title: Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin.
abstract: Melatonin, the secretory product of the pineal gland, is known to be neuroprotective in cerebral ischemia, which is so far mostly attributed to its antioxidant properties. Here we show that melatonin directly inhibits the mitochondrial permeability transition pore (mtPTP). mtPTP contributes to the pathology of ischemia by releasing calcium and cytochrome c (cyt c) from mitochondria. Consistently, NMDA-induced calcium rises were diminished by melatonin in cultured mouse striatal neurons, similar to the pattern seen with cyclosporine A (CsA). When the mouse striatal neurons were subjected to oxygen-glucose deprivation (OGD), melatonin strongly prevented the OGD-induced loss of the mitochondrial membrane potential. To assess the direct effect of melatonin on the mtPTP activity at the single channel level, recordings from the inner mitochondrial membrane were obtained by a patch-clamp approach using rat liver mitoplasts. Melatonin strongly inhibited mtPTP currents in a dose-dependent manner with an IC50 of 0.8 microM. If melatonin is an inhibitor of the mtPTP, it should prevent mitochondrial cyt c release as seen in stroke models. Rats underwent middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. Melatonin (10 mg/kg ip) or vehicle was given at the time of occlusion and at the time of reperfusion. Indeed, infarct area in the brain sections of melatonin-treated animals displayed a considerably decreased cyt c release along with less activation of caspase-3 and apoptotic DNA fragmentation. Melatonin treatment diminished the loss of neurons and decreased the infarct volume as compared with untreated MCAO rats. Our findings suggest that the direct inhibition of the mtPTP by melatonin may essentially contribute to its anti-apoptotic effects in transient brain ischemia.
authors.affiliation: Institute for Medical Neurobiology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.forename: Detlef
authors.initials: D
authors.lastname: Siemen
authors.forename: Gerald
authors.initials: G
authors.lastname: Wolf
authors.forename: Thomas F W
authors.initials: TF
authors.lastname: Horn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects; D015687:Cell Hypoxia; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D023421:Models, Animal; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D008550:Melatonin