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Nitric Oxide Plays a Critical Role in the Recovery of Lewis Rats from Experimental Autoimmune Encephalomyelitis and the Maintenance of Resistance to Reinduction¹

Nikki C. O’Brien^2,*,, Brett Charlton, William B. Cowden and David O. Willenborg^*

^* Neurosciences Research Unit, Canberra Hospital; and John Curtin School of Medical Research, Australian National University, Canberra, Australian Capitol Territory, Australia

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS and an animal model for the human demyelinating disease, multiple sclerosis. In the Lewis rat, myelin basic protein (MBP)-CFA-induced EAE is an acute monophasic disease from which animals recover fully, do not relapse, and develop a robust long-term resistance to further active reinduction of disease. In this paper, we report that rats recovering from MBP-CFA-induced EAE have significantly increased serum levels of reactive nitrogen intermediates indicative of increased NO production. These levels remain elevated after the recovery period and increase even further early after a rechallenge with MBP-CFA, and all animals are totally refractory to a second episode of disease. Oral treatment of rats with N-methyl-L-arginine acetate (L-NMA), beginning at peak disease on day 11 postimmunization, results in significant prolongation of disease and an alteration in the presentation of clinical symptoms from that of solely hind limb paresis/paralysis to severe fore limb involvement as well. Treatment of fully recovered rats with L-NMA 24 h before a rechallenge with MBP-CFA leads to decreased serum reactive nitrogen intermediate levels and results in a second episode of EAE in 100% of animals. Furthermore, L-NMA treatment of fully recovered rats in the absence of a rechallenge immunization leads to spontaneous relapse of disease.

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