ACETYL-L-CARNITINE (ALCAR) PREVENTS HYPOBARIC HYPOXIA-INDUCED SPATIAL MEMORY IMPAIRMENT THROUGH EXTRACELLULAR RELATED KINASE-MEDIATED NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 PHOSPHORYLATION
ACETYL-L-CARNITINE (ALCAR) PREVENTS HYPOBARIC HYPOXIA-INDUCED SPATIAL MEMORY IMPAIRMENT THROUGH EXTRACELLULAR RELATED KINASE-MEDIATED NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 PHOSPHORYLATION
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DOI：
10.1016/j.neuroscience.2009.02.086
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发表时间：
2009-06-30
期刊：
影响因子：
3.3
通讯作者：
Ilavazhagan, G.
中科院分区：
文献类型：
--
作者：
Barhwal, K.;Hota, S. K.;Ilavazhagan, G.
暴露于低压缺氧（一种涉及氧气供应量减少的疾病）已知与氧化应激、神经退行性变和记忆障碍有关。大脑的多因素反应和与之相关的复杂信号通路限制了几种抗氧化剂在改善低压缺氧引起的记忆障碍中的治疗功效。因此，本研究旨在研究乙酰左旋肉碱（ALCAR）的潜力，乙酰左旋肉碱是一种已知的抗氧化剂，据报道可以增强神经营养素介导的生存机制，改善缺氧引起的神经退行性变和记忆障碍。核因子红细胞 2 相关因子 2 (Nrf2) 是一种关键转录因子，参与针对脑损伤和神经系统疾病相关氧化应激的细胞防御机制。该研究旨在了解暴露于低压缺氧后 Nrf2 稳定的机制。结果显示，连续 14 天暴露于低压低氧（7620 m）的 Sprague-Dawley 大鼠的参考记忆受损，但在低氧暴露期间给予 ALCAR 后，这种情况有所改善。该研究还揭示了 Nrf2 通过一种新型酪氨酸激酶 A (TrkA) 受体介导的机制来调节 ALCAR 增强的抗氧化反应。在暴露于低压缺氧期间，使用 ALCAR 还观察到自由基生成、脂质过氧化和蛋白质氧化减少，同时硫氧还蛋白增加和谷胱甘肽水平降低。因此，本研究揭示了 ALCAR 在低压缺氧条件下的治疗潜力，并阐明了该药物的新作用机制。 (C) 2009 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Exposure to hypobaric hypoxia, a condition involving decreased availability of oxygen is known to be associated with oxidative stress, neurodegeneration and memory impairment. The multifactorial response of the brain and the complex signaling pathways involved therewith limits the therapeutic efficacy of several antioxidants in ameliorating hypobaric hypoxia-induced memory impairment. The present study was therefore aimed at investigating the potential of acetyl-L-carnitine (ALCAR), a known antioxidant that has been reported to augment neurotrophin-mediated survival mechanisms, in ameliorating hypoxia-induced neurodegeneration and memory impairment. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor involved in the cellular defense mechanism against oxidative stress related to brain injury and neurological disorders. The study was designed to understand the mechanisms involving Nrf2 stabilization following exposure to hypobaric hypoxia. The results displayed reference memory impairment in Sprague-Dawley rats exposed to hypobaric hypoxia (7620 m) for 14 consecutive days which however improved on administration of ALCAR during hypoxic exposure. The study also revealed Nrf2 regulated augmented antioxidant response on administration of ALCAR which was through a novel tyrosine kinase A (TrkA) receptor-mediated mechanism. A decrease in free radical generation, lipid peroxidation and protein oxidation was also observed along with a concomitant increase in thioredoxin and reduced glutathione levels on administration of ALCAR during exposure to hypobaric hypoxia. The present study therefore reveals the therapeutic potential of ALCAR under conditions of hypobaric hypoxia and elucidates a novel mechanism of action of the drug. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.