PMID- 29729893 OWN - NLM STAT- MEDLINE DCOM- 20190220 LR - 20220410 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 137 DP - 2018 Jul 15 TI - Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice. PG - 141-155 LID - S0028-3908(18)30168-0 [pii] LID - 10.1016/j.neuropharm.2018.04.013 [doi] AB - Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-IkappaB-alpha, p-NF-kappaB p65, TNF-alpha, IL-6, Bax, and cleaved caspase-3 were increased in the hippocampus. These changes (except for those in NE and Bax) were reversed with chronic administration of MEM. These results suggest that MEM-induced antidepressant effects are associated with enhanced hippocampal cell proliferation and neuroprotection via the PKA-ERK-CREB-BDNF/Bcl-2-caspase-3 pathway and increased DA levels. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Takahashi, Kohei AU - Takahashi K AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. FAU - Nakagawasai, Osamu AU - Nakagawasai O AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: osamun@tohoku-mpu.ac.jp. FAU - Nemoto, Wataru AU - Nemoto W AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. FAU - Kadota, Shogo AU - Kadota S AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. FAU - Isono, Jinichi AU - Isono J AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. FAU - Odaira, Takayo AU - Odaira T AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. FAU - Sakuma, Wakana AU - Sakuma W AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. FAU - Arai, Yuichiro AU - Arai Y AD - Course of Judo-therapy, Faculty of Health Science, Tokyo Ariake University of Medical and Health Science, 2-9-1 Ariake, Koto-Ku, Tokyo 135-0063, Japan. FAU - Tadano, Takeshi AU - Tadano T AD - Complementary and Alternative Medicine Clinical Research and Development, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan. FAU - Tan-No, Koichi AU - Tan-No K AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180504 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Neuroprotective Agents) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - VTD58H1Z2X (Dopamine) RN - W8O17SJF3T (Memantine) SB - IM MH - Animals MH - Apoptosis/drug effects/physiology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Proliferation/*drug effects/physiology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - Depressive Disorder/*drug therapy/pathology/physiopathology MH - Disease Models, Animal MH - Dopamine/metabolism MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Hippocampus/*drug effects/physiopathology MH - Inflammation/drug therapy/pathology/physiopathology MH - Male MH - Memantine/*pharmacology MH - Mice MH - Microglia/drug effects/pathology/physiology MH - Neuroprotective Agents/*pharmacology MH - Olfactory Bulb/*injuries OTO - NOTNLM OT - Apoptosis OT - Cell proliferation OT - Depression OT - Emotional behavior OT - Neuroinflammation OT - Olfactory bulbectomy EDAT- 2018/05/08 06:00 MHDA- 2019/03/21 06:00 CRDT- 2018/05/07 06:00 PHST- 2017/10/31 00:00 [received] PHST- 2018/04/05 00:00 [revised] PHST- 2018/04/10 00:00 [accepted] PHST- 2018/05/08 06:00 [pubmed] PHST- 2019/03/21 06:00 [medline] PHST- 2018/05/07 06:00 [entrez] AID - S0028-3908(18)30168-0 [pii] AID - 10.1016/j.neuropharm.2018.04.013 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jul 15;137:141-155. doi: 10.1016/j.neuropharm.2018.04.013. Epub 2018 May 4.