Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation
Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation
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DOI：
10.1016/j.neuroscience.2006.11.065
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发表时间：
2007-03-02
期刊：
影响因子：
3.3
通讯作者：
Rho, J. M.
中科院分区：
文献类型：
--
作者：
Maalouf, M.;Sullivan, P. G.;Rho, J. M.
增加血清酮水平的饮食方案，如热量限制和生酮饮食，为许多急性和慢性神经系统疾病提供了强大的保护。然而，其潜在机制仍不清楚。以前的研究表明，生酮饮食可能会降低大脑中的自由基水平。因此，一种可能性是酮可能通过抗氧化活性介导神经保护。在本研究中，我们研究了酮β-羟基丁酸和乙酰乙酸对急性分离的大鼠新皮层神经元谷氨酸兴奋性毒性的影响，使用细胞电生理和单细胞荧光成像技术。此外，我们探讨了酮对暴露于高水平钙的急性分离线粒体的影响。β-羟基丁酸和乙酰乙酸（1 mM）的组合减少神经元死亡，并防止10 μ M谷氨酸诱导的神经元膜特性的变化。酮也显着降低线粒体产生的活性氧和相关的兴奋性毒性变化，通过增加线粒体呼吸链中的NADH氧化，但不影响内源性抗氧化剂谷胱甘肽的水平。总之，我们证明酮通过增加NAD（+）/NADH比值和增强新皮层神经元线粒体呼吸来减少谷氨酸诱导的自由基形成。这种机制可能部分地通过在氧化应激面前恢复正常的生物能量功能来促进酮的神经保护活性。(c)2007年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Dietary protocols that increase serum levels of ketones, such as calorie restriction and the ketogenic diet, offer robust protection against a multitude of acute and chronic neurological diseases. The underlying mechanisms, however, remain unclear. Previous studies have suggested that the ketogenic diet may reduce free radical levels in the brain. Thus, one possibility is that ketones may mediate neuroprotection through antioxidant activity. In the present study, we examined the effects of the ketones beta-hydroxybutyrate and acetoacetate on acutely dissociated rat neocortical neurons subjected to glutamate excitotoxicity using cellular electrophysiological and single-cell fluorescence imaging techniques. Further, we explored the effects of ketones on acutely isolated mitochondria exposed to high levels of calcium. A combination of beta-hydroxybutyrate and acetoacetate (1 mM each) decreased neuronal death and prevented changes in neuronal membrane properties induced by 10 mu M glutamate. Ketones also significantly decreased mitochondrial production of reactive oxygen species and the associated excitotoxic changes by increasing NADH oxidation in the mitochondrial respiratory chain, but did not affect levels of the endogenous antioxidant glutathione. In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD(+)/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.