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Role of mitochondrial respiratory chain in neuronal toxicity due to carbon monoxide poisoning

线粒体呼吸链在一氧化碳中毒神经元毒性中的作用

基本信息

批准号：
17590586
负责人：
HARA Shuichi
金额：
$ 2.3万
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：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The mitochondrial respiration chain is one of pathways associated with reactive oxygen species (ROS) generation in the cell. Interruption of this chain results in stimulation of ROS generation. In this study, it was examined whether the mitochondrial respiration chain was associated with hydroxyl radical (・OH) generation in rat striatum in carbon monoxide (CO) poisoning by means of brain microdialysis, since CO inhibits the complex IV in the respiratory chain. MPP^+ (complex I inhibitor), malonate (complex II inhibitor) and NaCN (complex IV inhibitor, like CO) stimulated ・OH generation in rat striatum by themselves. CO in combination with MPP^+ or NaCN resulted in the additive potentiation of ・OH generation, while the effect of the combined treatment with CO and malonate was synergistical. NaCN had no such synergistic effect when combined with malonate, suggesting that the synergistic potentiation of ・OH generation by CO and malonate may be derived from CO actions other than the inhibition of the complex IV. On the other hand, the CO-induced ・OH generation was suppressed and potentiated by nitric oxide (NO) synthase (NOS) inhibitors, N^G-nitro-L-arginine methyl ester and N^G-monomethyl-L-arginine, respectively. The effects of these NOS inhibitors were attenuated by the NO precursor, L-arginine, while D-arginine strongly stimulated the CO-induced ・OH generation in the presence of NOS inhibitors. These findings suggest that the CO-induced ・OH generation may be mediated by complex mechanisms. If NO participates in the mechanisms, NOS, but not NO per se, might play a role. Although NO modifies the mitochondiral repiratory chain, it is unclear whether NO plays a role in the synergistic potentiation in ・OH generation by CO and malonate.

线粒体呼吸链是细胞内产生活性氧(ROS)的途径之一。这一链的中断会刺激ROS的产生。本研究通过脑微透析的方法，研究了一氧化碳(CO)中毒大鼠纹状体线粒体呼吸链是否与·OH产生有关，因为CO抑制了呼吸链中的复合体IV。MPP~+(复合体I抑制剂)、丙二酸(复合体II抑制剂)和NaCN(复合体IV抑制剂，如CO)可单独刺激大鼠纹状体产生·OH。CO与MPP^+或NaCN联合处理对·OH产生有相加增强作用，而CO与丙二酸联合处理具有协同作用。氰化钠与丙二酸合用时无协同作用，提示CO和丙二酸对·OH的协同增强作用可能来源于CO的作用，而不是抑制络合物IV。一氧化氮合酶抑制剂N^G-硝基-L-精氨酸甲酯和N^G-单甲基-L-精氨酸分别抑制和增强CO诱导的·OH生成。这些一氧化氮合酶抑制剂的作用可被一氧化氮合酶前体L-精氨酸减弱，而D-精氨酸在一氧化氮合酶抑制剂的存在下可强烈地刺激CO诱导的·OH的产生。这些发现表明，CO诱导的·OH的产生可能是由复杂的机制介导的。如果NO参与了这些机制，则可能是一氧化氮合酶发挥作用，而不是一氧化氮本身。尽管NO可以改变线粒体呼吸链，但目前尚不清楚NO是否在CO和丙二酸协同增强产生·OH中起作用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nittric oxide-independent cGMP efflux in the striatum of rats exposed to carbon monoxide, as determined by microdialysis

通过微透析测定暴露于一氧化碳的大鼠纹状体中不依赖一氧化氮的 cGMP 流出

DOI：
发表时间：
2007
期刊：
Journal of Pharmacological Sciences (印刷中)
影响因子：
0
作者：
Takeshi Saito;Hiroyasu Mase;Sanae Takeichi;Sadaki Inokuchi.;Ayako Kuriki;Hara S.et al.
通讯作者：
Hara S.et al.

Nitric oxide-independent cGMP efflux in the striatum of rats exposed to carbon monoxide, as determined by microdialysis

通过微透析测定暴露于一氧化碳的大鼠纹状体中不依赖一氧化氮的 cGMP 流出