title: Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus.
abstract: Glucocorticoids, hormones that are released in response to stress, induce neuronal cell damage. The hippocampus is a primary target of glucocorticoids in the brain, the effects of which include the suppression of cell proliferation and diminished neurogenesis in the dentate gyrus. Our previous study found that melatonin, synthesized primarily in the pineal, pretreatment prevented the negative effects of dexamethasone, the glucocorticoid receptor agonist, on behavior and neurogenesis in rat hippocampus. In the present study, we attempted to investigate the interrelationship between melatonin and dexamethasone on the underlying mechanism of neural stem cell proliferation. Addition of dexamethasone to hippocampal progenitor cells from eight-week old rats resulted in a decrease in the number of neurospheres; pretreatment with melatonin precluded these effects. The immunocytochemical analyses indicated a reduction of Ki67 and nestin-positive cells in the dexamethasone-treated group, which was minimized by melatonin pretreatment. A reduction of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and G1-S phase cell cycle regulators cyclin E and CDK2 in dexamethasone-treated progenitor cells were prevented by pretreatment of melatonin. Moreover, luzindole, a melatonin receptor antagonist blocked the positive effect of melatonin whereas RU48, the glucocorticoid receptor antagonist blocked the negative effect of dexamethasone on the number of neurospheres. Moreover, we also found that dexamethasone increased the glucocorticoid receptor protein but decreased the level of MT1 melatonin receptor, whereas melatonin increased the level of MT1 melatonin receptor but decreased the glucocorticoid receptor protein. These suggest the crosstalk and cross regulation between the melatonin receptor and the glucocorticoid receptor on hippocampal progenitor cell proliferation.
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Thailand.
authors.forename: Kasima
authors.initials: K
authors.lastname: Ekthuwapranee
authors.affiliation: Center for Neuroscience, Faculty of Science, Mahidol University, Thailand.
authors.forename: Areechun
authors.initials: A
authors.lastname: Sotthibundhu
authors.affiliation: Department of Anatomy, Faculty of Medicine, Chiang Mai University, Thailand.
authors.forename: Chainarong
authors.initials: C
authors.lastname: Tocharus
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Thailand; Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Thailand. Electronic address: piyarat.gov@mahidol.ac.th.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D044094:Receptors, Melatonin; D003907:Dexamethasone; D048049:Extracellular Signal-Regulated MAP Kinases; D008550:Melatonin
keywords: Adult neurogenesis; Dexamethasone; Glucocorticoid; Melatonin; Proliferation; Stress