title: Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function.
abstract: Oxidative stress and mitochondrial dysfunction play indispensable role in memory and learning impairment. Growing evidences have shed light on anti-oxidative role for melatonin in memory deficit. We have previously reported that inhibition of protein kinase A by H-89 can induce memory impairment. Here, we investigated the effect of melatonin on H-89 induced spatial memory deficit and pursued their interactive consequences on oxidative stress and mitochondrial function in Morris Water Maze model. Rats received melatonin (50 and 100μg/kg/side) and H-89(10μM) intra-hippocampally 30min before each day of training. Animals were trained for 4 consecutive days, each containing one block from four trials. Oxidative stress indices, including thiobarbituric acid (TBARS), reactive oxygen species (ROS), thiol groups, and ferric reducing antioxidant power (FRAP) were assessed using spectrophotometer. Mitochondrial function was evaluated through measuring ROS production, mitochondrial membrane potential (MMP), swelling, outer membrane damage, and cytochrome c release. As expected from our previous report, H-89 remarkably impaired memory by increasing the escape latency and traveled distance. Intriguingly, H-89 significantly augmented TBARS and ROS levels, caused mitochondrial ROS production, swelling, outer membrane damage, and cytochrome c release. Moreover, H-89 lowered thiol, FRAP, and MMP values. Intriguingly, melatonin pre-treatment not only effectively hampered H-89-mediated spatial memory deficit at both doses, but also reversed the H-89 effects on mitochondrial and biochemical indices upon higher dose. Collectively, these findings highlight a protective role for melatonin against H-89-induced memory impairment and indicate that melatonin may play a therapeutic role in the treatment of oxidative- related neurodegenerative disorders.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Rojin
authors.initials: R
authors.lastname: Sharif
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Aghsami
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Gharghabi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sanati
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran; College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, MB, Canada; Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: Khorshidahmad
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Vakilzadeh
authors.affiliation: Department of Neuroscience, School of Advanced Science and Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hajar
authors.initials: H
authors.lastname: Mehdizadeh
authors.affiliation: Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, M5S 3M2, Toronto, ON, Canada.
authors.forename: Shervin
authors.initials: S
authors.lastname: Gholizadeh
authors.affiliation: Department of Neuroscience, School of Advanced Science and Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ghorban
authors.initials: G
authors.lastname: Taghizadeh
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran. Electronic address: msharifzadeh@tums.ac.ir.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sharifzadeh
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D007546:Isoquinolines / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000633:toxicity*; D014991:Xylazine / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D014991:Xylazine; D045304:Cytochromes c; D008550:Melatonin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Hippocampus; Melatonin; Mitochondrial function; Oxidative stress; Protein kinase A; Spatial memory