Antidepressant effect of BE360, a new selective estrogen receptor modulator, and its mechanism in ovariectomized mice

[Speaker] Wakana Sakuma:1
[Co-author] Osamu Nakagawasai:1, Wataru Nemoto:1, Takayo Odaira:1, Takumi Ogawa:2, Kiminori Ohta:2, Yasuyuki Endo:2, Koichi Tan-No:1
1:Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan, 2:Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan

[Background] The prevalence of major depressive disorder is higher in women than in men, and this may be associated with decline in estrogen levels that occur during the menopausal transition. We have reported that ovariectomized (OVX) mice are vulnerable to stress and exhibit behavioral phenotypes similar to animal models of depression when subjected to subchronic stress. Estrogen supplementation has alleviated depressive-like behavior in OVX mice, though the supplementation is not generally used for postmenopausal depression due to the risk of uterine cancer. The aim of this study was to investigate the effect of a new selective estrogen receptor modulator BE360 on depressive-like behavior and uterus weight in OVX mice.
[Methods] Female ddY mice of 8 weeks of age were divided randomly two groups : Sham-operated and OVX groups. All groups were assigned to a daily stress (1 h/day) for 7 days from the 7th day after operation. BE360 was administrated subcutaneously to mice using a mini-osmotic pump for 2 weeks after OVX surgery. We performed forced swimming test (FST) on the 14th day after surgery to evaluate an antidepressant effect of BE360. The expression of phosphorylated cyclic-AMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BDNF) and Bcl-2 were measured by immunohistochemistry or western blotting. Neurogenesis in the hippocampal dentate gyrus (DG) was assessed by the analysis of cells expressing 5-bromo-2'-deoxyuridine (BrdU) uptake.
[Results] Immobility time on the FST significantly prolonged in OVX group in comparison to Sham group, and the prolongation significantly decreased by the chronic administration of BE360. Further, uterus weight was not influenced in the BE360-administrated OVX group, whereas the uterus weight was increased in the estradiol-administrated OVX group. Moreover, BE360 significantly increased expression of p-CREB, BDNF and Bcl-2 in dorsal hippocampus and number of BrdU-positive cells in the DG of OVX mice.
[Conclusions] These results indicate that BE360 has antidepressant effect by promoting hippocampal neurogenesis via CREB/BDNF, Bcl-2 signaling pathways, and suggest that BE360 may become valuable therapeutic compound against postmenopausal depression.

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