title: Mitochondrial permeability transition pore inhibitors prevent ethanol-induced neuronal death in mice.
abstract: Ethanol induces brain injury by a mechanism that remains partly unknown. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). Here, we tested the effect of ethanol and PTP inhibitors on mitochondrial physiology and cell viability both in vitro and in vivo. Direct addition of ethanol up to 100 mM on isolated mouse brain mitochondria slightly decreased oxygen consumption but did not affect PTP regulation. In comparison, when isolated from ethanol-treated (two doses of 2 g/kg, 2 h apart) 7-day-old mouse pups, brain mitochondria displayed a transient decrease in oxygen consumption but no change in PTP regulation or H2O2 production. Conversely, exposure of primary cultured astrocytes and neurons to 20 mM ethanol for 3 days led to a transient PTP opening in astrocytes without affecting cell viability and to a permanent PTP opening in 10 to 20% neurons with the same percentage of cell death. Ethanol-treated mouse pups displayed a widespread caspase-3 activation in neurons but not in astrocytes and dramatic behavioral alterations. Interestingly, two different PTP inhibitors (namely, cyclosporin A and nortriptyline) prevented both ethanol-induced neuronal death in vivo and ethanol-induced behavioral modifications. We conclude that PTP opening is involved in ethanol-induced neurotoxicity in the mouse.
authors.affiliation: Inserm , U1055, Laboratoire de Bioénergétique Fondamentale et Appliquée (LBFA) et SFR Biologie Environnementale et Systémique (BEeSy), Grenoble, F-38041, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lamarche
authors.forename: Carole
authors.initials: C
authors.lastname: Carcenac
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gonthier
authors.forename: Cecile
authors.initials: C
authors.lastname: Cottet-Rousselle
authors.forename: Christiane
authors.initials: C
authors.lastname: Chauvin
authors.forename: Luc
authors.initials: L
authors.lastname: Barret
authors.forename: Xavier
authors.initials: X
authors.lastname: Leverve
authors.forename: Marc
authors.initials: M
authors.lastname: Savasta
authors.forename: Eric
authors.initials: E
authors.lastname: Fontaine
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009661:Nortriptyline / Q000494:pharmacology; D011247:Pregnancy
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009243:NAD; D000431:Ethanol; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D009661:Nortriptyline; D053148:Caspase 3