Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice. (15th July 2018)

• Record Type: Journal Article
• Authors: Takahashi, Kohei; Nakagawasai, Osamu; Nemoto, Wataru; Kadota, Shogo; Isono, Jinichi; Odaira, Takayo; Sakuma, Wakana; Arai, Yuichiro; Tadano, Takeshi; Tan-No, Koichi
• Is Part Of: Neuropharmacology. Volume 137(2018)
• Page Start: 141
• Page End: 155
• Publication Date: 2018-07-15
• Subjects: Apoptosis -- Cell proliferation -- Depression -- Emotional behavior -- Olfactory bulbectomy -- Neuroinflammation; ANOVA analysis of variance -- Bax Bcl-2-associated protein X -- Bcl-2 B cell lymphoma/leukemia gene 2 -- BDNF brain-derived neurotrophic factor -- BrdU 5-bromo-2′-deoxyuridine -- CREB cAMP-responsive element binding protein -- DA dopamine -- DARPP-32 dopamine- and cAMP-regulated phosphoprotein-32 -- DOPAC dihydroxyphenylacetic acid -- DG dentate gyrus -- ERK extracellular signal-regulated protein kinase -- GFAP glial fibrillary acidic protein -- HVA homovanillic acid -- Iba1 ionized calcium binding adaptor molecule 1 -- IL-6 interleukin-6 -- i.p. intraperitoneally -- IκB-α NF-κB inhibitor-α -- MAO monoamine oxidase -- MEM memantine -- MHA 3-methoxy-4-hydroxymandelic acid -- NMDA N-methyl-d-aspartate -- NE norepinephrine -- NeuN neuronal nuclear antigen -- NF-κB nuclear factor-kappa B -- OBX olfactory bulbectomized -- p.o. per os -- PBS phosphate-buffered saline -- PFC prefrontal cortex -- PKA protein kinase A -- PLSD Protected Least Significant Difference -- ROI region of interest -- SEM standard error of the mean -- TH tyrosine hydroxylase -- TNF-α tumor necrosis factor-α; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.04.013
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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-IκB-α, p-NF-κB p65, TNF-α, 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. Highlights: Memantine improves depressive-like behavior in olfactory bulbectomized (OBX) mice. Memantine increases dopamine levels in the hippocampus. Memantine promotes hippocampal cell proliferation via the PKA-ERK-CREB-BDNF pathway. Memantine attenuates OBX-induced neuroinflammation in the hippocampus. Memantine modulates apoptosis in the hippocampus of OBX mice.