ACETYL-L-CARNITINE PROVIDES EFFECTIVE IN VIVO NEUROPROTECTION OVER 3,4-METHYLENEDIOXIMETHAMPHETAMINE-INDUCED MITOCHONDRIAL NEUROTOXICITY IN THE ADOLESCENT RAT BRAIN
ACETYL-L-CARNITINE PROVIDES EFFECTIVE IN VIVO NEUROPROTECTION OVER 3,4-METHYLENEDIOXIMETHAMPHETAMINE-INDUCED MITOCHONDRIAL NEUROTOXICITY IN THE ADOLESCENT RAT BRAIN
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DOI：
10.1016/j.neuroscience.2008.10.041
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发表时间：
2009-01-23
期刊：
影响因子：
3.3
通讯作者：
Summavielle, T.
中科院分区：
文献类型：
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作者：
Alves, E.;Binienda, Z.;Summavielle, T.
3，4-亚甲基二氧甲基苯丙胺（MDMA，摇头丸）是一种世界范围内滥用的兴奋剂，具有持续的神经毒性作用，在青少年中流行率很高。MDMA诱导突触前储存囊泡大量释放5-HT，随后进行单胺氧化酶B（MAO-B）代谢，显着增加线粒体水平的氧化应激。L-肉碱及其酯，乙酰-L-肉碱（ALC），促进长链游离脂肪酸穿过线粒体膜的运输，增强神经元的抗氧化防御。在这里，我们展示了ALC对抗MDMA暴露的神经毒性作用的潜力。将青春期雄性Wistar大鼠分为四组：对照盐水溶液，与MDMA溶液等容，i. p.给药; MDMA（4x10 mg/kg MDMA，i.p.）; ALC/MDMA（100 mg/kg ALC，MDMA前30 min，i.p.）和ALC（100 mg/kg，i.p.）。暴露后2周处死大鼠，分析大脑的脂质过氧化、羰基形成、线粒体DNA（mtDNA）缺失以及呼吸链线粒体复合物I（NADH脱氢酶，NDII）和IV（细胞色素c氧化酶，COXI）的DNA编码亚基表达改变。还评估了5-HT和5-羟基吲哚乙酸（5-HIAA）的水平。本研究首次成功证明ALC预处理可在线粒体水平上对MDMA诱导的神经毒性发挥有效的神经保护作用，减少羰基形成，减少mtDNA缺失，改善呼吸链组分的表达，并防止大鼠脑中几个区域5-HT水平的降低。这些结果表明ALC应用于预防和治疗神经退行性疾病的潜在益处。(C)2009年美洲土著人民研究所。由爱思唯尔有限公司出版。保留所有权利。
3,4-Methylenedioximethamphetamine (MDMA, ecstasy) is a worldwide abused stimulant drug, with persistent neurotoxic effects and high prevalence among adolescents. The massive release of 5-HT from pre-synaptic storage vesicles induced by MDMA followed by monoamine oxidase B (MAO-B) metabolism, significantly increases oxidative stress at the mitochondrial level. L-Carnitine and its ester, acetyl-L-carnitine (ALC), facilitate the transport of long chain free fatty acids across the mitochondrial membrane enhancing neuronal anti-oxidative defense. Here, we show the potential of ALC against the neurotoxic effects of MDMA exposure. Adolescent male Wistar rats were assigned to four groups: control saline solution, isovolumetric to the MDMA solution, administered i.p.; MDMA (4x10 mg/kg MDMA, i.p.); ALC/MDMA (100 mg/kg 30 min of ALC prior to MDMA, i.p.) and ALC (100 mg/kg, i.p.). Rats were killed 2 weeks after exposure and brains were analyzed for lipid peroxidation, carbonyl formation, mitochondrial DNA (mtDNA) deletion and altered expression of the DNA-encoded subunits of the mitochondrial complexes I (NADH dehydrogenase, NDII) and IV (cytochrome c oxidase, COXI) from the respiratory chain. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were also assessed. The present work is the first to successfully demonstrate that pretreatment with ALC exerts effective neuroprotection against the MDMA-induced neurotoxicity at the mitochondrial level, reducing carbonyl formation, decreasing mtDNA deletion, improving the expression of the respiratory chain components and preventing the decrease of 5-HT levels in several regions of the rat brain. These results indicate potential benefits of ALC application in the prevention and treatment of neurodegenerative disorders. (C) 2009 IIBRO. Published by Elsevier Ltd. All rights reserved.