Multiple sclerosis (MS) is a disease of unknown etiology for which experimental autoimmune encephalomyelitis (EAE) serves as a model. There is compelling evidence that peroxynitrite anion (PN) is present in the central nervous system (CNS) of laboratory animals with EAE and in MS lesions. PI's laboratory has evidence supporting the presence of high levels of PN in and near the inflammatory lesions of EAE, and in inflamed MS-affected human CNS. PI and others have shown that inhibiting PN inhibits EAE. PN is a strong oxidant with many detrimental effects, including the inhibition of mitochondrial electron transport, direct damage to proteins, lipid peroxidation which damages membranes, and DNA fragmentation. PN is generated by the rapid reaction of nitric oxide (NO) with superoxide, at a diffusion-limited rate. Many of toxic effects formerly attributed to excess NO are now realized to be due to PN. Furthermore, the breakdown product of PN, nitrogen dioxide, is also highly toxic to membranes. Ultrastructurally, it is clear that myelin membranes are a target of attack in MS, and oligodendroglia cells are lost from chronic MS lesions. Our hypothesis is that PN generation is a key component in the pathogenesis of inflammatory CNS demyelination by causing or increasing the destruction of oligodendroglia cells and/or myelin membranes, and enhancing inflammation. The proposed study will expand and confirm our findings of PN generation in MS and EAE- affected tissues. This proposal will also address the mechanisms by which PN may act in the pathogenesis of CNS inflammatory demyelination. We will examine the effects of PN on oligodendroglia, the cells that make CNS myelin, and on CNS myelin vesicles prepared from human myelin. We will determine what CNS proteins are altered by tyrosine nitration due to PN. Since there now have been identified pharmaceutic agents which can inhibit the production of PN, our findings from these studies may indicate an area with therapeutic potential for MS.
| Cross, Anne H; Ramsbottom, Michael J; Lyons, Jeri-Anne (2006) NOS2 regulates cytokine production and VLA-4 expression in experimental autoimmune encephalomyelitis. J Neuroimmunol 173:79-86 |
| Cross, A H; San, M; Stern, M K et al. (2000) A catalyst of peroxynitrite decomposition inhibits murine experimental autoimmune encephalomyelitis. J Neuroimmunol 107:21-8 |
