title: Overexpression of SIRT1 protein in neurons protects against experimental autoimmune encephalomyelitis through activation of multiple SIRT1 targets.
abstract: Treatment of experimental autoimmune encephalomyelitis (EAE) with resveratrol, an activator of sirtuin 1 (SIRT1), reduces disease severity. This suggested that activators of SIRT1, a highly conserved NAD-dependent protein deacetylase, might have immune-modulating or neuroprotective therapeutic effects in EAE. Previously, we showed that SIRT1 expression increases in EAE, suggesting that it is an adaptive response. In this study, we investigated the potential function of SIRT1 in regulating EAE using SIRT1-overexpressing mice. The current studies examine potential neuroprotective and immunomodulatory effects of SIRT1 overexpression in chronic EAE induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55. SIRT1 suppressed EAE clinical symptoms compared with wild-type EAE mice and prevented or altered the phenotype of inflammation in spinal cords; as a result, demyelination and axonal injury were reduced. Significant neuroprotective effects were observed, with fewer apoptotic cells found in the spinal cords of SIRT1-overexpressing EAE mice associated with increased brain-derived neurotrophic factor and NAD levels. Earlier, we showed that brain-derived neurotrophic factor and NAD play crucial neuroprotective roles in EAE. These results suggest that SIRT1 reduces neuronal loss in this chronic demyelinating disease model and that this is associated with a reduction in inflammation.
authors.affiliation: Veterans Affairs Maryland Healthcare System, Baltimore, MD 21201, USA.
authors.forename: Vamshi K
authors.initials: VK
authors.lastname: Nimmagadda
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Bever
authors.forename: Narasimha R
authors.initials: NR
authors.lastname: Vattikunta
authors.forename: Saifi
authors.initials: S
authors.lastname: Talat
authors.forename: Vakas
authors.initials: V
authors.lastname: Ahmad
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Nagalla
authors.forename: David
authors.initials: D
authors.lastname: Trisler
authors.forename: Susan I V
authors.initials: SI
authors.lastname: Judge
authors.forename: Walter
authors.initials: W
authors.lastname: Royal
authors.forename: Krish
authors.initials: K
authors.lastname: Chandrasekaran
authors.forename: James W
authors.initials: JW
authors.lastname: Russell
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Makar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D009243:NAD / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000276:immunology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D013267:Stilbenes; D009243:NAD; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
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