title: AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model.
abstract: AMP-activated protein kinase (AMPK) signaling is reported to protect neurons under pathologic conditions; however, its effect on oligodendrocytes (OLs) remains to be elucidated. We investigated whether AMPK signaling protects OLs to restore central nervous system (CNS) functions in an experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Increased inflammation and demyelination in the CNS and peripheral immune responses were consistent with the observed clinical impairments in EAE animals, which were attenuated by treatment with metformin compared with vehicle. In addition, expressions of neurotrophic factors and of signatory genes of OL lineages were increased in the CNS of metformin-treated EAE animals. Likewise, metformin attenuated inflammatory response and enhanced expressions of neurotrophic factors, thereby protecting OLs via AMPK activation in mixed glial cultures stimulated with lipopolysaccharide/interferon γ in vitro, as evidenced by analysis of the expression of signatory genes of O1(+)/MBP(+) OLs and their cellular populations. Metformin also attenuated oxidative stress and malondialdehyde-containing protein levels, with corresponding induction of antioxidative defenses in OLs exposed to cytokines via AMPK activation. These effects of metformin were evident in the CNS of EAE animals. These data provide evidence that AMPK signaling is crucial to protect OLs and, thus, CNS functions in EAE animals. We conclude that AMPK activators, including metformin, have the potential to limit neurologic deficits in multiple sclerosis and related neurodegenerative disorders.
authors.affiliation: Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Ajaib S
authors.initials: AS
authors.lastname: Paintlia
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Paintlia
authors.forename: Sarumathi
authors.initials: S
authors.lastname: Mohan
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D002490:Central Nervous System / Q000201:enzymology / Q000502:physiology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D008687:Metformin / Q000494:pharmacology; D009457:Neuroglia / Q000201:enzymology / Q000502:physiology; D009836:Oligodendroglia / Q000201:enzymology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002491:Central Nervous System Agents; D016207:Cytokines; D017382:Reactive Oxygen Species; D008687:Metformin; D055372:AMP-Activated Protein Kinases