Neuroprotective properties of nitric oxide

The discoveries of physiological roles of nitric oxide (.NO) as the mediator of endothelium-derived relaxing factor (EDRF) action and the activator of guanylyl cyclase to increase cyclic guanosine monophosphate (cGMP), which lead to vasorelaxation in the cardiovascular system, have been awarded with the 1998 Nobel Prize of Medicine. The present review discusses putative beneficial effects of .NO in the central nervous system (CNS). In addition to its prominent roles of the regulation of cerebral blood flow and the modulation of cell to cell communication in the brain, recent in vitro and in vivo results indicated that .NO is a potent antioxidative agent. .NO terminates oxidant stress in the brain by (i) suppressing iron-induced generation of hydroxyl radicals (.OH) via the Fenton reaction, (ii) interrupting the chain reaction of lipid peroxidation, (iii) augmenting the antioxidative potency of reduced glutathione (GSH) and (iv) inhibiting cysteine proteases. It is apparent that .NO--a relative long half-life nitrogen-centered weak radical--scavenges those short-lived, highly reactive free radicals such as superoxide anion (O2.-), .OH, peroxyl lipid radicals (LOO.) and thiyl radicals (i.e., GS.), yielding reactive nitrogen species including nitrites, nitrates, S-nitrosoglutathione (GSNO) and peroxynitrite (ONOO-). GSNO is 100-fold more potent than GSH; it completely inhibits the weak peroxidative effect of ONOO-. Moreover, CO2 and .NO neutralize prooxidative effects of ONOO-. CO2 prevents protein oxidation but not 3-nitrotyrosine formation caused by ONOO-. Finally, neuroprotective effects of GSNO and .NO have been demonstrated in brain preparations in vivo. These novel neuroprotective properties of .NO and GSNO may have their physiological significance, since oxidative stress depletes GSH while increasing GS. and .NO formation in astroglial and endothelial cells, resulting in the generation of a more potent antioxidant GSNO and providing additional neuro-protection at microM concentrations. This putative GSNO pathway (GSH-->GS.-->GSNO-->.NO + GSSG-->GSH) may be an important part of endogenous antioxidative defense system, which could protect neurons and other brain cells against oxidative stress caused by oxidants, iron complexes, proteases and cytokines. In conclusion, .NO is a potent antioxidant against oxidative damage caused by reactive oxygen species, which are generated by Fenton reaction or other mechanisms in the brain via redox cycling of iron complexes.