title: Neuroprotection of agomelatine against cerebral ischemia/reperfusion injury through an antiapoptotic pathway in rat.
abstract: Agomelatine is an agonist of the melatonergic MT1/MT2 receptors and an antagonist of the serotonergic 5-HT receptors. Its actions mimic melatonin in antioxidative and anti-inflammation. However, the protective mechanism of agomelatine in ischemic/reperfusion (I/R) injury has not been investigated. In this study, cerebral I/R injury rats were induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The rats were randomly divided into 6 groups (12 rats per group): sham-operated; vehicle-treated I/R; 20 mg/kg, 40 mg/kg, and 80 mg/kg agomelatine-treated I/R; and 10 mg/kg melatonin-treated I/R. Agomelatine and melatonin were intraperitoneally administrated to the rats 1 h before MCAO induction. After reperfusion for 24 h, the brain samples were harvested for evaluating the infarct volume, histological changes, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining as well as cleaved caspase-3, Bax, Bcl-XL, nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase (HO-1) levels. Agomelatine treatment significantly decreased apoptosis, with decreases in Bax and cleaved caspase-3, and increased Bcl-XL, along with a decrease in apoptotic neuronal cells. Moreover, agomelatine was also found to markedly increase the expression of HO-1, the antioxidative enzymes, and the activity of superoxide dismutase (SOD) mediated by Nrf2 pathway. Agomelatine treatment protects the brain from cerebral I/R injury by suppressing apoptosis and agomelatine has antioxidant properties. Hence, there exists the possibility of developing agomelatine as a potential candidate for treating ischemic stroke.
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Wijitra
authors.initials: W
authors.lastname: Chumboatong
authors.affiliation: Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Sarinthorn
authors.initials: S
authors.lastname: Thummayot
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand; Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
authors.affiliation: Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Chainarong
authors.initials: C
authors.lastname: Tocharus
authors.affiliation: Faculty of Medicine, Mahasarakham University, MahaSarakham, Thailand.
authors.forename: Jinatta
authors.initials: J
authors.lastname: Jittiwat
authors.affiliation: Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Electronic address: jtocharus@gmail.com.
authors.forename: Jiraporn
authors.initials: J
authors.lastname: Tocharus
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D051379:Mice; D000066829:Neuroprotection / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000975:Antioxidants; D006993:Hypnotics and Sedatives; C084711:agomelatine; D009281:Naphthalenes
keywords: Agomelatine; Antioxidant; Apoptosis; Cerebral ischemia/reperfusion; Melatonin; Nrf2