The presence of proinflammatory cytokines and induction of inducible nitric oxide synthase (iNOS) in brain lesions of patients with multiple sclerosis (MS) provided evidence that NO/ONOO' along with free radicals of oxygen (02-) play an important role in the pathophysiology of MS. Studies from our laboratory have shown that cAMP inhibitors of protein phosphatases 1/2 A regulate the production of NO and induction of iNOS in astrocytes and macrophages by different mechanisms. NO alters the cellular redox by altering the expression of antioxidant enzymes. We have also shown that antioxidants (N-acetyl cysteine) and mevalonate inhibitors (lovastatin and sodium phenylacetate) block the induction of proinflammatory cytokines and that of iNOS and the production of NO in activated cultured astrocytes, macrophages and microglia. The objective of this proposal is to decipher the mechanism of the induction or regulation of iNOS in astrocytes and macrophages by PKA and protein phosphatases 1/2 A and the role of iNOS in the disease process of experimental allergic encephalitis (EAE), an animal model of MS. Achievement of these goals will be facilitated by understanding the molecular mechanism of activation of NFkB in the differential induction of iNOS by PKA and protein phosphatases 1/2 A in astrocytes and macrophages. Studies are proposed to identify the protein phosphatase (protein phosphatase I or protein phosphatase 2A) that is responsible for the induction of proinflammatory cytokines NFkB and activation of iNOS in astrocytes and macrophages. The possible role of NO/ONOO' in the pathophysiology of EAE will be investigated by using mice models which lack iNOS (iNOS knock out) and those which express increased levels of iNOS. We also propose to test the possible therapeutic effect of antioxidants drugs (N-acetylcysteine) and mevalonate inhibitors (lovastatin and sodium phenylacetate) in halting/slowing the progression of the disease process in EAE.
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