[Neuronal response to radical stress]

Glutamate and reactive oxygen species including nitric oxide (NO) and superoxide anion (O2.-) have been postulated to play pivotal roles in the pathogenesis of the neuronal cell loss that is associated with several neurological disease states including Parkinson's disease and amyotrophic lateral sclerosis. In mesencephalic cultures, nondopaminergic neurons but not dopaminergic neurons are susceptible to NO cytotoxicity, although both types of neurons are damaged by glutamate. Methylphenylpyridium ion (MPP+) selectively enhances glutamate and NO cytotoxicity against dopaminergic neurons of mesencephalic cultures. It is suggested that glutathione plays an important role in the expression of NO-mediated glutamate cytotoxicity in dopaminergic neurons. In cultured spinal neurons, glutamate coadministered with the glutamate transporter inhibitor selectively damages motor neurons. Motor neurons are injured by NO, whereas nonmotor neurons are protected by NO through the guanylyl cyclase-cGMP cascade. It is suggested that selective motor neuronal death caused by chronic low-level exposure to glutamate is mediated by the formation of NO in nonmotor neurons. It is possible that neurotoxicity induced by NO and O2.- associated with neurodegenerative disorders is regulated by intracellular defense systems such as glutathione and cGMP.