AN IN VITRO APPROACH TO ASSESS THE NEUROTOXICITY OF VALPROIC ACID-INDUCED OXIDATIVE STRESS IN CEREBELLUM AND CEREBRAL CORTEX OF YOUNG RATS
AN IN VITRO APPROACH TO ASSESS THE NEUROTOXICITY OF VALPROIC ACID-INDUCED OXIDATIVE STRESS IN CEREBELLUM AND CEREBRAL CORTEX OF YOUNG RATS
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DOI：
10.1016/j.neuroscience.2012.08.060
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发表时间：
2012-12-06
期刊：
影响因子：
3.3
通讯作者：
Parvez, S.
中科院分区：
文献类型：
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作者：
Chaudhary, S.;Parvez, S.
丙戊酸（VPA）是一种支链短链脂肪酸，通常用作抗癫痫药物和情绪稳定剂。VPA是一种相对安全的药物，但其在较高浓度下的使用与特异质神经毒性相关。涉及大脑皮层和小脑的研究可以阐明支链脂肪酸（如VPA）诱导的神经毒性是否由氧化应激介导。本研究以幼年大鼠大脑皮层和小脑为模型，探讨丙戊酸钠的神经毒性作用。氧化应激指标，如脂质过氧化（LPO）和蛋白质羰基（PC）的形成进行了评估，以可视化是否突破第一道防线。氧化应激标志物、LPO和PC水平显著升高。非酶抗氧化剂的作用也被证明为还原型谷胱甘肽（GSH）和非蛋白巯基活性（NP-SH）的显著消耗，但总巯基（T-SH）和蛋白巯基（P-SH）的浓度没有显著增加或减少。VPA还显示小脑和大脑皮层中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）的活性显著降低。黄嘌呤氧化酶（XO）的活性也有显著升高。对乙酰胆碱酯酶（AChE）和钠钾ATP酶（Na+，K+-ATP酶）活性降低，单胺氧化酶（MAO）活性升高的神经毒性生物标志物进行了研究。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破译支链脂肪酸诱导的神经毒性的细胞和分子机制。(C)2012年IBRO。由爱思唯尔有限公司出版。保留所有权利。
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.