].

DHEA is also called a “neurosteroid” since it is producedn the central nervous system [3]. DHEA and its sulfated formHEA sulfate (DHEAS) are the most abundant steroids in

he blood [4,45]. DHEA is a negative modulator of GABAAeceptors that interacts with the barbiturate site of the GABAAeceptor complex [47,49]. DHEA could oppose the effect ofoss of striatal DA on the direct and indirect output striatalathways.

It is well documented that estrogens display modulatory

nd neuroprotective activities on DA neurochemistry andehaviors mediated by DA [6,22,23]. There is also evidencehat DHEA modulates dopaminergic activity [53] and pro-ects DA neurons [25].

Aging 27 (2006) 1684–1693 1685

We previously reported that the circling behavior of hemi-arkinsonian MPTP monkeys is increased after administra-ion of DHEA alone and DHEA combined to a threshold dosef l-Dopa [9]. The present study sought if our initial findingsan be generalized to other moderately and severely impairedPTP monkeys. We used bilaterally lesioned MPTP mon-

eys in order to better assess motor behavior than hemi-esioned monkeys where ipsi and contra-lateral rotationsere measured. Detailed motor behavior, including locomo-

or activity, parkinsonian and dyskinetic scores, was mea-ured after DHEA administration alone and in combinationith l-Dopa. The present study therefore assessed in detailotor activity of parkinsonian monkeys and showed thatHEA improved the intensity and duration of motor acti-ation.

. Methods

.1. Animals and treatments

Twelve ovariectomized MPTP female macaca fascicularisonkeys weighing between 3.76 and 3.95 kg (six moder-

tely impaired and six severely impaired) were used in thistudy. Monkeys were divided into two groups based on theirarkinsonian score which were respectively 8 and 12 foroderately and severely impaired monkeys. This division

n two groups was to probe if DHEA is as effective in morer less impaired MPTP monkeys. During induction of thearkinsonian syndrome, they received the neurotoxin MPTPSigma–Aldrich, Oakville, Ont., Canada) dissolved in sterileater and injected subcutaneous first with 3 mg/dose. The

ollowing week, each animal received MPTP by means ofn Alzet pump (0.5 mg/day) during a month when sustainedarkinsonian features appeared (moderately or severelympaired). The animals were used at least 5 months afterhe induction of their parkinsonian state, at which timehey had stabilized. The experiments was divided in threearts:

1) DHEA (Sigma–Aldrich, Oakville, Ont., Canada) testedalone (1, 5, 15 mg/kg) versus vehicle. The vehicle con-sisted of a methylcellulose solution and was administeredby nasogastric gavage.

2) DHEA (1, 5, 15 mg/kg) tested with a threshold dose of l-Dopa methylester (T.l-Dopa; Sigma–Aldrich, Oakville,Ont., Canada). The threshold dose was the minimal l-Dopa dose able to modify the parkinsonian state ofmonkeys (1–2 points) and was different for each monkey(4–8 mg/kg s.c.).

3) DHEA (1, 5, 15 mg/kg) tested with high doses of l-Dopamethylester (50 or 100 mg depending of the monkey).

The high dose of l-Dopa was used to induce dyskine-sias (which were still moderate in these animals) andto seek if DHEA induced locomotor activation withoutincreasing dyskinesias. Three monkeys received 50 mg

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686 N. Belanger et al. / Neurobio

for all experiments using high doses of l-Dopa and threereceived 100 mg. The dose (50 or 100 mg) was chosento produce motor activation without being excessive; thiscan lead in these monkeys to extreme agitation (with pos-sible injuries) and auto-mutilation. Since all monkeysserved as their own controls this did not influence theDHEA and DHEA + l-Dopa results.

The administration of l-Dopa (Sigma–Aldrich, Oakville,nt., Canada) was subcutaneous. An injection of Benserazide

50 mg; Hoffman-Laroche, Mississauga, Ont., Canada) wasdministered subcutaneous with l-Dopa to prevent its degra-ation in periphery. DHEA was prepared as a suspension inethylcellulose and the solution was kept at 4 ◦C, 24 h before

he administration by nasogastric gavage.Monkeys were first treated with l-Dopa (three times a

eek) for priming until a stable antiparkinsonian behavioras observed. When the effect of DHEA was investigated

lone, priming of the monkeys was continued with adminis-ration of l-Dopa/Benserazide (100/25 mg, per o.s.; Prolopa,offman-Laroche, Mississauga, Ont., Canada) twice weekly,days before each administration of DHEA.Treatments were administered in the morning at 9:00 a.m.

nd behavior was measured for 15 min periods with a disabil-ty scale by an evaluator blind to the experimental treatmentntil the effect disappeared [10]. This scale scores from 0normal) to 3, diability of posture, locomotor activity (mobil-ty), gait, tremor, climbing, grooming, vocalization and socialnteraction. The parkinsonian score obtained is the sum of thecores for each parameter for a maximal score of 16; we usednd detailed this scale elsewhere [10]. Mean parkinsoniannd dyskinesia scores were the average of scores measuredn the 15 min periods until the effect disappeared. The mini-

um parkinsonian score was the lowest 15 min score and theaximun dyskinesia score was the highest 15 min score mea-

ured in the observation period. Dyskinesias were inducedith administration of the high dose of l-Dopa without anyther procedure. The severity of dyskinesias were also scoredvery 15 min for the face, neck, trunk, arms and legs fromone (0), mild (1), moderate (2) to severe (3). The differencen intensity of dyskinesia for a given body segment is basedn the assessment of the amplitude of the abnormal move-ents and their frequency; each body segment was scored

eparately. The dyskinetic score was the sum of the scoresor all body segments, for a maximum score of 21 points.yskinesias were mainly choreic in nature but dystonia was

lso seen.Home cage locomotor activity of monkeys was monitored

ith the use of an electronic locomotor activity monitoringystem fixed on each cage (Dataquest IV; Data-science). Aollar on each monkey transmits a radiowave frequency sig-al to a receiver attached to the cage, which is connected

o a computer. The locomotor activity of each animal wasumulated every 5 min continuously.

Monkeys were fed each day at 2:00 p.m. and the diurnalycle was from 6:00 a.m. to 6:00 p.m. This experiment was

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Aging 27 (2006) 1684–1693

n accordance with the rules of the Canadian Council of Pro-ection of the Animals (CCPA).

Blood samples of 2 ml were collected in tubes contain-ng EDTA before and after about 1 h of administration ofehicle or 5 mg/kg of DHEA. Blood was centrifuged at000× g at 4 ◦C for 10 min. Plasma steroid levels were mea-ured by a gas chromatographic mass spectrometric methodeveloped to measure steroid hormone levels in rat and mon-ey serum [12]. Briefly, DHEA was extracted from serumy liquid–liquid and solid-phase extraction. Derivatizationeactions were performed to improve chromatographic andetection response of the steroids. Unconjugated DHEA wasuantified by means of a sensitive gas chromatographic/masspectrometric (GC/MS) method, using chemical ionizationCI).

.2. Statistical analysis

Experimental non-parametric data were compared usinghe non-parametric Friedman’s test followed by multipleomparison based on Friedman rank sums. Statistical com-arisons of parametric data (locomotor activity and DHEAlood concentrations) were performed using an ANOVA forepeated measures followed by post-hoc analysis with Fisherrobability of least significance difference test. For the anal-sis of locomotor activity, square root transformation of theata was used to stabilize variance [51]. A value of P < 0.05as required for the results to be considered statistically sig-ificant.

. Results

DHEA tested alone improved significantly the meanarkinsonian score compared to vehicle with decreases of 55,6 and 48% for the DHEA doses of 1, 5 and 15 mg/kg respec-ively and 29% for l-Dopa treatment in moderately affected

PTP monkeys (Fig. 1A). DHEA reduced significantly butess the parkinsonism in severely impaired MPTP monkeysompared to the vehicle with decreases of 13, 24 and 11%or the DHEA doses of 1, 5 and 15 mg/kg (Fig. 1B) and 32%or l-Dopa treatment. DHEA given alone did not produceyskinesias or any side-effects. Plasma DHEA concentra-ions increased significantly (time × treatment, F(1,4) = 9.33,< 0.05) an hour following administration 5 mg/kg DHEA

before 9.6 ± 1.3, after DHEA 29.7 ± 3.7, P < 0.01) andemained unchanged following vehicle (before 17.9 ± 1.6,fter vehicle 13.4 ± 7.0).

For all MPTP monkeys investigated DHEA combinedith a T.l-Dopa improved their mean parkinsonian score

Fig. 2). T.l-Dopa dose was adjusted for each monkey to behe minimal l-Dopa dose able to modify the parkinsonian

tate of monkeys; its administration reduced the parkinsoniancore of 11% in moderately and of 15% in severely impaired

PTP monkeys. All doses of DHEA tested (1, 5, 15 mg/kg)ombined with T.l-Dopa administered to moderately

N. Belanger et al. / Neurobiology of Aging 27 (2006) 1684–1693 1687

Fig. 1. Effect of DHEA compared to l-Dopa (50 or 100 mg depending onthe monkey) and vehicle on mean parkinsonian score of (A) moderately and(*

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Fig. 2. Effect of DHEA combined to a threshold dose of l-Dopa (T.l-Dopa) (4–8 mg/kg) on the mean parkinsonian score of (A) moderately and(*

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B) severely impaired MPTP monkeys. Each bar represents mean ± S.E.M.*P < 0.01 vs. vehicle and ††P < 0.01 vs. l-Dopa.

mpaired MPTP monkeys, significantly reduced the meanarkinsonian score compared to vehicle (65, 64 and 61%espectively) and T.l-Dopa treatments (Fig. 2A). DHEAt 1 and 5 mg/kg with T.l-Dopa also reduced significantlyhe parkinsonism in severely impaired MPTP monkeysompared to vehicle (37 and 40% respectively) and T.l-opa treatments (Fig. 2B). The dose of 15 mg/kg of DHEA

ombined to T.l-Dopa improved significantly the meanarkinsonian score compared to vehicle (21%) treatment butas not significantly different than the T.l-Dopa group.Fig. 3 details the results of Fig. 2 with the time course of

reatment on parkinsonian score for severely affected MPTPonkeys. DHEA extended the l-Dopa effect by 15–45 min

epending on the monkey (Fig. 3B). Interestingly, in severelyffected monkeys, each doses of DHEA (1, 5, 15 mg/kg) com-ined to T.l-Dopa (Fig. 3B), as well as the dose of 5 mg/kgf DHEA alone (Fig. 3A), were significantly effective dur-ng this period. In the severely affected MPTP monkeys, theHEA effect alone or with l-Dopa was greater at 5 mg/kg

ompared to 1 mg/kg (Figs. 1 and 2). Similar results werebtained with the moderately impaired MPTP monkeys (dataot shown).

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B) severely impaired MPTP monkeys. Each bar represents mean ± S.E.M.*P < 0.01 vs. vehicle and ††P < 0.01 vs. l-Dopa.

Fig. 4 presents details of the experiment of Fig. 2 showingn improvement of individual parameters of the parkinso-ian score (posture, mobility, gait, vocalization and tremor)nd the home-cage activity data in severely impaired mon-eys. DHEA combined with threshold l-Dopa improvedignificantly the locomotor activity compared to vehicle ando threshold l-Dopa (F(2,10) = 91.01, P < 0.001). Climbing,rooming, vocalization and social interaction were not gen-rally and consistently affected by the DHEA administrationlone or with l-Dopa at the three doses of this steroid testeddata not shown). The home-cage activity data of moderatelympaired monkeys was not presented because of missing dataue to equipment failure.

The high dose of l-Dopa administered to moderatelympaired MPTP monkeys reduced by 44% the mean andy 50% the minimum parkinsonian scores compared to theehicle treatment (Fig. 5). Addition of DHEA to the highose of l-Dopa did not give an additional improvement ofhe mean parkinsonian scores (50, 45 and 46% for 1, 5 and

5 mg/kg of DHEA) but the minimum score did improveith 1 mg/kg (65%) and 5 mg/kg (80%) of DHEA compared

o vehicle. Addition of DHEA to l-Dopa did not affect the

1688 N. Belanger et al. / Neurobiology of Aging 27 (2006) 1684–1693

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ig. 3. Time course of the effect of administration of DHEA alone and a tarkinsonian score of severely impaired MPTP monkeys as compared to vehhown. *P < 0.05 vs. vehicle.

yskinetic scores; DHEA did not change onset and durationf these anormal movements. For ethical reasons experimen-ations with high l-Dopa doses were limited to the moder-tely impaired MPTP monkeys because this often inducestereotypes, severe liking, auto-mutilation and hypotensionn MPTP animals.

. Discussion

DHEA administered alone improved the parkinsoniancore of MPTP monkeys and potentiated intensity and dura-ion of the effect of a low dose l-Dopa. Furthermore, whenHEA was combined with a high dose of l-Dopa it didot increase dyskinesias. The motor effect of DHEA wasbserved both in moderately and severely impaired mon-eys but was more prominent in the former. This suggestshat severity of denervation of the nigrostriatal pathway ismplicated in the difference in response. DHEA such asstrogens [27] can affect various dopaminergic targets of the

igrostriatal pathways such as DA synthesis, uptake, trans-orters and receptors and downstream signalization, some ofhich are destroyed in severely impaired MPTP monkeys

23,27].

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d dose of l-Dopa (T.l-Dopa) (A) as well as their combination (B) on theatment and basal levels. The extension of duration of the l-Dopa activity is

The enzyme hydroxysteroid sulfotransferase is showno be present in the rat striatum supporting a pos-ible striatal transformation of DHEA and DHEA-S55]. Both DHEA and DHEA-S are negative modula-ors of the GABAA receptors, they are reported to inhibitinding of [3H]flunitrazepam, [3H]muscimol and [35S]t-utylbicyclophosphorothionate (TBPS) in the rat cerebel-um and cerebral cortex [49]. DHEA-S is shown to reducehe amplitude of inhibitory postsynaptic potentials causedy GABA inputs, depresses the depolarizing responses tolutamate, and blocks the glutamate-induced action poten-ials [45]. An increase in synaptic concentrations of DHEAnd DHEA-S could increase neuronal excitability and CNSrousal [46]. Thus DHEA and DHEA-S, by their antagonisticction on GABAA receptors in basal ganglia, could possiblytimulate the output pathways of the striatum by decreasingnhibitory GABAergic activity [15]. DHEA also potentiateseuronal N-methyl-d-aspartate (NMDA) response mediatedia � receptors [11]. NMDA receptors are abundant in theutput structures of the basal ganglia [18] and may also be

mplicated in the DHEA effects observed here.

An alternative mechanism of action of DHEA would bets transformation into other active steroids such as testos-erone and estradiol by the converting enzymes aromatase and

N. Belanger et al. / Neurobiology of Aging 27 (2006) 1684–1693 1689

Fig. 4. Effect of 5 mg/kg DHEA combined to a threshold dose of l-Dopa (T.l-Dopa) (4–8 mg/kg) in severely impaired MPTP monkeys on locomotor activityand individual parameters (posture, mobility, gait, vocalization and tremor) measured in the parkinsonian score. Climbing, grooming and social interaction aren addition†

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ot included because they were in general not significantly changed by theP < 0.05; ††P < 0.01 vs. T.l-Dopa.

ydroxysteroid dehydrogenase present in the brain [69,75].romatase expression was found in the embryonic and post-atal mouse striatum [38], 3�-hydroxysteroid dehydroge-ase mRNA and protein is present in the rat striatum [35].n addition 17�-hydroxysteroid dehydrogenase is shown toe present in the human striatum [72]. We have previouslyhown that administration in hemiparkinsonian monkeys ofstradiol (0.1 mg/kg) such as DHEA (1–15 mg/kg) potenti-ted l-Dopa locomotor activation [9]. It is therefore possi-le that DHEA is active through conversion into estradiol.he effective estradiol doses in our previous study [9] were

ess than the DHEA doses in accordance with the dosessed in animals and humans for these steroids. Thus only

partial conversion of DHEA into estradiol would be suf-cient to reach the levels of estradiol shown to be active

n monkeys. Presence of estrogen receptors (ER) are gen-rally found to be low or absent in the basal ganglia of

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of DHEA. Each bar represents mean ± S.E.M. **P < 0.01 vs. vehicle and

odents and primates [20,54] but both are found in the ratubstantia nigra [41]. ER� are found in GPe [28] and ER�re detected in thalamus and STN [54]. The modulationf the motor information in the thalamus and the pres-nce of ER in the thalamic and STN areas suggest thathey could be implicated in the motor behavior. NumerousA endpoints in the caudate-putamen respond to estrogen

timulation compared to non-aromatizable androgens andhis has been related to presence of ER� but not androgeneceptor bearing projections to the caudate [21]. In womenoses of 30–50 mg of oral DHEA can increase serum andro-en levels to physiological range for young adults but its not known if also androgen brain levels are increased

19].

Alternatively, ER in other brain areas such as the amygdalaay be implicated in the estradiol effects in the caudate-

utamen [21]. Rapid membrane effects of estrogen are also

1690 N. Belanger et al. / Neurobiology of

Fig. 5. Effect of DHEA combined with l-Dopa (50 or 100 mg depending onthe monkey) on (A) the mean and minimum parkinsonian scores and (B) themk†

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ean and maximum dyskinetic scores in moderately impaired MPTP mon-eys. Each bar represents mean ± S.E.M. *P < 0.05; **P < 0.01 vs. vehicle.P < 0.05 vs. l-Dopa.

ocumented in the striatum and could be implicated in theHEA activity [50].DHEA may also be beneficial in MPTP monkeys by its

ntiglucocorticoid activity [37]. At doses less than 5 mg/kg,HEA affects the immune system of both experimental ani-als and humans [66]. Immune system alterations occur inD [24]. As in other CNS degenerative diseases, there isvidence of inflammation in damaged regions in the brainsf PD patients. These observations suggest that immune sys-em mechanisms are involved in the pathogenesis of neuronalamage in PD. Inflammation initiated by neuronal damagen the striatum and the substantia nigra in PD may aggra-ate the course of the disease. These observations suggesthat treatment with anti-inflammatory drugs may act to slowrogression of PD [24].

The experiments reported here were designed to probe inetail the motor effects of DHEA with and without l-Dopa atifferent doses and in more or less impaired MPTP monkeys.hey were not designed to decipher which steroid is active

n the locomotor activation. Additional experiments will beequired to answer this question. Nevertheless the present

ndings have important clinical implication. DHEA could bepro-drug of estradiol. Its conversion in the blood has been

eported in humans to be very low. Hence, 50 mg/day DHEArally, daily for a year was investigated in a double-bind,

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Aging 27 (2006) 1684–1693

lacebo-controlled study in healthy elderly 60–79 year olden and women; no potentially harmful accumulation ofHEAs and active steroids was recorded [5]. In the lightf the large WHI studies on hormone replacement therapy2,56,57,59], DHEA could be an alternative to estradiol thatas less deleterious peripheral effects.

Estradiol and DHEA treatments were shown to protectgainst DA loss in animal models of PD in mice [25] andats [67]. In MPTP monkeys estradiol treatment for 7 daysas shown to reduce dyskinesias without affecting l-Dopa

ntiparkinsonian activity [33]. Duration of treatment andoses used were different than our previous acute study [9]nd could explain the different beneficial effect observed. Inumans dyskinesias were also reported to be reduced withstrogens [7]. The present groups of MPTP monkeys hadoderate dyskinesias and provided a good model to assess

ossible increase of dyskinetic score; experiments with moreeverely dyskinetic monkeys would be required to assess aossible reduction of dyskinesias with DHEA.

In humans with PD their are limited studies reporting treat-ents with estrogens and to our knowledge none with DHEA.lanchet et al. [13] observed after 10 days of treatment with7�-estradiol a significant reduction in the antiparkinsonianhreshold dose of l-Dopa; dyskinesia scores were unaltereduring 17�-estradiol treatment compared with placebo. Noffect of 17 �-estradiol in PD patients was reported in an othertudy [62]. No change of DHEA-S in the plasma of malend female patients with PD is reported compared to aged-atched healthy subjects [31] whereas lower DHEA levelsere associated with more severe parkinsonian movements

n schizophrenic patients [36]. Recent reports show thatdministration of DHEA improves patients with schizophre-ia corresponding to increased plasma levels of DHEA andHEA-S [63,65]. Plasma DHEA and DHEA-S concentra-

ions were measured in first-episode schizophrenia [64], inhronic illness [26,34,58], with length of hospitalization [64],atients with predominantly positive symptoms compared tohose with negative symptoms [34]. In schizophrenia it ispeculated that DHEA may serve as a biological adaptiveechanism with higher DHEA and DHEA-S levels as a pro-

ecting or compensatory factor in early illness [64]. Hence,ore studies in larger and more defined groups of PD patients

re required to have a better assessment the effect of DHEAn PD.

Many reviews report various actions of DHEA in experi-ental animals and humans [3,5,29,39,40,52,66,73,74]. Svec

nd Porter [66] reviewed the literature in which DHEAas administered to either humans or experimental animals

o discern the DHEA physiologic functions. Reports wereivided into five areas: neurologic, immunologic, cardiovas-ular, oncologic, and metabolic. Particular attention was paido dosage and route of administration. This analysis showed

hat at the lowest doses, DHEA has effects on neurologicnd immunologic tissues, suggesting that these two sites maye physiologic targets. DHEA also affects cardiologic andetabolic functions as well as tumor growth, but such actions

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equire higher doses and may reflect ‘pharmacologic’ activ-ties [40,66]. The present results and our previous report [9]howed effective locomotor activation with small doses ofHEA in MPTP monkeys in line with a physiological neu-

ological target [66] and the daily dose of ∼0.7 mg/kg/day50 mg pill) that is “suggested” in the over-the-counter prepa-ations sold in the United States. The DHEA doses adminis-ered were associated with an increase DHEA plasma levelsn these monkeys; our MPTP monkeys had low DHEA basalevels [44].

The present DHEA study confirms and expands our previ-us observations in hemiparkinsonian monkeys in bilaterallyoderately and severely impaired MPTP monkeys. TheseHEA results are significant in the light of the important

ge-associated decline in both men and women of this steroid8]. DHEA treatment could improve parkinsonism in the firsttages of the disease without the l-Dopa side effects. DHEAombined with lower doses of l-Dopa could relieve motorymptoms while reducing or preventing the appearance ofyskinesias. DHEA prevents MPTP-induced striatal DA lossn mice [25] and may also be beneficial to slow progressionf PD.

cknowledgements

We wish to thank Steve Brochu for technical assistance.his research was supported by grants from the Cana-ian Institutes of Health Research of Canada to T.D.P. and.J.B.

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