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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037766-07
Application #
6948770
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
1998-08-01
Project End
2009-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
7
Fiscal Year
2005
Total Cost
$337,625
Indirect Cost
Name
Medical University of South Carolina
Department
Pediatrics
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Singh, Inderjit; Nath, Narender; Saxena, Nishant et al. (2018) Regulation of IL-10 and IL-17 mediated experimental autoimmune encephalomyelitis by S-nitrosoglutathione. Immunobiology 223:549-554
Saxena, Nishant; Won, Jeseong; Choi, Seungho et al. (2018) S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis. Free Radic Biol Med 121:57-68
Choi, Seungho; Won, Je-Seong; Carroll, Steven L et al. (2018) Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer's Disease. Neuroscience 384:41-53
Singh, Inderjit; Samuvel, Devadoss J; Choi, Seungho et al. (2018) Combination therapy of lovastatin and AMP-activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model. Immunology 154:434-451
Shah, Navjot; Singh, Inderjit (2017) MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy. Mol Neurobiol 54:1392-1403
Kim, Jinsu; Choi, Seungho; Saxena, Nishant et al. (2017) Regulation of STAT3 and NF-?B activations by S-nitrosylation in multiple myeloma. Free Radic Biol Med 106:245-253
Nie, Xingju; Lowe, Danielle W; Rollins, Laura Grace et al. (2016) Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia. Neurosci Res 108:24-33
Samuvel, Devadoss J; Saxena, Nishant; Dhindsa, Jasdeep S et al. (2015) AKP-11 - A Novel S1P1 Agonist with Favorable Safety Profile Attenuates Experimental Autoimmune Encephalomyelitis in Rat Model of Multiple Sclerosis. PLoS One 10:e0141781
Annamalai, Balasubramaniam; Won, Je-Seong; Choi, Seungho et al. (2015) Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation. Biochem Biophys Res Commun 458:214-9
Baarine, Mauhamad; Khan, Mushfiquddin; Singh, Avtar et al. (2015) Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy. PLoS One 10:e0143238

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