Multiple Sclerosis (MS) is an autoimmune, demyelinating disease in which the induction of proinflammatory events orchestrated by inflammatory mediators (secreted by activated infiltrating mononuclear cells and endogenous glial cells i.e. astrocytes and microglia) determines the outcome of the inflammatory reaction in the pathobiology (loss of myelin, oligodendrocytes and axons) of MS. Studies from our laboratory were the first to document the anti-inflammatory properties of statins in cells in culture and in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Because of the observed anti-inflammatory properties of statins, these drugs are now being tested in a number of neuroinflammatory disorders including MS, stroke and Alzheimer's disease. However, little is known regarding their mechanisms of action in the inflammatory disease process. Statins as inhibitors of the enzyme HMG-CoA reductase regulate the mevalonate pathway by decreasing the synthesis of isoprenoids required for secondary protein modifications, and cholesterol, required for the synthesis of membranes especially receptor rich cellular membrane domains known as """"""""lipid rafts"""""""" and ubiquinone and dolichol required for mitochondrial electron transport chain and N-glycosylation of glycoproteins, respectively. The proposed studies are designed to identify the metabolite(s) of the mevalonate pathway responsible for the anti-inflammatory activity of Iovastatin and its effects on structure and function of """"""""lipid rafts"""""""". These receptor rich lipid raft domains are rich in cholesterol, sphingomyelin and ceramide and isoprenylated GTPases for transmission of proinflammatory cytokine-mediated signaling processes. Studies are designed to understand the mechanism of action(s) of statins on recruitment of receptor and their effector proteins and that of small GTPase for induction of proinflammatory signals through these lipid raft domains. Therefore, it is of interest to study the mechanism of action of statins on lipid raft structure and function in inflammatory responses that are responsible for the EAE/MS disease processes of. In depth knowledge of the mechanisms of action of these drugs may offer the possibility of developing effective therapy for MS patients. We are very excited about the possibility that these basic studies initiated from our laboratory may become the basis of therapeutics for MS and other inflammatory diseases. ? ?
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