Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti‐apoptotic effects of melatonin
- 19 March 2004
- journal article
- fj express-summary
- Published by Wiley in The FASEB Journal
- Vol. 18 (7), 869-871
- https://doi.org/10.1096/fj.03-1031fje
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.Keywords
This publication has 69 references indexed in Scilit:
- Administration of Melatonin After Onset of Ischemia Reduces the Volume of Cerebral Infarction in a Rat Middle Cerebral Artery Occlusion Stroke ModelStroke, 2003
- Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke modelJournal of Pineal Research, 2002
- Significance of Melatonin in Antioxidative Defense System: Reactions and ProductsNeurosignals, 2000
- Melatonin increases striatal dopaminergic function in 6-OHDA-lesioned ratsNeuroReport, 1998
- Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in miceJournal of Pineal Research, 1998
- Melatonin administration protects CA1 hippocampal neurons after transient forebrain ischemia in ratsBrain Research, 1997
- Increased brain damage after stroke or excitotoxic seizures in melatonin‐deficient ratsThe FASEB Journal, 1996
- Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymesThe FASEB Journal, 1996
- Melatonin stimulates brain glutathione peroxidase activityNeurochemistry International, 1995
- Effects of melatonin on microtubule assembly depend on hormone concentration: Role of melatonin as a calmodulin antagonistJournal of Pineal Research, 1994