Wang Jing, Li Hao-Yuan, Shen Shi-Yu, Zhang Jia-Rui, Liang Ling-Feng, Huang Hui-Jie, Li Bing, Wu Gen-Cheng, Zhang Yu-Qiu, Yu Jin
Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Center Laboratories, Jinshan Hospital of Fudan University, Shanghai, 201508, China.
J Steroid Biochem Mol Biol. 2021 Mar;207:105807. doi: 10.1016/j.jsbmb.2020.105807. Epub 2020 Dec 17.
Postmenopausal depression is mainly caused by the deprivation of ovarian hormones during menopausal transition, it is of great importance to study on the treatment that could effectively relieve symptoms of menopausal depression with fewer side effects. Activation of G-protein-coupled estrogen receptor (GPER) has long been reported to facilitate neuronal plasticity and improve cognition in animals. Meanwhile, it could participate in regulation of intracellular signaling pathways through the characteristic of GPER, ameliorate intracellular mitochondrial function and oxidative stress. However, the impact of GPER on regulating estrogen deprived-depressant and anxious behaviors is still largely unknown. Here we used the ovariectomized female rats to imitate the condition of menopause. Owing to the lateral ventricle administration of G-1 which specifically react with GPER receptor intracerebrally, Ovariectomized (OVX) female rats showed depressive- or anxiety-like phenotypes with attenuated mitochondrial function. In addition, G-1 facilitated PKA activation, which further accelerated TSPO phosphorylation and alleviated menopausal depression- and anxiety-like behaviors. Moreover, PKA inhibitor PKI could partially antagonized the anti-anxiety and anti-depression effects of G-1. Taken together, we concluded that GPER activation might exhibit antidepressant and anxiolytic effect by elevating TSPO phosphorylation via protein kinase A signaling and rescuing the redox status in menopausal female rats.
绝经后抑郁症主要由绝经过渡期间卵巢激素缺乏引起，研究能够有效缓解绝经后抑郁症症状且副作用较少的治疗方法具有重要意义。长期以来，有报道称激活G蛋白偶联雌激素受体（GPER）可促进动物的神经元可塑性并改善认知。同时，它可通过GPER的特性参与细胞内信号通路的调节，改善细胞内线粒体功能和氧化应激。然而，GPER对调节雌激素缺乏所致的抑郁和焦虑行为的影响仍 largely未知。在这里，我们使用去卵巢雌性大鼠来模拟绝经状态。由于向侧脑室注射与GPER受体在脑内特异性反应的G-1，去卵巢（OVX）雌性大鼠表现出抑郁或焦虑样表型，线粒体功能减弱。此外，G-1促进蛋白激酶A（PKA）激活，进而加速转运体蛋白18 kDa（TSPO）磷酸化，减轻绝经后抑郁和焦虑样行为。此外，PKA抑制剂PKI可部分拮抗G-1的抗焦虑和抗抑郁作用。综上所述，我们得出结论，激活GPER可能通过蛋白激酶A信号通路提高TSPO磷酸化水平并恢复绝经后雌性大鼠的氧化还原状态，从而发挥抗抑郁和抗焦虑作用。
