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Study on the mechanism of carbon monoxide-induced damage to the central nervous system

一氧化碳所致中枢神经系统损伤机制研究

基本信息

批准号：
12670406
负责人：
HARA Shuichi
金额：
$ 1.92万
依托单位：
Tokyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Dopamine (DA) is neurotoxic and stimulation of its oxidative metabolism enhances oxidative stress, which is also toxic. A massive increase in extracellular DA in the brain caused by ischemia and hypoxia may be involved in neuronal cell injury following such insults. The present study was conducted to examine the effect of CO exposure on the striatal dopaminergic system in free-moving rats by using in vivo microdialysis. In addition, the effect of CO on the nitric oxide (NO) system was examined, since NO has neurotoxic and neuroprotective effects and influences DA release. CO exposure induced a significant increase in extracellular DA and a decrease in its oxidative metabolites. The DA increase was abolished by blocking the voltage-dependent sodium channel, and potentiated by inhibiting DA uptake as well as by inhibiting monoamine oxidase (MAO). Although the hypoxic hypoxia-induced increase in extracellular DA is primarily due to inhibition of DA uptake, the present results suggest that MAO inhibition and enhancement of DA release may be at least partly involved in the CO-induced increase in extracellular DA. In addition, withdrawal of CO resulted in acceleration of the oxidative metabolism of DA. On the other hand, CO exposure resulted in suppression of NO production and a decrease in a precursor of NO, arginine(Arg), in the striatum. Exogenous L-Arg, but not D-Arg or L-citrulline, attenuated the CO-induced suppression of NO production, suggesting that this suppression of NO production may be at least partly due to a decrease in extracellular L-Arg. The attenuation by exogenous L-Arg was weaker in the hypoxic hypoxia-induced suppression of NO production than in the CO-induced suppression. The present findings suggest that neurotoxicity of CO might be mediated by complex mechanisms, in addition to hypoxia.

多巴胺（DA）具有神经毒性，其氧化代谢的刺激增强氧化应激，这也是有毒的。脑缺血和缺氧引起的细胞外DA大量增加可能参与了此类损伤后的神经元细胞损伤。本研究采用体内微透析技术研究CO暴露对自由活动大鼠纹状体多巴胺能系统的影响。此外，CO对一氧化氮（NO）系统的影响进行了检查，因为NO具有神经毒性和神经保护作用，并影响DA的释放。CO暴露诱导细胞外DA的显着增加和其氧化代谢产物的减少。阻断电压依赖性钠通道可消除DA的增加，抑制DA摄取和抑制单胺氧化酶（MAO）可增强DA的增加。虽然缺氧引起的细胞外DA的增加主要是由于抑制DA的摄取，但本研究结果表明，MAO抑制和DA释放的增加可能至少部分参与了CO引起的细胞外DA的增加。此外，CO的戒断导致DA的氧化代谢加速。另一方面，CO暴露导致抑制NO的产生和减少NO的前体，精氨酸（Arg），在纹状体。外源性L-Arg，而不是D-Arg或L-瓜氨酸，减弱了CO诱导的NO产生抑制，表明这种NO产生抑制可能至少部分是由于细胞外L-Arg的减少。外源性L-Arg对低氧诱导的NO生成抑制的减弱作用弱于CO诱导的抑制作用。目前的研究结果表明，CO的神经毒性可能介导的复杂机制，除了缺氧。