Guan Jing, Yang Beibei, Fan Yi, Zhang Ji
State Key Laboratory of Reproductive Medicine, Nanjing Maternity and Child Health Care Hospital, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Neuroimmunomodulation. 2017;24(1):60-66. doi: 10.1159/000478908. Epub 2017 Aug 16.
Epidemiological studies have shown that women of reproductive age have much less possibility of developing Parkinson disease (PD) than men. The beneficial effect of estrogen also has been well-described in both culture and animal models of PD. G protein-coupled estrogen receptor (GPER) is a membrane-associated estrogen receptor, and displayed a neuroprotective role in a mouse model of PD. Since GPER is highly expressed in microglia, we speculate that GPER mediates the neuroprotective function of estradiol through suppressing the neuroinflammation of PD.
We investigated the effects of GPER agonist G1 and GPER antagonist G15 on the neurodegeneration of dopaminergic neuron, the activation of microglia, and the production of IL-1β, TNF-α, and IL-6 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of parkinsonism. Furthermore, we confirmed the effects of GPER activation on the production of IL-1β, TNF-α, and IL-6 in an in vitro MPP+ model in BV2 microglial cells.
After 12-day treatment with G1, mice showed an increase in the number of tyrosine hydroxylase-immunoreactive cells, reduced activation of microglia, and the abatement of proinflammatory cytokines, and the anti-inflammatory effect of G1 was abolished by G15. Meanwhile, in vitro studies demonstrated that GPER activation also reduced the release of proinflammatory cytokines from BV2 microglial cells after MPP+ stimulation.
Our data suggest that GPER mediates the anti-neuroinflammatory effect of estrogen in experimental PD progression.
流行病学研究表明，育龄女性患帕金森病（PD）的可能性远低于男性。雌激素的有益作用在PD的细胞培养和动物模型中也得到了充分描述。G蛋白偶联雌激素受体（GPER）是一种膜相关雌激素受体，在PD小鼠模型中发挥神经保护作用。由于GPER在小胶质细胞中高表达，我们推测GPER通过抑制PD的神经炎症来介导雌二醇的神经保护功能。
我们研究了GPER激动剂G1和GPER拮抗剂G15对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病动物模型中多巴胺能神经元的神经退行性变、小胶质细胞的激活以及白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）产生的影响。此外，我们在BV2小胶质细胞的体外MPP+模型中证实了GPER激活对IL-1β、TNF-α和IL-6产生的影响。
用G1治疗12天后，小鼠酪氨酸羟化酶免疫反应性细胞数量增加，小胶质细胞激活减少，促炎细胞因子减少，G15消除了G1的抗炎作用。同时，体外研究表明，GPER激活还减少了MPP+刺激后BV2小胶质细胞促炎细胞因子的释放。
我们的数据表明，GPER在实验性PD进展中介导雌激素的抗神经炎症作用。
