AN IN VITRO APPROACH TO ASSESS THE NEUROTOXICITY OF VALPROIC ACID-INDUCED OXIDATIVE STRESS IN CEREBELLUM AND CEREBRAL CORTEX OF YOUNG RATS

Valproic acid (VPA), a branched short-chain fatty acid, is generally used as an antiepileptic drug and a mood stabilizer. VPA is a relatively safe drug, but its use in higher concentrations is associated with idiosyncratic neurotoxicity. Investigations involving cerebral cortex and cerebellum can shed light on whether neurotoxicity induced by branched chain fatty acids like VPA is mediated by oxidative stress. The aim of our investigation was to evaluate the neurotoxic potential of VPA by using preparation of cerebral cortex and cerebellum of young rats as an in vitro model. Oxidative stress indexes such as lipid peroxidation (LPO) and protein carbonyl (PC) formation were evaluated to visualize whether the first line of defence was breached. The levels of oxidative stress markers, LPO and PC were significantly elevated. Non-enzymatic antioxidants' effect was also demonstrated as a significant depletion in reduced glutathione (GSH) and non-protein thiol activity (NP-SH), but there was no significant increase or decrease in the concentrations of total thiol (T-SH) and protein thiol (P-SH). VPA also showed significant reduction in the activities of glutathione metabolizing enzymes such as glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and other antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) in cerebellum and cerebral cortex. A significant elevation was also observed in the activity of xanthine oxidase (XO). Some neurotoxicity biomarkers were investigated in which the activity of acetylcholinesterase (AChE) and sodium potassium ATPase (Na+, K+-ATPase) was decreased and monoamine oxidase (MAO) was increased. These results indicate that VPA induces oxidative stress by compromising the antioxidant status of the neuronal tissue. Further studies are required to decipher the cellular and molecular mechanisms of branched chain fatty acid-induced neurotoxicity. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.