THE POTENTIAL ROLE OF NITRIC-OXIDE IN MULTIPLE-SCLEROSIS

Nitric oxide (. NO) and its reactive derivative peroxynitrite (ONOO-) have been implicated in the pathogenesis of multiple sclerosis (MS). T hey ore cytotoxic to oligodendrocytes and neurones in culture by inhib iting the mitochondrial respiratory chain (complexes II/III and IV) an d inhibiting certain key intracellular enzymes. Recently NO has been i mplicated as a Possible aetiological factor in reversible conduction b lock in demyelinated axons. Inducible nitric oxide synthase (iNOS) is upregulated in the central nervous system of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In some EAE models inhibiting iNOS activity decreases disease severity whilst in other models disease activity is exacerbated. Raised levels of nitrate and nitrite, stable end-products of . NO/ONOO-, ore found in the cere brospinal fluid serum and urine of patients with MS. CSF levels of nit rate and nitrite correlate with blood-brain-barrier dysfunction, which suggests that NO may ploy a role in inflammatory blood-brain-barrier dysfunction. In a longitudinal study on 24 patients with relapsing rem itting and secondary Progressive MS, raised serum nitrate and nitrite levels correlated with a relapsing course and infrequent relapses. How ever, no correlation was found between raised serum levels of nitrate and nitrite and MRI activity, disease progression, or the development of cerebral atrophy. In autoimmune mediated CNS demyelinating disease NO may be a double-edged sword, mediating tissue damage on the one han d and on the other hand modulating complex immunological functions whi ch may be protective.