MICE WITH AN INACTIVATION OF THE INDUCIBLE NITRIC-OXIDE SYNTHASE GENEARE SUSCEPTIBLE TO EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

Nitric oxide (NO) generated by the inducible nitric oxide synthase (iN OS) has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study mice genetically deficient for iNOS are shown to be susceptible to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG). In iNOS (-/-) mice the cour se of disease was earlier in onset and more aggressive compared to con trol animals. A disease-relevant compensatory up-regulation of neurona l (n)NOS and endothelial (e)NOS with increased production of NO in iNO S (-/-) mice is excluded by 1) the failure to detect increased nNOS an d eNOS mRNA, 2) the absence of detection of nitrosylated tyrosine resi dues in EAE tissue indicating absence of NO-derived peroxynitrite, and 3) the lack of disease-preventing effects of N-G-nitro-L-arginine met hyl ester. In conclusion, these results do not support the hypothesis that NO is crucial for the development of EAE.