Nitric Oxide as a Neuronal Messenger

This observation led to the finding that a soluble enzyme from rat forebrain catalyzes the NADPH-dependent formation of NO and L-citrulline from L-ar-ginine by calcium-dependent mechanisms (Knowles et al., 1989). A subsequent study revealed that glutamate and NMDA stimulate NO and L-citrulline formation in rat cerebellar slices and that this is associated with a concomitant stimulation of cyclic GMP formation (Bredt and Snyder, 1989), thus establishing a link between NMDA-receptor activation and cyclic GMP formation (Fig. 4). These investigators went on to purify and characterize NO synthase from cerebellum (Bredt and Snyder, 1990 Bredt et al., 1991) and to show the localization of NO synthase in the brain to discrete neuronal populations (Bredt et al., 1990). 

It is not clear whether NO functions as a neurotransmitter per se or just as a neuromodulator in the CNS. A function of a neurotransmitter would require 

Attention then turned to the mechanism of glutamate-induced neurotoxicity in the brain. Evidence was provided that NO mediates glutamate neurotoxicity in primary cortical cultures (Dawson et ai, 1991). NO synthase inhibitors and hemoglobin prevented NMDA- and glutamate-induced neurotoxicity on the other hand, L-arginine reversed the effect of NO synthase inhibitors, and sodium nitroprusside (which decomposes to NO) caused neurotoxicity that paralleled cyclic GMP formation. In the cerebral cortex, NO synthase immunoreactivity was found to be confined to a discrete population of aspiny neurons comprising 

1-2% of the total neuronal population (Bredt et al., 1990), and that these same neurons stained selectively for NADPH diaphorase (Snyder and Bredt, 1991). It is of interest that neurons containing NO synthase are resistant to degeneration in Huntington s chorea, Alzheimer s disease, and hypoxic-ischemic brain injury. These same neurons are resistant also to glutamate neurotoxicity (Koh et al., 1988 Koh and Choi, 1988). 

The precise mechanism by which NO causes glutamase neurotoxicity is unknown. Calcium must be required because of the requirement for NMDA- and glutamate-induced NO formation in brain tissue (Garthwaite etal., 1988). Although both NMDA-receptor agonists and sodium nitroprusside induce specific neurotoxicity as well as cyclic GMP formation in brain tissue (Dawson et al., 1991), it is unlikely that cyclic GMP is the ultimate cause of the neurotoxicity. Instead, NO is most likely involved in producing target cell death. One possible mechanistic pathway is that locally synthesized NO and superoxide anion react with each other to yield peroxynitrite anion (Beckman et al., 1990), which can destroy cell membranes either directly via interaction with cellular thiols (Radi et al., 1991) or indirectly via decomposition to hydroxyl and other free radicals (Beckman et al., 1990). 

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Snyder SH, Bredt DS. Nitric oxide as a neuronal messenger. Trends Pharmacol Sci... 

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