title: Bax and calpain mediate excitotoxic oligodendrocyte death induced by activation of both AMPA and kainate receptors.
abstract: Sustained activation of AMPA and kainate receptors in rat oligodendrocytes induces cytosolic calcium overload, mitochondrial depolarization, and an increase of reactive oxygen species, resulting in cell death. Here, we provide evidence that Bax, a proapoptotic member of the Bcl-2 protein family, is involved in excitotoxic apoptotic death of oligodendrocytes and that calpain mediates Bax activation. Cultured Bax(-/-) oligodendrocytes, obtained from the optic nerve of Bax knock-out mice, were resistant to AMPA and kainate receptor-mediated insults. In turn, both mitochondrial calcium uptake and mitochondrial alterations after excitotoxic insults were diminished in Bax-null oligodendrocytes. Moreover, pretreatment with furosemide, a blocker of Bax translocation to mitochondria, significantly protected rat and mouse oligodendrocytes from AMPA- and kainate-induced damage; in contrast, bongkrekic acid, a blocker of the mitochondrial permeability transition pore, had no effect. Finally, we analyzed the participation of calpain, which cleaves Bax and is activated by AMPA and kainate, in oligodendrocyte death. Pretreatment with 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD150606), a broad cell-permeable calpain inhibitor, and two additional calpain inhibitors diminished Bax activation, inhibited its translocation to mitochondria, and attenuated all apoptotic events resulting from excitotoxic insults to rat oligodendrocytes. Together, these results indicate that Bax and calpain are essential intermediaries of the mitochondria-dependent death pathway, triggered by AMPA and kainate receptor activation in oligodendrocytes.
authors.affiliation: Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Departamento de Neurociencias, Facultad de Medicina y Odontología, Universidad del País Vasco, 48940 Leioa, Spain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Sánchez-Gómez
authors.forename: Elena
authors.initials: E
authors.lastname: Alberdi
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000819:agonists / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*
chemical_list: D002154:Calpain; D015853:Cysteine Proteinase Inhibitors; D009498:Neurotoxins; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D051028:bcl-2-Associated X Protein