Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110 062, India.
Neuroscience. 2012 Dec 6;225:258-68. doi: 10.1016/j.neuroscience.2012.08.060. Epub 2012 Sep 6.
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.
丙戊酸（VPA）是一种支链短链脂肪酸，通常用作抗癫痫药和情绪稳定剂。VPA 是一种相对安全的药物，但在较高浓度下使用与特发性神经毒性有关。涉及大脑皮层和小脑的研究可以阐明像 VPA 这样的支链脂肪酸引起的神经毒性是否是由氧化应激介导的。我们的研究目的是通过使用年轻大鼠大脑皮层和小脑的制备物作为体外模型来评估 VPA 的神经毒性潜力。评估氧化应激指标，如脂质过氧化（LPO）和蛋白质羰基（PC）形成，以观察第一道防线是否被突破。氧化应激标志物，LPO 和 PC 的水平显着升高。非酶抗氧化剂的作用也得到了证明，即还原型谷胱甘肽（GSH）和非蛋白巯基活性（NP-SH）的显着消耗，但总巯基（T-SH）和蛋白巯基（P-SH）的浓度没有显着增加或减少。VPA 还显着降低了谷胱甘肽代谢酶如谷胱甘肽-S-转移酶（GST）、谷胱甘肽还原酶（GR）和谷胱甘肽过氧化物酶（GPx）以及其他抗氧化酶如超氧化物歧化酶（SOD）、过氧化氢酶（CAT）的活性小脑和大脑皮层中的活性。黄嘌呤氧化酶（XO）的活性也显着升高。研究了一些神经毒性生物标志物，其中乙酰胆碱酯酶（AChE）和钠钾-ATP 酶（Na（+），K（+）-ATP 酶）的活性降低，单胺氧化酶（MAO）的活性增加。这些结果表明 VPA 通过损害神经元组织的抗氧化状态诱导氧化应激。需要进一步的研究来阐明支链脂肪酸诱导的神经毒性的细胞和分子机制。
