Contrasting roles for nitric oxide and peroxynitrite in the peroxidation of myelin lipids

Peroxynitrite is formed by the reaction of nitric oxide (NO) and superoxide . Since widespread peroxynitrite activity was observed during experimental allergic encephalomyelitis (EAE), the effect of this strong lipid-peroxidiz ing agent on myelin integrity was examined. Incubation of myelin suspension s with the peroxynitrite donor 3-morpholinosydnonimine (SIN-I) resulted in the formation of the lipid peroxidation product, malondialdehyde (MDA). MDA formation was inhibited in the presence of butylated hydroxytoluene, which interrupts the progression of the lipid peroxidation chain reaction. Super oxide dismutase inhibited the effect of SIN-I, which indicates a role for s uperoxide, and contradicts a role for its dismutation product, hydrogen per oxide. The latter was confirmed by the failure of the catalase to inhibit M DA formation. Neither NO nor superoxide alone induced significant MDA forma tion in myelin, indicating that peroxynitrite formation is required for mye lin-lipid peroxidation. Interestingly, NO actually inhibited lipid peroxida tion in myelin, as demonstrated using simple NO donors. On the other hand, the simultaneous production of superoxide, as achieved with the NO-donor SI N-I, negated the inhibitory effect of NO. Finally, the production of isopro stanes, novel products generated during lipid peroxidation, was examined. P eroxynitrite-induced peroxidation of myelin resulted in isoprostane formati on. Furthermore, increased levels of F-2-isoprostanes and neuroprostanes we re observed in spinal cords of mice during early progressive stages of auto immune encephalomyelitis. (C) 1999 Elsevier Science B.V. All rights reserve d.