MPP+ and glutamate in the degeneration of nigral dopaminergic neurons

Abstract

Glutamate neurotoxicity can be an experimental oxidative stress, and we investigated glutamate toxicity against cultured rat mesencephalic neurons. Although glutamate showed similar toxicity against dopaminergic and nondopaminergic neurons, nitric oxide (NO) showed neurotoxicity restricted exclusively in nondopaminergic neurons. An inhibitor of NO synthase had no significant effect on the glutamate toxicity against dopaminergic neurons, however, it had a significant antagonistic effect on that against nondopaminergic neurons. These findings indicate the presence of two mechanisms of glutamate neurotoxicity, one being not mediated by NO, found in dopaminergic neurons, and the other being mediated via NO, found in nondopaminergic neurons. In contrast to NO, peroxynitrite (ONOO(-)), an active metabolite of NO, caused significant cytotoxicity against dopaminergic and nondopaminergic neurons, suggesting that conversion of NO to ONOO(-) is suppressed in dopaminergic neurons. After pretreatment with small doses of methyl-4-phenylpyridium ion (MPP(+)), NO caused significant cytotoxicity against dopaminergic neurons, and glutamate toxicity was enhanced only against dopaminergic neurons. Therefore, sublethal dose of MPP(+) enhances glutamate toxicity against dopaminergic neurons, probably by the facilitation of suppressed NO conversion to ONOO(-) in dopaminergic neurons. Finally, to provide basic data for neuroprotective therapy in Parkinson's disease, we investigated neuroprotection against glutamate toxicity by dopamine agonists. Preincubation with the D2 type dopamine agonists provides neuroprotection against glutamate neurotoxicity and the protective effects blocked by a D2 antagonist, indicating that D2 agonists provide protection mediated not only by the inhibition of dopamine turnover, but also via D2 type dopamine receptor.