Song Qiaoli, Huang Weiming, Ye Wenbin, Yan Huan, Wang Liting, Yang Yan, Cheng Xi, Zhang Weiqiang, Zheng Jie, He Ping, He Yaojuan, Fang Dajun, Han Xinjia
Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Front Aging Neurosci. 2022 Jul 8;14:869274. doi: 10.3389/fnagi.2022.869274. eCollection 2022.
Estradiol (E) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E-treated PD rats. These results suggest that the neuroprotective role of E in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.
雌二醇（E）已被证明对治疗围绝经期抑郁症（PD）有效；然而，其下游信号通路尚未完全阐明。瞬时受体电位通道6（TRPC6）在促进神经元发育和兴奋性突触形成中起重要作用。目前，我们发现与围绝经期女性相比，PD女性血清中的E和脑源性神经营养因子（BDNF）水平显著下降，同时TRPC6水平明显降低。为进一步揭示TRPC6对神经元存活和兴奋性的影响，通过完全切除左侧卵巢并切除右侧卵巢的80%，随后进行21天的慢性不可预测轻度应激，建立了类PD大鼠模型。每日进行以下处理，持续21天：胃内给予E（2mg/kg）、腹腔注射BDNF/TrB信号通路抑制剂（K252a，100μg/kg）和TRPC6激动剂（OAG，0.6mg/kg），以及脑室内注入抗BDNF抗体以阻断BDNF（0.5μg/24μl/大鼠）。与对照大鼠相比，PD大鼠血清中的BDNF和TRPC6水平较低；诱导出了类似抑郁的行为，海马区神经元死亡率增加，PD组突触后致密部（PSD）厚度和不对称突触数量显著减少。E治疗显著上调了血清中BDNF和TRPC6的水平，PSD厚度和不对称突触数量增加表明神经元兴奋性增强，而这些作用被K252a逆转；TRPC6激动剂与K252a联合使用改善了神经元变性，并增加了E治疗的PD大鼠中诱导的神经元兴奋性。K252a或抗BDNF抗体抑制了E治疗的PD大鼠中神经元BDNF和TRPC6表达的增加；TRPC6激动剂与抗BDNF抗体联合治疗减少了神经元死亡，并增加了E治疗的PD大鼠海马CA1区神经元中BDNF和TRPC6的表达。这些结果表明，E在PD中的神经保护作用与增强BDNF/TRPC6通路的活性密切相关，有助于提供新的预防和策略。
