Role of Nitric Oxide in MPTP-Induced Dopaminergic Neuron Degeneration

摘要

The oxidative stress hypothesis of Parkinson's disease (PD) is thought to involve the superoxide radical and nitric oxide (NO). It is believed that these two react with each other to produce peroxynitrite, a compound that damages cellular components in the nigrostriatal dopaminergic pathway of the brain. MPTP (l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine) a meperidine analog that mimics most of the hallmarks of PD, is the drug of choice for investigations into the mechanism(s) of PD. Our studies indicate that of the three isoforms of the nitric oxide synthase (NOS) enzyme, both neuronal NOS (nNOS) and inducible NOS (iNOS) are up-regulated in the SNpc following MPTP administration due to increases in the nNOS and iNOS proteins. Also found was that MPTP had no effect on endothelial NOS (eNOS). During our studies, we noted a significant glial response in the SNpc of mice following MPTP treatments. We showed that microglia are a primary source of nitric oxide (NO). Also noted, was that microglia are a major source of the superoxide radical through the activation of NADPH oxidase. In our studies, we demonstrated several markers of both the oxidative modification and the nitration of key cellular components of the nigrostriatal dopaminergic in the MPTP mouse model and in postmortem PD tissues.