EXTENSIVE PEROXYNITRITE ACTIVITY DURING PROGRESSIVE STAGES OF CENTRAL-NERVOUS-SYSTEM INFLAMMATION

Nitric oxide (NO) production has been associated with disease activity in multiple sclerosis and experimental autoimmune encephalomyelitis ( EAE). This free radical can be transformed by superoxide to peroxynitr ite, an extremely toxic oxidant which causes lipid peroxidation. In ad dition, peroxynitrite nitrates tyrosine residues, resulting in nitroty rosine, which can be identified immunohistochemically. The results of this study indicate that peroxynitrite is formed very early during EAE development, correlating with clinical disease activity. Nitrotyrosin e-positive cells display a widespread distribution in brain and spinal cord during severe disease and are associated with both perivascular infiltrates and parenchymal sites. Double-staining procedures demonstr ated that a subpopulation of CD11b-positive cells (macrophages/microgl ia) reacted with nitrotyrosine antibodies. Immunostaining for inducibl e NO synthase demonstrated a similar distribution as nitrotyrosine sta ining. These experiments indicate that peroxynitrite is formed during progressive stages of disease activity.