title: Melatonin modulates permeability transition pore and 5-hydroxydecanoate induced KATPchannel inhibition in isolated brain mitochondria.
abstract: There is increasing recognition of the magnitude of mitochondria in neurodegenerative disorders. Mitochondria play a key role in apoptotic and necrotic cell death. Melatonin (Mel), an indoleamine produced in several organs including the pineal gland has been known for its neuroprotective actions. In our study, we have investigated whether the mitochondrial ATP sensitive potassium (mtKATP) channel blocker 5-hydroxydecanoate (5-HD) and calcium (Ca2+) affects permeability transition pore (PTP) alterations in isolated brain mitochondria treated with melatonin (Mel) and cyclosporin A (CsA). Mitochondrial swelling, mitochondrial membrane potential (Δψm), ROS measurement and mitochondrial respiration were evaluated in isolated brain mitochondria. In our results, mitochondrial swelling stimulated by exposing Ca2+ions and 5-HD associated by mPTP opening as depicted by modulation of CsA and Mel. In addition, Ca2+and 5-HD decreased Δψm, depleted intracellular ROS, and inhibition of mitochondrial respiration (state 3 and state 4) in isolated brain mitochondria. Addition of Mel and CsA has shown significant restoration in mitochondrial swelling, Δψm, intracellular ROS measurement and mitochondrial respiration in isolated brain mitochondria. Therefore, we speculate the modulatory effect of Mel and CsA in mitochondria treated with 5-HD and Ca2+hinders the mPTP-mediated mitochondrial dysfunction and cellular oxidative stress. We conclude that inhibition of mPT is one likely mechanism of CsA's and its neuroprotective actions. Development of neuroprotective agents including Mel targeting the mPTP therefore bears hope for future treatment of severe neurodegenerative diseases.
authors.affiliation: School of Medicine, University of Alabama at Birmingham, Birmingham, AL-35294 USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Waseem
authors.affiliation: Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110 062, India.
authors.forename: Heena
authors.initials: H
authors.lastname: Tabassum
authors.affiliation: Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110 062, India. Electronic address: sparvez@jamiahamdard.ac.in.
authors.forename: Suhel
authors.initials: S
authors.lastname: Parvez
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D016572:Cyclosporine / Q000378:metabolism; D003652:Decanoic Acids / Q000378:metabolism*; D006880:Hydroxy Acids / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents / Q000378:metabolism*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000032:analysis
chemical_list: D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C052853:5-hydroxydecanoic acid; D016572:Cyclosporine; D008550:Melatonin
keywords: 5-Hydroxydecanoate; K(ATP) channels; Melatonin; Mitochondria; Oxidative stress; Permeability transition pore