Antidepressant effect of BE360, a new selective estrogen receptor modulator, activated via CREB/BDNF, Bcl-2 signaling pathways in ovariectomized mice
Antidepressant effect of BE360, a new selective estrogen receptor modulator, activated via CREB/BDNF, Bcl-2 signaling pathways in ovariectomized mice
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DOI：
10.1016/j.bbr.2020.112764
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发表时间：
2020-06
影响因子：
2.7
通讯作者：
W. Sakuma;O. Nakagawasai;W. Nemoto;T. Odaira;Takumi Ogawa;K. Ohta;Y. Endo;K. Tan-No
中科院分区：
文献类型：
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作者：
W. Sakuma;O. Nakagawasai;W. Nemoto;T. Odaira;Takumi Ogawa;K. Ohta;Y. Endo;K. Tan-No
我们以前曾报道，碳硼烷化合物BE 360，一种新的选择性雌激素受体调节剂，具有治疗痴呆症的潜力。本研究旨在探讨BE 360对亚慢性应激致绝经后抑郁模型小鼠抑郁样行为的影响及其机制。使用微型渗透泵皮下给予BE 360，持续2周。采用强迫游泳试验评价抑郁样行为。通过分析5-溴-2 '-脱氧尿苷（BrdU）摄取后表达双皮质素（DCX）的细胞来测量海马齿状回（DG）中的神经发生。磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB），脑源性神经营养因子（BDNF）和Bcl-2的水平采用免疫组织化学或免疫印迹法进行测定。OVX +应激暴露小鼠的抑郁样行为在BE 360长期治疗后得到改善。在OVX +应激暴露的小鼠中，BE 360治疗增加海马中的p-CREB、BDNF和Bcl-2表达。免疫组化结果显示，在OVX +应激小鼠海马DG中BrdU/DCX双阳性细胞数量显著减少，而在BE 360亚慢性处理后增加。目前的研究表明，BE 360通过海马神经发生发挥抗抑郁作用，可能通过CREB/BDNF，Bcl-2信号通路激活。这些结果表明，BE 360可能具有治疗绝经后抑郁症的潜力。
We have previously reported that the carborane compound BE360, a novel selective estrogen receptor modulator, has a therapeutic potential against dementia. This study aimed to explore the effects and underlying mechanisms of BE360 on depression-like behaviors in ovariectomized (OVX) mice subjected to subchronic stress, which are postmenopausal depression models. BE360 was subcutaneously administrated using a mini-osmotic pump, for 2 weeks. Depression-like behaviors were evaluated using the forced swimming test. Neurogenesis in the hippocampal dentate gyrus (DG) was measured by analyzing cells expressing doublecortin (DCX) following 5-bromo-2’-deoxyuridine (BrdU) uptake. The levels of phosphorylated cyclic-AMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and Bcl-2 were measured using immunohistochemistry or immunoblotting. Depression-like behaviors in OVX + Stress-exposed mice improved after chronic treatment with BE360. BE360 treatment in OVX + Stress-exposed mice increased p-CREB, BDNF, and Bcl-2 expressions in the hippocampus. Immunohistochemistry showed that the number of BrdU/DCX double-positive cells in the DG of the hippocampus, which decreased significantly in OVX + Stress-exposed mice, increased after subchronic treatment with BE360. The present study demonstrates that BE360 exerts antidepressant effects via hippocampal neurogenesis, potentially activated through CREB/BDNF, Bcl-2 signaling pathways. These results indicate that BE360 may have therapeutic potential against postmenopausal depression.