dc.creatorVivinetto, Ana Laura
dc.creatorCastañares, Clara Nicole
dc.creatorGarcia Keller, Constanza
dc.creatorMoyano, Ana Lis
dc.creatorFalcón, Cristian Roberto
dc.creatorPalandri, Anabela
dc.creatorRozés Salvador, María Victoria
dc.creatorRojas, Juan Ignacio
dc.creatorPatrucco, Liliana
dc.creatorMonferran, Clara Graciela
dc.creatorCancela, Liliana Marina
dc.creatorCristiano, Edgardo
dc.creatorSchnaar, Ronald L.
dc.creatorLopez, Pablo H. H.
dc.date.accessioned2022-09-05T10:19:23Z
dc.date.accessioned2022-10-15T04:14:25Z
dc.date.available2022-09-05T10:19:23Z
dc.date.available2022-10-15T04:14:25Z
dc.date.created2022-09-05T10:19:23Z
dc.date.issued2022-04
dc.identifierVivinetto, Ana Laura; Castañares, Clara Nicole; Garcia Keller, Constanza; Moyano, Ana Lis; Falcón, Cristian Roberto; et al.; Myelin-associated glycoprotein activation triggers glutamate uptake by oligodendrocytes in vitro and contributes to ameliorate glutamate-mediated toxicity in vivo; Elsevier Science; Biochimica et Biophysica Acta - Molecular Basis of Disease; 1868; 4; 4-2022; 1-15
dc.identifier0925-4439
dc.identifierhttp://hdl.handle.net/11336/167274
dc.identifierCONICET Digital
dc.identifierCONICET
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/4344053
dc.description.abstractBackground: Myelin-associated glycoprotein (MAG) is a key molecule involved in the nurturing effect of myelin on ensheathed axons. MAG also inhibits axon outgrowth after injury. In preclinical stroke models, administration of a function-blocking anti-MAG monoclonal antibody (mAb) aimed to improve axon regeneration demonstrated reduced lesion volumes and a rapid clinical improvement, suggesting a mechanism of immediate neuroprotection rather than enhanced axon regeneration. In addition, it has been reported that antibody-mediated crosslinking of MAG can protect oligodendrocytes (OLs) against glutamate (Glu) overload by unknown mechanisms. Purpose: To unravel the molecular mechanisms underlying the protective effect of anti-MAG therapy with a focus on neuroprotection against Glu toxicity. Results: MAG activation (via antibody crosslinking) triggered the clearance of extracellular Glu by its uptake into OLs via high affinity excitatory amino acid transporters. This resulted not only in protection of OLs but also nearby neurons. MAG activation led to a PKC-dependent activation of factor Nrf2 (nuclear-erythroid related factor-2) leading to antioxidant responses including increased mRNA expression of metabolic enzymes from the glutathione biosynthetic pathway and the regulatory chain of cystine/Glu antiporter system xc− increasing reduced glutathione (GSH), the main antioxidant in cells. The efficacy of early anti-MAG mAb administration was demonstrated in a preclinical model of excitotoxicity induced by intrastriatal Glu administration and extended to a model of Experimental Autoimmune Encephalitis showing axonal damage secondary to demyelination. Conclusions: MAG activation triggers Glu uptake into OLs under conditions of Glu overload and induces a robust protective antioxidant response.
dc.languageeng
dc.publisherElsevier Science
dc.relationinfo:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1016/j.bbadis.2021.166324
dc.relationinfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S092544392100257X
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectEXCITOTOXICITY
dc.subjectEXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
dc.subjectGLUTAMATE
dc.subjectMULTIPLE SCLEROSIS
dc.subjectMYELIN
dc.subjectMYELIN-ASSOCIATED GLYCOPROTEIN
dc.subjectNEURODEGENERATION
dc.subjectNEUROPROTECTION
dc.subjectOLIGODENDROCYTE
dc.subjectSTROKE
dc.titleMyelin-associated glycoprotein activation triggers glutamate uptake by oligodendrocytes in vitro and contributes to ameliorate glutamate-mediated toxicity in vivo
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:ar-repo/semantics/artículo
dc.typeinfo:eu-repo/semantics/publishedVersion


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