Valproic Acid Induced Neurotoxicological Manifestations and its Mitigation by Melatonin in Rat Brain Synaptosomes

Abstract

Background and aims: A short branched chain fatty acid, valproic acid (VPA), has been used worldwide for decades in the intervention of seizure disorders, neuropathic pain and migraine. However, several adverse effects of VPA have been reported over the years. The aim of our investigation was to evaluate the adverse effects of VPA on synaptic functions by using synaptosomal preparation of rat brain as an in vitro model and the possible protective role of melatonin against VPA induced neurotoxicity. Melatonin is an antioxidant and scavenger of free radicals secreted by the pineal gland.

Methods: In the present investigation, synaptosomes prepared from rat brain were co-treated with melatonin (10 μmol) and VPA (5 mmol) for 2 h under in vitro conditions.

Results: In this study, co-treatment of melatonin with VPA significantly restored the elevated levels of lipid peroxidation (LPO) and protein oxidation. In addition, melatonin prevented VPA induced alterations in non-enzymatic antioxidant defence reduced glutathione (GSH) and activities of synaptosomal integral enzymes such as AChE, Na⁺, K⁺ -ATPase and MAO. A significant increase in the generation of reactive oxygen species (ROS) induced by VPA was observed and melatonin ameliorated elevated level of ROS generation. Moreover, the enhanced level of NO and diminished activity of synaptosomal mitochondrial membrane potential was completely prevented by melatonin treatment.

Conclusion: Our results corroborate the use of melatonin as a nutraceutical and mitigatory agent against VPA induced neurotoxicity in brain synaptosomes.

Keywords: Melatonin; Neurotoxicity; Oxidative stress; Synaptosomes; Valproic acid.