Inhibition of nitric oxide synthase initiates relapsing remitting experimental autoimmune encephalomyelitis in rats, yet nitric oxide appears to be essential for clinical expression of disease

Myelin basic protein-CFA-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic disease from which animals recov er. In this model, spontaneous relapses do not occur and rats develop, a re sistance to further active reinduction of disease. Previously, we reported that oral administration of the NO synthase inhibitor N-methyl-L-arginine a cetate (L-NMA) to recovered rats precipitated a second episode of disease i n 100% of animals. Further studies now show that this second clinical episo de is actually a chronic relapsing disease that persists for months. This o ccurs only in rats that have recovered from actively induced EAE and not in rats recovered from passively induced EAE, suggesting the need for a perip heral Ag depot to induce secondary disease. We have also determined that cl inical signs of EAE in L-NMA-treated recovered rats do not appear until L-N MA treatment has stopped. This is despite the fact that, at the same time p oint, CNS inflammatory lesions in. symptomless animals receiving L-NMA are qualitatively and quantitatively similar to those with severe disease sympt oms from whom L-NMA treatment has been withdrawn. The latter animals have s ignificantly higher levels of reactive nitrogen intermediates in the cerebr ospinal fluid than the former group. This study examines the mechanism of r einduction of disease by L-NMA treatment, and the findings suggest a dual r ole for NO in regulation of pathology in EAE that is dependent on site and timing of NO production.