Vinpocetine Alleviates Valproic Acid-Induced Hepatotoxicity and Neurotoxicity Through Activation of cAMP and PI3K/AKT/CREB Pathway in Rats

Abstract

Valproic acid (VPA) is a frequently prescribed treatment for many psychiatric disorders, particularly for epilepsy. However, it has been associated with possible side effects including hepatotoxicity and neurotoxicity. The present study investigated the protective effect of vinpocetine (Vinpo) against VPA-induced hepatotoxicity and hippocampal neurotoxicity in rats. Vinpo (5 and 10 mg/kg/day; p.o) was given for 14 days, with/without VPA (500 mg/kg/day; p.o) in adult male Wistar rats. VPA showed marked increase in hepatic and hippocampal MDA levels with increased liver function enzymes as well as a marked decline in serum total antioxidant capacity (TAC). Simultaneously, VPA administration resulted in a significant reduction in cAMP, cAMP response element binding protein (CREB), and PI3K/AKT protein levels in liver tissue and hippocampus. These results were confirmed by histological degenerative changes in both tissues. VPA also associated with increased hepatic and dentate gyrus nuclear factor kappa (NF-κB) immunoexpression with increased Glial fibrillary acidic protein (GFAP) expression in the dentate gyrus. Administration of Vinpo markedly attenuated VPA-induced toxicity in rats by its anti-oxidant effect on MDA and TAC levels. Vinpo resulted in a significant increase in the levels of cAMP/CREB and PI3K/AKT in liver and hippocampus tissues, together with significant decrease in NF-κB nuclear expression. Vinpo ameliorated astrogliosis as indicated by reduction in the expression of GFAP. Vinpo exerted a hepatoprotective and neuroprotective role against VPA-induced toxicity by cAMP and PI3K/AKT dependent activation of CREB and this hold a promise as a safe and effective adjuvant while treating psychiatric patients with VPA.