title: Melatonin pretreatment prevented the effect of dexamethasone negative alterations on behavior and hippocampal neurogenesis in the mouse brain.
abstract: Glucocorticoids play various physiological functions via the glucocorticoid receptor (GR). Glucocorticoid is associated with the pathophysiology of depression. Dexamethasone (DEX), a synthetic GR agonist, has a greater affinity for GR than the mineralocorticoid receptor (MR) in the hippocampus of pigs and may mimic the effects of GR possession. DEX decreases neurogenesis and induces damage to hippocampal neurons that is associated with depressive-like behavior. Melatonin, a hormone mainly synthesized in the pineal gland, is a potent free radical scavenger and antioxidant. Melatonin alters noradrenergic transmission in depressed patients. It may be interesting to further explore the mechanism of melatonin that is associated with the role of stress as a key factor to precipitate depression and as a factor altering neurogenesis. In this study, we assessed the capability of melatonin to protect the hippocampus of mouse brains to counteract the effects of chronic DEX treatment for 21 days on depressive-like behavior and neurogenesis. Our results revealed that chronic administration of DEX induced depressive-like behavior and that this could be reversed by pretreatment with melatonin. Moreover, the number of 5-bromo-2-deoxyuridine (BrdU)-immunopositive cells and doublecortin (DCX; the neuronal-specific marker) protein levels were significantly reduced in the DEX-treated mice. Pretreatment with melatonin was found to renew BrdU and DCX expression in the dentate gyrus. Furthermore, pretreatment with melatonin prevented DEX-induced reductions in GR and an extracellular-signal-regulated kinase (ERK1/2) in the hippocampal area. Melatonin may protect hippocampal neurons from damage and reverse neurogenesis after chronic DEX by activating brain-derived neurotrophic (BDNF) and ERK1/2 cascades. These results revealed that melatonin pretreatment prevented the reduction of cell proliferation, immature neuron precursor cells, and GR and ERK1/2 expression. This finding indicates that melatonin attenuates the DEX-induced depressive-like behavior, supporting the notion that melatonin possesses anti-stress and neurogenic actions.
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Thailand; National Institute for Child and Family Development, Mahidol University, Thailand.
authors.forename: Nootchanart
authors.initials: N
authors.lastname: Ruksee
authors.affiliation: Faculty of Medicine, Mahasarakham University, Thailand; Department of Biology, Faculty of Science, Mahasarakham University, Thailand.
authors.forename: Walaiporn
authors.initials: W
authors.lastname: Tongjaroenbuangam
authors.affiliation: Department of Biology, Faculty of Science, Mahasarakham University, Thailand.
authors.forename: Thanutchaporn
authors.initials: T
authors.lastname: Mahanam
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; D000893:Anti-Inflammatory Agents / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003863:Depression / Q000139:chemically induced / Q000517:prevention & control*; D003907:Dexamethasone / Q000009:adverse effects*; D000089662:Doublecortin Protein; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002492:Central Nervous System Depressants; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D048049:Extracellular Signal-Regulated MAP Kinases; D008550:Melatonin
keywords: Depression; Dexamethasone; ERK1/2; Glucocorticoid receptor; Hippocampus; Melatonin; Neurogenesis; Stress