THE ROLE OF NITRIC-OXIDE IN MULTIPLE-SCLEROSIS

During the past decade nitric oxide has emerged as an important mediat or of physiological and pathophysiological processes. Elevated nitric oxide biosynthesis has been associated with nonspecific immune-mediate d cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid arthritis, insulin-dependent diabetes, inflammatory bowel disease, and mutiple sclerosis. Recent ev idence suggests, however, that nitric oxide is also immunoregulatory a nd suppresses the function of activated proinflammatory macrophages an d T lymphocytes involved in these diseases. This article reviews the r ole of nitric oxide in the biology of central nervous system glial cel ls (astrocytes and microglia) as it pertains to the pathogenesis of mu ltiple sclerosis in humans and experimental allergic encephalitis, the animal model of this disease. Although nitric oxide has been clearly implicated as a potential mediator of microglia-dependent primary demy elination, a hallmark of multiple sclerosis, studies with nitric oxide synthase inhibitors in the encephalitis model have been equivocal. Th ese data are critically reviewed in the context of what is know from c linical research on the nitric oxide pathway in multiple sclerosis. Sp ecific recommendations for future preclinical animal model research an d clinical research on the nitric oxide pathway in patients are sugges ted. These studies are necessary to further define the role of nitric oxide in the pathology of multiple sclerosis and to fully explore the potential for nitric oxide synthase inhibitors as novel therapeutics f or this disease.