الفهرس 
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Abstract
VPA is one of the most widely prescribed antiepileptic drugs and is regarded
as a first choice for most forms of seizures. It is associated with a number of
adverse effects like pancreatitis, liver toxicity, teratogenicity and cutaneous
reactions.
ROS formation, lipid peroxidation, defect in cellular antioxidant enzymes,
and glutathione depletion is documented in different experimental models of VPA
hepatotoxicity. Hence, NAC which preserve glutathione molecule in its reduced
form; GSH, might provide protection against VPA-induced hepatotoxicity.
VPA is associated with decreased carnitine levels and occasionally with true
carnitine deficiency by depleting carnitine stores, especially with high-dose or
long-term therapy through several mechanisms, particularly reduction in tubular
reabsorption of both free carnitine and acyl carnitine during VPA treatment. Lcarnitine supplementation in patients receiving VPA may result in subjective and
objective improvements and to prevent valproic acid induced hepatotoxicity.
This research aimed to study the effect of VPA on the liver and testes in
adult male albino rats both by comparing between the protective effect of Nacetylcysteine and L-carnitine on hepatic and testicular toxicity induced by VPA
administration.
This is an experimental study, conducted on sixty adult male albino rats
weighing (185-210 gm) in accordance with the guide of the care and use of
laboratory animals approved by the Ethical Committee of Sohag University, the
study continued along 45 days and rats was divided into six groups randomly eachSummary
117
group contains 10 rats received treatment dissolved in distilled water and given
orally by gavage tube:
➢ group I: received the solvent “distilled water”.
➢ group II: received NAC 150 mg/kg/day dissolved in distilled water
➢ group III: group which received L-carnitine 500 mg/kg/day.
➢ group IV: received VPA 400 mg/kg/day.
➢ group V: received VPA 400 mg/kg and NAC 150 mg/kg/.
➢ GroupVI: received VPA 400 mg/kg and L-carnitine 500 mg/kg/day
At the end of the study “45 days”, rats were sacrificed.
.
This study revealed that there was high significant difference between group I and
group IV as regard ALT, AST and serum testosterone hormone in the form of
marked increase in ALT and AST and marked decrease in serum testosterone
hormone.
There was high significant difference between group IV and group V in the
form of significant decrease in ALT and AST and significant increase in serum
testosterone hormone.
There was high significant difference between group IV and group VI in
the form of highly significant decrease in ALT and AST and highly significant
increase in serum testosterone hormone.
There was high significant difference between group V and group VI
showing that ALT and AST were significantly lower in group VI in comparison
with group V while serum testosterone hormone was significantly higher in group
VI in comparison with group V.Summary
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There was no significant difference between group I, II and III as regard
ALT, AST or serum testosterone hormone.
These results were also confirmed histopathologically, as VPA treated group
revealed disorganization of hepatic architecture, large cell change, inflammatory
cell infiltrate, marked dilatation and congestion of central vein with foci of
inflammatory cell infiltrate and hepatic degeneration. NAC plus VPA treated group
showed decreased inflammation with mild hydropic degeneration of hepatocytes
and foci of mild chronic inflammatory cell infiltrate. However, L-carnitine plus
VPA treated group showed preservation of normal appearance of hepatocytes and
marked decrease in congestion when compared to valproic acid treated group and
Valproic acid plus NAC group.
Regarding the testis, VPA treated group revealed disorganization of the
seminiferous tubules, reduced number of spermatogenic cells, diminished number
of layers of spermatogenic cells up to sperms, degenerative changes and
hypocellularity of the seminiferous tubules, interstitial tissue edema and
hemorrhage between the tubules with decreased number of sperms within the
tubular lumen when compared to the control and the antioxidant treated groups.
However, NAC treated group showed more organization of spermatogonic
cells with mild edema and congestion as compared to valproic acid treated group
but small number of sperms within the lumen. On the other side, L-carnitine treated
group revealed preservation of normal structure of seminiferous tubules and nearly
normal spermatogenic cord with increasing number of sperms within the lumen ofSummary
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the tubules when compared to valproic acid treated group and Valproic acid plus
NAC group although edema was still present.Conclusion
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CONCLUSION
Sodium Valporate induces hepatotoxicity and testicular toxicity in high
doses as 400 mg/kg in male albino rats. There is a protective role for both NAC
and L-carnitine when either it is administered with VPA in chronic treatment.
However, L-carnitine has more protective effect than NAC due to its antioxidant
effect against free radicals in addition to correction of L-carnitine deficiency that
occur with chronic VPA administration due to its effect on carnitine metabolism.
Recommendations
1. Further studies about the protective role of:
A. L-carnitine against VPA toxicity on other organs like kidney and brain
could be done.
B. L-carnitine, NAC and other antioxidants against VPA induce organ
toxicity.
C. Combined intake of L-carnitine and NAC against VPA induced organ
toxicity.
D. Antioxidants against different doses of VPA.
E. Study the effect of lower doses of L-carnitine.
F. Compare the results of same doses of L-carnitine and NAC.
G. Compare the protective effect of both NAC and L-carnitine on other
animal species
2. More studies should be conducted on children who are on VPA and study of
the long term protective role of antioxidants.
3. Studies on the effect of antioxidant protective role in cases of acute VPA
toxicity should be done.