17β-Estradiol augments the neuroprotective effect of agomelatine in depressive- and anxiety-like behaviors in ovariectomized rats
17β-Estradiol augments the neuroprotective effect of agomelatine in depressive- and anxiety-like behaviors in ovariectomized rats
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DOI：
10.1007/s00213-020-05580-2
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发表时间：
2020-06-13
影响因子：
3.4
通讯作者：
Khattab, Mahmoud M.
中科院分区：
文献类型：
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作者：
El-Khatib, Yasmine A.;Sayed, Rabab H.;Khattab, Mahmoud M.
理由和客观雌二醇下降与绝经后妇女的抑郁和焦虑有关。 Agomelatine (Ago) 是褪黑激素 MT1/MT2 受体的激动剂和血清素 5-HT2c 受体的拮抗剂。本研究旨在评估 Ago 与 17 β-雌二醇 (E2) 联合使用对年轻成年雌性大鼠卵巢切除术 (OVX) 诱导的抑郁和焦虑样行为的影响。方法 OVX 大鼠从手术后 1 周开始单独使用 Ago（40 mg/kg/天，口服）治疗 10 天，或在行为测试前联合使用两剂 E2（40 μg/kg/天，皮下注射）。结果 E2 的联合给药增强了 Ago 的抗抑郁和抗焦虑作用，表现为强迫游泳试验中不动时间的减少，以及在高架十字迷宫中张开臂的时间和进入张开臂的次数的增加。与此同时，Ago 增加了海马去甲肾上腺素、多巴胺、褪黑激素和脑源性神经营养因子 (BDNF)。同时，Ago 治疗的大鼠表现出海马核因子 kappa beta (NF-kB) P65 表达和促炎细胞因子水平降低。 Ago 上调 OVX 大鼠海马区雌激素受体（ER α 和 β）mRNA 表达，并升高血清雌二醇水平。 E2 与 Ago 联合给药可协同降低 NF-kB P65 表达和促炎细胞因子，并增加 BDNF 水平。结论 E2 通过其抗炎和神经营养作用增强了 Ago 对 OVX 大鼠的神经保护作用。应进一步研究 E2 和 Ago 的联合治疗作为治疗与更年期相关的抑郁、焦虑和睡眠障碍的选择。
Rationale and objective Estradiol decline has been associated with depression and anxiety in post-menopausal women. Agomelatine (Ago) is an agonist of the melatonergic MT1/MT2 receptors and an antagonist of the serotonergic 5-HT2c receptors. The present study aimed to evaluate the effects of combining Ago with 17 beta-estradiol (E2) on ovariectomy (OVX)-induced depressive- and anxiety-like behaviors in young adult female rats. Methods OVX rats were treated with Ago (40 mg/kg/day, p.o.) for 10 days starting 1 week after surgery alone or combined with two doses of E2 (40 mu g/kg/day, s.c.) given before behavioral testing. Results Co-administration of E2 enhanced the anti-depressant and anxiolytics effects of Ago as evidenced by decreased immobility time in the forced swimming test, as well as increased time spent in the open arms and number of entries to open arms in the elevated plus-maze. In parallel, Ago increased hippocampal norepinephrine, dopamine, melatonin, and brain-derived neurotrophic factor (BDNF). Meanwhile, Ago-treated rats exhibited reduced hippocampal nuclear factor kappa beta (NF-kB) P65 expression and pro-inflammatory cytokine level. Ago upregulated estrogen receptor (ER alpha and beta) mRNA expression in the hippocampus of OVX rats and elevated serum estradiol levels. Co-administration of E2 with Ago synergistically decreased NF-kB P65 expression and pro-inflammatory cytokines, and increased BDNF levels. Conclusion E2 augmented the neuroprotective effect of Ago in OVX rats via its anti-inflammatory and neurotrophic effects. The combined treatment of E2 and Ago should be further investigated as a treatment of choice for depression, anxiety, and sleep disturbances associated with menopause.