INDUCIBLE NITRIC-OXIDE SYNTHASE AND NITROTYROSINE ARE FOUND IN MONOCYTES MACROPHAGES AND/OR ASTROCYTES IN ACUTE, BUT NOT IN CHRONIC, MULTIPLE-SCLEROSIS/

We have examined the localization of inducible nitric oxide synthase ( iNOS) and nitrotyrosine (the product of nitration of tyrosine by perox ynitrite, a highly reactive derivative of nitric oxide [NO]) in demyel inating lesions from (i) two young adult patients with acute multiple sclerosis (MS), (ii) a child with MS (consistent with diffuse sclerosi s), and (iii) five adult patients with chronic MS. Previous reports ha ve suggested a possible correlation between iNOS, peroxynitrite, relat ed nitrogen-derived oxidants, and the demyelinating processes in MS.We have demonstrated iNOS-immunoreactive cells in both acute-MS and diff use-sclerosis-type lesions. In acute-MS lesions, iNOS was localized in both monocytes/macrophages and reactive astrocytes. However, foamy (m yelin-laden) macrophages and the majority of reactive astrocytes were iNOS negative. In specimens from the childhood MS patient, iNOS protei n was present only in a subpopulation of reactive or hypertrophic astr ocytes. In contrast, no iNOS staining was detected in chronic-MS lesio ns. Immunohistochemical staining of acute-MS lesions,vith an antibody to nitrotyrosine revealed codistribution of iNOS- and nitrotyrosine-po sitive cells, although nitrotyrosine staining was more widespread in c ells of the monocyte/macrophage lineage. In diffuse sclerosis-type les ions, nitrotyrosine staining was present in hypertrophic astrocytes, w hereas it was absent in chronic-MS lesions. These results suggest that NO and nitrogen-derived oxidants may play a role in the initiation of demyelination in acute-MS lesions but not in the later phase of the d isease.