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

2001 Fiscal Year Final Research Report Summary

• Project/Area Number: 12670406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Legal medicine
• Research Institution: Tokyo Medical University
• Principal Investigator: HARA Shuichi Tokyo Medical University, Medicine, Assistant Professor, 医学部, 講師 (70208651)
• Project Period (FY): 2000 – 2001
• Keywords: Carbon monoxide / Dopamine / Nitric oxide / Microdialysis / Striatum / Rat / Hypoxia

Research Abstract

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.