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

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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.