Prophylactic Effect Of Antioxidants As Free Radical Scavengers In Endotoxemia.

J. Drug Res. Egypt, Vol. 27, No.1-2 (2006) 98

Prophylactic Effect Of Antioxidants As Free Radical Scavengers In

Endotoxemia.

Wafaa Hassan; Nashwah Zaki and Lobna Hassanin

National Organization for Drug Control and Research

ABSTRACT: oxidative stress plays a key role in sepsis induced by endotoxin

lipopolysaccharide (LPS) which is known to enhance the formation of reactive oxygen species

(ROS). In this study, biochemical parameters indicative of hepatic injury and oxidative stress

were tested in rat liver following LPS challenge, with or without treatment with the

antioxidants alpha lipoic acid (ALA) and Antox (antioxidant drug preparation).

Treatment with LPS alone resulted in a significant (P<0.05) alteration in liver oxidative status

observed as elevation in alanine and aspartate aminotransferase (ALT& AST) activities ,

malondialdehyde (MAD, index of lipid peroxidation) level and nitric oxide (NO)

concentration. Also, activities of reduced glutathione (GSH), superoxide dismutase (SOD) and

glutathione peroxidase (GSH-Px) were significantly (P<0.05) reduced in LPS-treated group,

as compared to control level.

Treatment for seven days with either ALA or Antox prior to or after LPS challenge

significantly (P<0.05) decrease ALT, AST, MDA and NO levels when compared to LPS

alone. On the other hand, administration of ALA and Antox prior to or after LPS treatment

significantly increase the activities of GSH, SOD and GSH-Px when compared with LPS

treated group.

These results indicate that either ALA or Antox may serve as a potentially effective

prophylactic agents in alleviating LPS- induced oxidative stress. The beneficial pretreatment

effects of the antioxidant against oxidative stress in this study may suggest a potential

chemopreventive effect of these compounds in septic prevention.

INTRODUCTION: Endotoxin lipopolysaccharide (LPS) are the principal

components of the outer membrane of Gram-negative

bacterial and have been recognized for many years as

key risk factors in the development of sepsis syndrome

(Galanos and Freudenberg, 1993).The initial symptoms

of sepsis encompass those usually associated with

acute inflammation, including fever or hypothermia,

tachypnea and tachycardia. When sepsis is

accompanied by hypotension plus organ dysfunction

and finally death, the condition is known as septic

shock (Cadenas and Cadenas, 2002; Victor et al., 2004

& 2005).

According to Cadenas and Cadenas (2002) and

Taniguchi et al.(2003) many of the adverse effects of

LPS in mammals are dependent on the activation of

cellular and soluble inflammatory mediators including

monocyte, macrophage, cytokin, and

polymorphonuclear leukocytes. In response to these

inflammatory cells, several reactive oxygen species are

produced, creating a status of oxidative stress (Victor et

al., 2000 and Dikalov et al., 2002).

Oxidative stress may be caused by reactive oxygen

intermediates, which are believed to be involved in the

development of many diseases (Gate et al., 1999).

Reactive oxygen intermediates, including singlet

oxygen, nitric oxide, hydrogen peroxide, and radicals

such as superoxide anion (Takeyama et al., 1996), are

important mediators of cellular injury and play a

putative role in LPS – associated oxidative stress

(Bautista and Spitzer, 1990).

Lipid peroxidation has been suggested to be a useful

indicator of oxidative stress (Lazzarino et al., 1995).

As reported by Sakaguchi et al. (1981) endotoxin

injection was shown to result in lipid peroxide

formation and membrane damage in experimental

animals, causing decreased levels of scavengers or

quenchers of free radicals. In addition, Sakaguchi et

al., 1989 suggested that Ca2+ may participate in free

radical formation in endotoxin-poisoned mice.

Furthermore, NO, a highly reactive radical produced

by activated macrophages, has emerged as another

important mediator of inflammatory responses

(Beckman and Koppenol,1996).Thus, NO radical was

shown to function efficiently as mediator, a messenger,

or a regulator of cell function in a number of

physiological systems and pathophysiological states.

Under physiological condition, a homeostatic balance

exists between the formation of reactive oxidizing

oxygen species and their removal by endogenous

antioxidant scavenging compounds (Gutteridge and

Mitchell, 1999).Oxidative stress occurs when this

balance is disrupted, by excessive production of ROS

and/or inadequate antioxidant defenses systems

(Gutteridge, 1995). The defense mechanisms against

oxidative stress include SOD, GSH and GSH-PX

(Halliwell and Gutteridge, 1989 and Iszard et al.,

1995). SOD catalyzes the dismutation of superoxide

free radicals to hydrogen peroxide and water and is

consider the crucial enzyme of antioxidant defense

system (Johnson and Macdonald, 2004). The tripeptide

glutathione (L-γ-glutamyl-L-cysteinyl-glycine), the

major thiol in mammalian cells, plays a crucial role in

detoxification and cellular defense (Guillemette et al.,

1993 and Dumaswalla et al., 2000). It prevents

interactions of reactive intermediates with critical

cellular constituents, such as the phospholipids of


biomembranes, nucleic acids, and proteins (Kaplawitz

et al., 1985 and Guillemette et al., 1993).

Alpha lipoic acid (ALA) is a disulphide derivative of

octanoic acid and has known to be a crucial prosthetic

group of various cellular enzymatic complexes. It is

taken up and reduced by cells to dihyrolipoate, a more

powerful antioxidant than the parent compound, which

is also exported to the extracellular medium; hence,

protection is affected in both extracellular and

intracellular environments. It's Functions as both a

water soluble and fat soluble antioxidant. Recently,

ALA acid has been identified as a potent antioxidant

and has been proposed to be a therapeutic agent in the

prevention or treatment of pathological conditions

mediated via oxidative stress, as in the case of

ischemia- reperfusion injury, diabetes, radiation injury

and oxidative damage of the central nervous system.

ALA also plays an important role in the synergism of

antioxidants. It directly recycles and extends the

metabolic life spans of vitamin C, glutathione, and

coenzyme Q10, and it indirectly renews vitamin E

(Biewenga et al., 1997 and Bustamante et al., 1998).

Vitamins are ideal antioxidants to increase tissue

protection from oxidative stress due to their easy,

effective and safe dietary administration in a wide

range of concentrations without harmful side effects

(Cadenas and Cadenas, 2002). Furthermore, selenium

(Se) is an essential trace element for mammalian cells.

It has regulatory functions in cell growth, cellular

death and modulates signal transduction in various

cells (Park et al., 2000). Se as an essential constituent

of GSH-Px plays an important role in scavenging ROS.

It is known that ROS and GSH are closely involved in

Se metabolism and bioactivity of various cells (Kim et

al., 2004).

Liver is one of the main target organs to respond in

endotoxemia, detoxification of endotoxin in liver is

considered to be mediated mainly by the

reticuloendothelial system (RES), particularly Kupffer

cells (Fukuda et al., 2004). Despite the ability of liver

to detoxify LPS, marked morphological and

biochemical alterations can occur in hepatic tissues

exposed to vast amount of LPS (Freudenberg and

Galanos, 1992 and Hewett and Roth, 1993). Therefore,

the objective of this study is to focus light on defense

antioxidant system enhancement using different

antioxidant regimens therapy in endotoxemic rat liver.

MATERIALS AND METHODS: Animals:-

Eighty male albino rat of the Spraque-Dawley strain,

weighing 180-200g were supplied by National

Organization for Drug Control and Research animal

house. They were housed in wire cages with natural

ventilation and illumination and allowed free water and

standard diet.

LPS challenge:-

Bacterial endotoxin (LPS) from Escherichia coli, stero-

type 055-B5 was purchased as lyophilized powder

from Sigma Chemical Company; dissolved in pyrogen

free saline (0.9%) to a concentration of

1mg/0.5 ml and administered intraperitoneally at a

single dose of 1mg/Kg body weight. This dose of LPS

was chosen in agreement with previous studies on rats

showing that intraperitoneally injection of 1mg/kg LPS

(E. coli 0111:B4) produced a pronounced liver injury

24 hr. post-challenge with no apparent mortality

(Suntres, 2003).

Drug treatment:-

Alfa lipoic acid: ALA was supplemented as thoitic

acid and was kindly donated by EVA Pharm Co.,

Egypt. Dose chosen for this study was 60 mg/kg which

is a suitable antioxidant dose as reported by recent

study of El-Halwagy and Hassanin (2006).

Antox drug: Antox was purchase form local pharmacy

and it is produced by Arab Company for

pharm.&medical plant Mepaco-Egypt. Each tablet

contains: Selenium (50.00 mcg), Ascorbic acid (100.00

mg), Vitamin E (30.00 mg), Vitamin A acetate

(5.54mg) and Medical yeast (105.00 mcg). The

therapeutic doses for rat were (4.5 mcg /kg, 9 mg /kg,

2.7 mg /kg, 0.5 mg /kg and 9.45 mcg /kg , respectively)

selected according to Paget and Barnes, 1964.

Experimental design:

Animals were randomly assigned into eight main

groups, each one comprises of ten rats.

Group I: Received an i.p. injection of pyrogen free

saline (0.9%) and served as control group.

Group II: Received a single i.p dose of LPS (1mg/kg

body weight).

Group III: Received ALA, daily oral dose, for seven

days treatment period.

Group IV: Received a therapeutic Antox daily oral

dose, for seven days treatment period.

Group V: Animals intoxicated with a single dose of

LPS (1mg/kg body weight) 2hr. prior to the beginning

of receiving a daily ALA oral dose, for seven days

treatment period.

Group VI: Animals intoxicated with a single dose of

LPS (1mg/kg body weight) 2hr. prior to the beginning

of receiving a therapeutic Antox daily oral dose, for

seven days treatment period)

Group VII: Animals received an oral daily ALA acid

dose, for successive seven days treatment period, and

then the animals were intoxicated with a single dose of

LPS (1mg/kg body weight).

Group VIII: Animals received a therapeutic Antox

daily oral dose, for successive seven days treatment

period. On the seventh day the animals were

intoxicated with a single dose of LPS (1mg/kg body

weight).

Ten animals were taken from each group after 21 hr.

of the last injection from either LPS or drugs treated

groups, for collecting blood samples and to be scarified

for collecting liver samples.

Blood collection:-

Blood samples were collected from the femoral vein

and drawn by vein puncture into serum separation

tubes allowed to clot for thirty minutes at room

temperature and then centrifuged at 1000 x g and 4ºC

per ten minutes. The collected serum samples were

stored at -80 ◦C for estimation of ALT and AST

activities.


Tissue preparation:- Livers were removed immediately after decapitation

and rinsed with cold ice saline to remove excess blood.

A portion of obtained samples were quickly weighed,

minced and homogenized in ice cold medium as 10 %

w/v homogenate according to the parameter measured.

The homogenates were then centrifuged at 5000x g and

below zero temperature for ten minutes, and the

supernatants were used for the assay of NO, SOD and

GSH-Px.

The MDA level, the end product of lipid

peroxidation, in liver homogenate was measured by

thiobarbituric acid reactive substance (TBARS) assay

according to Simon et al. (1994).The amounts of stable

nitrite, the end product of nitric oxide in liver

supernatant were measured by a colorimetric assay, as

described by Green et al. (1982) based on the Griess

reaction. The concentration of reduced glutathione

(GSH) in liver homogenate was determined according

to the method of Beutler et al. (1963). Superoxide

dismutase (SOD) activity was determined in liver

supernatant following the method of Marklund and

Marklund (1974). Glutathione peroxidase activity was

measured using a technique based on Paglia and

Valentine (1967). The activities of serum ALT and

AST were estimated according to the method of

Bergmeyer et al., 1977 using Stanbio reagent Kits

(USA). The protein content of liver tissues were

determined according to Bradford (1976).The

absorbance of different assay were read using a

shimadzu UV-1601 spectrophotometer.

The data obtained from the biochemical analysis of

different groups are represented in figures as Mean ±

Standard error (X ± SE). The significance of the

difference between the groups was calculated by one-

way analysis of variance (ANOVA) followed by

Duncan and Dunnett t (2-sided) at p<0.05 (Winter et

al., 1991) using the Spss-PC computer software

package version 10.

RESULTS: Rats challenged with LPS revealed a highly significant

increase (P<0.05) in MDA level as compared to control

group (61%). Antox and ALA singly- treated groups

showed different degree of decreases, where the

recorded value difference reached minimal among

Antox treated group (-32.5%) against control group.

All combined treatments reflected significant

reductions versus LPS-treated group treatment. Post

treatment with Antox recorded the lowest MDA level

in comparison to LPS-group (-49.2%) as shown in

figure (1).

Nitric oxide levels revealed some what the same

MDA profile, where LPS - treated group showed

significant increase (P<0.05) compared to the control

group (53.9%). Also, Antox individually treated group

recorded the lowest NO level among all treated groups

(-29.8%).On one hand, the treated groups received LPS

prior to the antioxidants treatment showed significant

decrease in response to LPS-treated group. On the

other hand, rats given daily antioxidants dose before

endotoxin challenge reflected non-significant changes

to LPS- treated group as shown in figure (2).

Figure (3) showed the hepatic concentration of GSH

in different animal groups under investigation. Animals

received LPS (1mg/Kg body weight.) showed

significant decrease (P< 0.05) in GSH level in

comparison with control. Antioxidants treatments

reflected significant increase in hepatic GSH level as

compared to control group. Post treatment of LPS-

injected animals with ALA and drug preparation

(Antox) showed significant increase in GSH level by

45.6 % and 51.3 %, respectively as compared to LPS-

treated group. Pretreatment of LPS- injected animals

with ALA and drug preparation (Antox) reflected non

significant increase in this parameter in comparison to

LPS- treated group.

The activity of hepatic SOD was declined

significantly (P<0.05) due to LPS injection when

compared to control group. ALA and Antox treatment

induced slightly increase in its activity as compared to

control. All combined treatments induced different

patterns of significant increases (P< 0.05) as compared

to LPS-treated group. Daily supplementation of ALA

prior to endotoxin challenge showed the best result to

overcome the decrease in SOD activity induced by

endotoxin as shown in figure (4).

As shown in figure (5) LPS administration reflect a

decline in the activity of hepatic GSH-Px in rat versus

the control group. On the other hand, antioxidants

individually treatments reflected significant increase in

hepatic GSH-Px activity compared to control one. All

combined antioxidant treatments induced significant

increase (P<0.05) as compared to LPS – treated group.

Figure (6) showed the activity of the serum ALT in

different animal groups. Animals received LPS

(1mg/Kg) showed significant increase P<0.05 in ALT

activity by 137.24 % in comparison with control.

Individually antioxidants treatments reflected

significant decreases in its activity as compared to

control one. Pretreatment of LPS- injected animals

with ALA and drug preparation (Antox) showed

significant decrease in ALT activity recorded (-31.01%

and -44.95%) respectively as compared to LPS–treated

group. The other post treatment of LPS- injected

animals with ALA and drug preparation (Antox)

reflected the same change in this parameter in

comparison to LPS- treated group with less degree than

pre treatment of LPS- injected animals with ALA and

drug preparation (Antox).

The activity of serum AST was significant increased

due to LPS injection than that recorded for control

group. ALA and Antox treatment induced slight

decreases in its activity as compared to control. All

combined treatments induced non significant changes

compared to both control and LPS –treated group (P<

0.05). Daily supplementation of antioxidants prior

endotoxin challenge showed more protective feature

than curative treatment groups in response to LPS-

treated group as shown in figure (7).


DISCUSSION: Systemic administration of LPS generally leads to its

rapid accumulation in kupffer cells, which are the

major cell type for the detoxification of endotoxin

(Ruiter et al., 1981 and Hewett and Roth, 1993). The

interaction of LPS with these hepatic phagocytes is

associated with their activation, and subsequently the

release of mediators that play a central role in the

pathogenesis of liver injury. These mediators include

ROS, NO and degradative enzymes as well as pro-

inflammatory mediators, such as TNFα. (Jaeschke et

al., 1996; Jaeschke, 2000 and Fukuda et al., 2004).

The present study showed that i.p. injection of LPS

caused increased levels of hepatic MDA, NO and the

activities of serum ALT, AST. It is possible that,

administration of LPS resulted in an increase in lipid

peroxidation reaffirming the involvement of ROS,

increase in NO level suggestive of activation of the

inflammatory response, and increase in serum ALT and

AST activities, indicative of liver injury, which run in

parallel with the observation of Hirano (1996) and

Victor et al. (2004 & 2005).

The enhanced production of MDA observed in our

study by LPS injection is in agreement with the in vivo

study of Kunimoto et al. (1987) and Mostafa et al.

(1994) and in vitro study of Sewerynek et al. (1995).

Several mechanisms were postulated to explain this

phenomenon. One depends on the enhanced release of

cytokines that promote the formation and release of

ROS and NO from microglial cells (Woodroofe, 1995),

and another mechanisms which were based on the

release of excitatory amino acids, aspartate and

glutamate, that induce free radical formation during

their physiological action (Moghaddam, 1993). A third

mechanism was related to the LPS-induced

mobilization of mitochondrial calcium, which in turn,

activates the arachidonic acid cascade that produces

ROS (Richter and Kass,1991).It has been suggested

that both superoxide anion and hydroxyl radical are

involved in the development of lipid peroxidation

during oxidative stress (Chiang et al.,2005).

A growing body of evidence suggests that sustained

production of NO resulting from up-regulation of

inducible NO synthase after LPS challenge may cause

hepatocellular injury, either directly or indirectly by

forming reactive nitrogen intermediates (Taylor et al.,

1998 and Li and Billiar, 1999). These finding run

parallel with our results where significant increase in

NO level was caused by LPS injection and this increase

was accompanied by a significant increase in serum

AST and ALT activities, which give good indication of

liver injury.

As reported by Duval et al. (1996) LPS can also

cause inducible NO synthase expression in kupffer

cells and hypatocytes of the liver. Consequently, there

is a potential for large amounts of NO to be generated

in the liver during sepsis; this could impair hepatic

function by directly injuring cells (Darley-Usmar et al.,

1995 and Li and Billiar, 1999). Furthermore, selective

inhibition of NO synthesis from inducible NO synthase

lessens the degree of oxidant stress, suggesting that

inducible NO synthase derived NO is a major player in

the development of oxidant stress after LPS

administration in the kidney ( Zhang et al.,2000 a) and

liver ( Zhang et al.,2000 b).

As regards the GSH, the results of the present study

showed a significant decline in GSH content of LPS-

treated rats. The fall in hepatic GSH content following

LPS injection is compatible with another similar study

by Mostafa et al. (1994) and Victor et al. (2003). As

recorded by Carbonell et al. (2000) and Victor et

al.(2003) the increased oxidative stress depletes

cellular stores of antioxidants such as GSH and vitamin

E. Moreover, in a rat LPS endotoxic shock model,

oxidative stress was apparent, with decreased plasma

antioxidant capacity, potentiated by depletion of liver

GSH (Carbonell et al., 2000 and Hsu et al., 2004).

Data obtained in the present work also disclosed a

significant reduction in the activity of hepatic SOD in

LPS-treated rats. These results coincide with those of

several investigators who noticed that oxidative stress

in rats induced by LPS resulted in reduced SOD

activity in liver (El-Sayed et al., 2004); kidney (Kanter

et al., 2005) and blood (Hsu et al., 2004 and Chiang et

al., 2005). Conversely, Ben-Shaul et al. (2001)

recorded that, in heart the activities of both cytosolic

and mitochondrial SOD enzymes were significantly

increased approximately by 20% in the LPS- treated

group.

Administration of ALA to rats prior to or after LPS

challenge remarkably decreased hepatic MDA level,

and conversely increased the antioxidant enzymes

activity (GSH, SOD, and GSH-Px) as compared with

LPS- treated group. These results agree with the

previous results obtained by Suntres (2003) and El-

Halwagy and Hassanin (2006), who recorded the role

of ALA in reduction oxidative stress.

It has been demonstrated that ALA, due to its dithiol

nature, can scavenge a number of ROS, including

hydroxyl radical, superoxide anion, and alkoxy radicals

(Biewenga et al., 1997 and Bustamante et al.,

1998).The reduction of LPS-induced lipid peroxidation

by ALA are also evidence to suggest that this

antioxidant, and perhaps its metabolite, might act as a

potent radical scavenging system.

The inhibition of free radicals-initiated lipid

peroxidation by ALA may be achieved via activation

of the enzymatic defense mechanism and reduced NO

production in LPS- treated rats. Mechanisms involved

in antioxidation including enzymatic (SOD) and non-

enzymatic (GSH) defense components (Halliwell and

Gutteridge, 1989 and Iszard et al., 1995). Our results

are in agreement with these observations, where dietary

supplementation of ALA improved the antioxidant

system as indicated by increased GSH, SOD and GSH-

Px contents.

Malarkodi et al. (2003) postulated that ALA helps to

overcome the oxidative stress by increasing the GSH

status which in turn exhibits increased free radical

scavenging property. In addition, Packer et al. (1995)

reported that ALA regenerates the glutathione pool by

reduction of oxidized glutathione. According to Van

der Laan et al. (1997) the antioxidants can shorten the

repair period for tissue injury caused by oxidative

stress.


The present study also declares that LPS administration

in rats resulted in a significant increase in NO level

which was attenuated by ALA treatment. Although the

mechanisms by which ALA attenuated the LPS

increases in NO can not be delineated from the results

of this study. It is possible that, the antioxidant might

exert its protective effect by down regulating the

expression of inducible NO synthase. Results from

studies examining the role of ALA on different models

of oxidant- induced liver injury revealed that, the

antioxidant was able to decrease the synthesis of NO

by preventing the up-regulation of inducible NO

synthase (Marley et al., 1999 and Suntres, 2003).

Another explanation for the reduction in NO levels

might be due to the direct scavenging effect of NO by

the sulphydryl groups of ALA (Burkart et al., 1993 and

Biewenga et al., 1997).

According to the present data, it is clear that,

combined supplementation of Antox either prior to or

after LPS challenge induced marked significant

reduction in hepatic MDA, NO levels and serum AST,

ALT activities, that was reflect the role of Antox to

overcome the oxidative stress and liver injury induced

by LPS challenge. These results accompanied by

improvement in the activity of antioxidant enzymes,

GSH, SOD and GSH-Px in Antox supplemented

groups as compared to the respective non-

supplemented one. Post- vitamin treatments were found

more effective in combating stress induced pro-

oxidant change than pre –vitamin treatments.

Based on these results, it is proposed that, Antox

treatment maintains the liver GSH within the normal

range and may have an inhibitory effect on the

generation of ROS (Jones, 1995). Similar to our results,

antioxidant supplementation has proven to be

beneficial in decreasing the oxidative stress induced by

endotoxin in a variety of tissues (Cadenase et al., 1998

and Kanter et al., 2005).

Antox contains three main antioxidant vitamins (C, A

and E) together with selenium. Vitamin C is an

important dietary antioxidant; it significantly decreases

the adverse effect of reactive species such as reactive

oxygen and nitrogen species that can cause oxidative

damage to macromolecules such as lipids, DNA and

proteins, which are implicated in chronic diseases

including cardiovascular, stroke, cancer,

neurodegenerative diseases and cataractogenesis

(Halliwell and Gutteridge, 1999). A potential role for

the antioxidant micronutrients vitamins A and C in

modulating oxidative stress generated by restrained

stress may determined their clinical usefulness as

supplemental nutritional therapeutic agent in disorders

affecting free radical metabolism.

It has been reported that, vitamin A and vitamin C

either individually or in combination are reported to

act as an effective antioxidant of major importance for

protection against diseases and degenerative processes

caused oxidative stress (Olas and Wachowicz, 2002

and Kanter et al., 2005).

The results obtained by Pinelli-Saavedra (2003) and

Das et al. (2004), postulated that vitamin E improved

the immune system by unknown ways in addition to its

antioxidant properties, it may also exhibit immuno-

modulator effect. Moreover, Jones (1995) suggested

that, the protective effect of vitamin E may be due to

its lipophilic antioxidant property which may induce

reduction of membrane lipid peroxidation and lipid

peroxide formation. Therefore vitamin E can scavenge

ROS, exerting a membrane stability effect and

maintaining hepatic cell management of oxidative

stress due to LPS administration (El-Sayed et al.,

2004).

In addition, selenium (Se) is an essential component

of GSH-Px, which is an important enzyme for process

that protects lipids in polyunsaturated membranes from

oxidative degradation (Barceloux, 1999). The results of

Sakaguchi et al. (2000) clearly demonstrated that lipid

peroxide level was markedly increased in the livers of

Se-deficient rats 18h after endotoxin injection

compared with those in the Se-adequate diet group

given endotoxin. The mechanism responsible for the

enhanced lipid peroxide formation is Se-deficient rats

given endotoxin was assumed to be as follows Se is a

component of GSH-Px, which catalyzes the reduction

of hydrogen and lipid peroxides via oxidation of GSH

(Mannervik, 1985). Thus, Se-deficiency would lead to

low GSH-Px, and in turn would lead to accumulation

of lipid peroxides. Sakaguchi et al. (2000) indicated

that Se plays a significant role, at least in part, in liver

injury caused by free radical generation in

endotoxemia.

It is possible that the preventive effect of Se on NO

and ROS production in endotoxemia is due to the

increased of GSH-Px activity (Asahi et al., 1995 and

Kim et al., 2004). Moreover, Kim and Stadtman (1997)

and Park et al. (2000) recorded that Se attenuates LPS -

induced oxidative stress through modulation of P38

MAPK and NF-kB signaling pathways. Several studies

such as Reddy et al. (1992) and Kheir-Eldin et al.

(2001) proved that co-administration of vitamin E with

Se gives a much better antioxidant effect than vitamin

E alone.

In conclusion, the results of the present study

indicated that treatment with alpha lipoic acid or Antox

were effective in reducing LPS-induced hepatic

oxidative stress, as evidenced by quenching free

radicals and elevation of the antioxidant systems.

Antox which contain vitamins (C, A and E) with

selenium produced the best results, and post-vitamin

treatments were found more effective in combating

stress induced pro-oxidant changes than pre-vitamin

treatments. Therefore, our results are encouraging for

its use as a curative agent of endotoxemia rather than

protective agent.


Figure (1) : The effect of different treatments in hepatic MDA level in endotoxemic rats

* significant versus control group at P<o.o5

♥ significant versus LPS group at P<o.o5

Figure (2) : The effect of different treatments in hepatic NO level in endotoxemic rats



Figure (3) : The effect of different treatments in hepatic GSH level in endotoxemic rats



0

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♥ *

* *

♥

* * * ♥ ♥


Figure (4) : The effect of different treatments in hepatic SOD activity in endotoxemic rats



Figure (5) : The effect of different treatments in hepatic GSH-Px activity in endotoxemic rats


♣significant versus control & LPS group at P<o.o5

Figure (6) : The effect of different treatments in serum GPT activity in endotoxemic rats


♣significant versus control & LPS group at P<o.o5

0

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40

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U/L


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♣ ♣ ♣ ♣

♥ ♥ ♥ ♥ *

* * *

♣ ♣ ♣ ♣


Figure (7) : The effect of different treatments in serum GOT activity in endotoxemic rats



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0

50

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.التاثير الوقائى لمضادات الشوادر الحرة فى التسمم الناتج عن التوكسين البكتيرى

زكي ، لبني حسنين ةوفاء حسن ، نشو

الهيئة القومية للرقابة و البحوث الدوائية

مع السلينيوم( يمكن C, E, A تهدف هذه الدراسة إلى إكتشاف ما إذا كان كال من حمض ألفاليبويك وعقار اآلنتوكس ) بما يحتويه من فيتامين

( المعروف بإ طالقه للشقائق الحرة. LPS) أن يمنع أكسدة الدهون ومن ثم أصابة الكبد عند اآلصابه بالتوكسين البكتيرى

( إلى ثمانى مجموعات )عشره جرذان لكل مجموعه( كاألتى: جرام ٢٢٠ -١٨٠) تم تقسيم ثمانين من ذكور الجرذان من ساللة سبراج دولى

المجموعة الضابطة. -١

بالتوكسين البكتيرى.نى مجم/كجم من وزن الجسم داخل التجويف البريتو ١المجموعة المصابة بجرعة واحدة مقدارها -٢

ولمدة سبعة مجم/ كجم من وزن الج٦٠المجموعة المعالجة عن طريق الفم بجرعة مقدارها -٣ أيام متتالية بحامض ألفا سم مرة واحدة يوميا

ويك.ليب

لمدة سبعة أيام متتالية بعقار اآلنتوكس. -٤ المجموعة المعالجة عن طريق الفم مرة واحدة يوميا

المجموعة المصابة بجرعة واحدة من التوكسين البكتيرى ثم بعد االصابة بساعتين عولجت بحامض ألفا ليبويك لمدة سبعة أيام متتالية. -٥

لتوكسين البكتيرى ثم بعد االصابة بساعتين عولجت بعقار اآلنتوكس لمدة سبعة أيام متتالية.المجموعة المصابة بجرعة واحدة من ا -٦

المجموعة المعالجة بحامض ألفا ليبويك لمدة سبعة أيام متتالية وفى اليوم السابع أصيبت بجرعة واحدة من التوكسين البكتيرى. -٧

السابع أصيبت بجرعة واحدة من التوكسين البكتيرى. الية وفى اليومالمجموعة المعالجة بعقار اآلنتوكس لمدة سبعة أيام متت -٨

بعد معالجة المجموعات المختلفة أخذ من كل مجموعة عشرة جرذان بعد احدى وعشرون ساعة من أخر حقن ليوخذ منها عينات الدم ثم تذبح بعد

ينات الكبد.ذلك للحصول على ع

لقد تسبب اعطاء التوكسين البكتيرى الى زيادة ذات داللة احصائية فى نشاط انزيمى النقل االمين اآلسبرتات والآلالنين أمينوترانس

( MDA) لى زياده تركيز مالون داى ألدهايدإ ( مشيرة بذلك الى الضرر الواقع على أنسجه الكبد كما دلت النتائج أيضاAST,ALTأمينيز)

( بشكل ملحوظ مما يدل على زيادة أكسدة الدهون. كما أدى حقن التوكسين أيضا الى نقص فى فاعلية اآلنزيمات المختصة NO) وأكسيد النيتريك

( وقد وجد أن إعطاء حامض GSH-Px( ومؤكسد الجلوتاثيون)SOD( والديسميوتيز فوق اآلكسدى)GSHباآلكسده مثل الجلوتاثيون المختزل)

, مما يثبت أن إلى تحسن فى قيم هذه المتغيرات سواء بعد أو قبل اآلصابة بالتوكسين البكتيرى قد أدى وعقار اآلنتوكس كال على حدى يبويكألفا ل

لكل من حامض ألفاليبويك وعقار اآلنتوكس دور عالجى ووقائى مضاد لآلكسدة لتأثير هذا التوكسين.

Prophylactic Effect Of Antioxidants As Free Radical Scavengers In Endotoxemia.

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