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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 118 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 119 the tubules when compared to valproic acid treated group and Valproic acid plus NAC group although edema was still present.Conclusion 120 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. |