Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of some phytochemical agents against valproic acid-induced hepatotoxicity in rats. Caffeic acid (50 mg/kg/day; p.o), cinnamic acid (50 mg/kg/day; p.o) and ellagic acid (60 mg/kg/day; p.o) were administered for 21 days, and VPA (250 mg/kg/day; i.p.) was given starting from the 8th day, for 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyl transferase (Þ-GT). In addition, it significantly increased malondialdehyde (MDA) and nitric oxide (NO) along with a marked decline in reduced glutathione content (GSH). At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, tumor necrosis factor-Ü production (TNF-Ü), alpha smooth muscle actin (Ü-SMA) and nuclear factor-kappa B (NF-mB) expression. These results were confirmed by histopathological and immunohistochemical examination. Treatment with caffeic acid, cinnamic acid or ellagic acid markedly attenuated valproic acid-induced injury by suppression of oxidative/nitrosative stress and inflammation, amendment of antioxidant defenses, as well as improvement of hepatocellular histological features

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