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）是神经毒性的，其氧化代谢的刺激增强了氧化应激，这也有毒。这种侮辱后，由缺血和缺氧引起的细胞外DA大大增加可能涉及神经元细胞损伤。进行了本研究以检查通过体内微透析的自由移动大鼠中CO暴露对纹状体多巴胺能系统的影响。此外，检查了CO对一氧化氮（NO）系统的影响，因为没有神经毒性和神经保护作用，并且会影响DA释放。 CO暴露会引起细胞外DA的显着增加，其氧化代谢产物降低。通过阻断电压依赖性钠通道来消除DA的增加，并通过抑制DA摄取以及抑制单胺氧化酶（MAO）来增强DA的增加。尽管缺氧缺氧引起的细胞外DA的增加主要是由于DA摄取的抑制作用，但目前的结果表明，MAO抑制和增强DA释放的释放可能至少部分参与了胞外DA的共同诱导的增加。此外，撤回CO导致了DA的氧化代谢加速。另一方面，CO暴露导致纹状体中NO，精氨酸（ARG）的前体抑制NO产生和降低。外源L-ARG，但不是D-Arg或L-citrulline，减弱了共同抑制NO生产的抑制，这表明这种NO生成的抑制至少可能部分是由于细胞外L-ARG的降低。在缺氧缺氧引起的无生产抑制中，外源L-ARG的衰减比共同诱导的抑制较弱。目前的发现表明，除缺氧外，CO的神经毒性可能是由复杂机制介导的。