Brain oxidation is an initial process in sleep induction
Brain oxidation is an initial process in sleep induction
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DOI：
10.1016/j.neuroscience.2004.09.057
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发表时间：
2005-01-01
期刊：
影响因子：
3.3
通讯作者：
Inoué, S
中科院分区：
文献类型：
--
作者：
Ikeda, M;Ikeda-Sagara, M;Inoué, S
中枢神经系统活动通常与警觉状态相关联，在清醒时主要活跃，在深度睡眠时主要不活跃。在神经元高活动期间，大量的氧气被用于维持神经元膜电位，随后产生细胞毒性活性氧（ROS）。谷胱甘肽是一种主要的内源性抗氧化剂，是防止ros介导的神经元变性的重要因素。谷胱甘肽也被认为是一种促进睡眠的物质，但睡眠和大脑氧化之间的关系尚不清楚。在这里，我们报告了静脉滴注有机过氧化物t-丁基过氧化氢，浓度低于触发神经变性的浓度（0.1 μ mol/ 100 μ mol/ 10 h），促进大鼠睡眠。此外，向视前/下丘脑前部（POAH）微量注射（2 nmol, 2 mul）或微透析（100 muM, 20 min） t-丁基过氧化氢可诱导睡眠神经调节性物质、一氧化氮和腺苷的释放，而不会引起神经退行性变。n -甲基-d -天冬氨酸受体拮抗剂d(-)-2-氨基-5-磷酸戊酸（d - ap5; 1 mM）共透析可抑制一氧化氮和腺苷的释放，提示谷氨酸诱导的神经元兴奋介导过氧化物诱导的一氧化氮和腺苷释放。事实上，在过氧化暴露期间，使用POAH器官型培养中表达的Ca2+指示蛋白（YC-2.1和线粒体靶向Pericam），可以观察到线粒体中的Ca2+释放和通过n -甲基- d-天冬氨酸受体延迟发作的Ca2+内流。在体外模型中，t-丁基过氧化氢（50 muM）引起树突肿胀，随后是细胞内Ca2+动员，D-AP5 （100 muM）或谷胱甘肽（500 muM）抑制t-丁基过氧化氢诱导的细胞内Ca2+动员，保护POAH神经元免受氧化应激。这些数据表明，在抗氧化系统的控制下，低水平的皮层下氧化可能通过POAH中Ca2+依赖性的睡眠诱导神经调节剂的释放来触发睡眠，因此我们提出，在调节睡眠的神经元回路中，清醒时适度增加的ROS可能是睡眠诱导的初始触发因素。(c) 2004 ibro。Elsevier Ltd.出版。版权所有。
CNS activity is generally coupled to the vigilance state, being primarily active during wakefulness and primarily inactive during deep sleep. During periods of high neuronal activity, a significant volume of oxygen is used to maintain neuronal membrane potentials, which subsequently produces cytotoxic reactive oxygen species (ROS). Glutathione, a major endogenous antioxidant, is an important factor protecting against ROS-mediated neuronal degeneration. Glutathione has also been proposed to be a sleep-promoting substance, yet the relationship between sleep and cerebral oxidation remains unclear. Here we report that i.c.v. infusion of the organic peroxide t-butyl-hydroperoxide at a concentration below that triggering neurodegeneration (0.1 mumol/ 100 mul/10 h) promotes sleep in rats. Also, microinjection (2 nmol, 2 mul) or microdialysis (100 muM, 20 min) of t-butyl-hydroperoxide into the preoptic/anterior hypothalamus (POAH) induces the release of the sleep-inducing neuromodulators, nitric oxide and adenosine, without causing neurodegeneration. Nitric oxide and adenosine release was inhibited by co-dialysis of the N-methyl-D-aspartate receptor antagonist, d(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 1 mM), suggesting that glutamate-induced neuronal excitation mediates the peroxide-induced release of nitric oxide and adenosine. Indeed, Ca2+ release from mitochondria and delayed-onset Ca2+ influx via N-methyl-D-aspartate receptors was visualized during peroxide exposure using Ca2+ indicator proteins (YC-2.1 and mitochondrial-targeted Pericam) expressed in organotypic cultures of the POAH. In the in vitro models, t-butyl-hydroperoxide (50 muM) causes dendritic swelling followed by the intracellular Ca2+ mobilization, and D-AP5 (100 muM) or glutathione (500 muM) inhibited t-butyl-hydroperoxide-induced intracellular Ca2+ mobilization and protected POAH neurons from oxidative stress.These data suggest that low-level subcortical oxidation under the control of an antioxidant system may trigger sleep via the Ca2+-dependent release of sleep-inducing neuromodulators in the POAH, and thus we propose that a moderate increase of ROS during wakefulness in the neuronal circuits regulating sleep may be an initial trigger in sleep induction. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.