Journal
JOURNAL OF NEUROIMMUNOLOGY
Volume 149, Issue 1-2, Pages 40-49Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jneuroim.2003.12.021
Keywords
EAE/MS; monocytes/macrophages; inflammation; nitric oxide; cytotoxicity
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Multiple sclerosis (MS) is a progressive immune-mediated disease characterized by the loss of the oligodendrocytes that constitute the myelin sheath. Recent reports show that glutamate-mediated excitotoxic death of oligodendrocytes contributes to pathogenesis in demyelinating disease. A link between the immune-mediated inflammatory response and glutamate-mediated excitotoxicity of oligodendrocytes could involve the interaction of inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Both enzymes are tightly coupled to neuronal excitotoxic death. We examined tissue from two controls and seven MS patients with chronic active lesions to determine the extent of COX-2 and iNOS expression. In contrast to the lack of expression in controls, there was a marked induction of COX-2 in all these MS lesions. COX-2 was frequently expressed in association with iNOS. COX-2 was found in areas that contained catabolites of myelin basic protein, indicating recent demyelination. COX-2 expression was found near damaged oligodendrocytes in cells that expressed the macrophage/microglia marker CD64, indicating that a substantial portion of the COX-2 in the lesions was expressed in immune-derived cells. We discuss these findings in the context of how COX-2 could be coupled with iNOS to contribute to excitotoxic death and damage of oligodendrocytes. (C) 2004 Elsevier B.V. All rights reserved.
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