Neuroprotective effect of a physiological ratio of testosterone and estradiol on corticosterone-induced apoptosis in PC12 cells via Traf6/TAK1 pathway
Neuroprotective effect of a physiological ratio of testosterone and estradiol on corticosterone-induced apoptosis in PC12 cells via Traf6/TAK1 pathway
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睾酮和雌二醇生理比例对皮质酮通过 Traf6/TAK1 途径诱导的 PC12 细胞凋亡的神经保护作用
DOI：
10.1016/j.tiv.2018.03.018
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发表时间：
2018-08-01
影响因子：
3.2
通讯作者：
Li, Yan
中科院分区：
文献类型：
--
作者：
Peng, Rui;Dai, Wen;Li, Yan
临床和实验研究表明，单独补充睾酮或雌二醇可能具有抗抑郁药的作用。然而，睾酮/雌二醇在治疗抑郁症方面的协同作用和潜在机制仍很大程度上尚不清楚。在这里，我们假设适当剂量的睾酮和雌二醇可能成为抑郁症的一种新的治疗策略。结果表明，适宜的睾酮/雌二醇比例为10：1(10(-8)摩尔/L睾酮和10(-9)摩尔/L雌二醇)，对皮质酮诱导的PC12细胞损伤有明显的协同抗凋亡作用。在PC12细胞中，睾酮/雌二醇比值的协同作用主要依赖于对Traf6/TAK1信号通路的抑制激活。此外，我们还发现，确定的睾酮/雌二醇比例可以通过AR/ERα介导的途径抑制Traf6蛋白的表达和泛素化。最后，用免疫共沉淀法发现Traf6与AR/ERα在PC12细胞中的内源性相互作用，并进一步验证了确定的睾酮/雌二醇比率在PC12细胞损伤中是如何发挥协同作用的。本研究表明，一定比例的睾酮/雌二醇通过抑制TRAF6/TAK1信号通路的激活，对皮质酮诱导的PC12细胞损伤具有协同作用，提示睾酮/雌二醇可能通过协同保护神经细胞的凋亡，从而改善抑郁症状。
Clinical and experimental studies suggested that testosterone or estradiol alone supplementation may have antidepressant-like effects. However, the synergistic effect of testosterone/estradiol on the treatment of depression and the underlying mechanism remain largely unknown. Here, we hypothesized that an appropriate dosage of testosterone combined with estradiol may became a new therapeutic strategy in depression. Our results indicated that an appropriate testosterone/estradiol ratio of 10:1 (10(-8) mol/L testosterone and 10(-9) mol/L estradiol) was found, which has a significant synergistic anti-apoptotic effect on PC12 cells injury stimulated by corticosterone. We then confirmed the synergistic effect of the defined testosterone/estradiol ratio in PC12 cells mainly depend on the inhibitory activation of Traf6/TAK1 signaling pathway. Furthermore, we found that the defined testosterone/estradiol ratio could suppress the expression and ubiquitination of Traf6 protein through AR/ER alpha-mediated pathways. Finally, endogenous interactions of Traf6 with AR/ER alpha in PC12 cells were found using co-immunoprecipitation assays, and further verified how the defined testosterone/estradiol ratio plays a synergistic role in injury of PC12 cells. The current study demonstrated that an appropriate testosterone/estradiol ratio has a synergistic effect on PC12 cells injury induced by corticosterone through suppressing the activation of Traf6/TAK1 signaling pathway, suggesting that testosterone/estradiol might synergistically protect against neuronal apoptosis to ameliorate depressive symptoms.