Table_2_Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7).pdf

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, and current treatment options are unsatisfactory on the long term. Several studies suggest a potential neuroprotective action by female hormones, especially estrogens. The potential role of progestogens, however, is less defined, and no studies have investigated the potential involvement of membrane progesterone receptors (mPRs). In the present study, the putative neuroprotective role for mPRs was investigated in SH-SY5Y cells, using two established pharmacological treatments for cellular PD models, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). Our results show that both the physiologic agonist progesterone and the specific mPR agonist Org OD 02-0 were effective in reducing SH-SY5Y cell death induced by 6-OHDA and MPP+, whereas the nuclear PR agonist promegestone (R5020) and the GABAA receptor agonist muscimol were ineffective. Experiments performed with gene silencing technology and selective pharmacological agonists showed that mPRα is the isoform responsible for the neuroprotective effects we observed. Further experiments showed that the PI3K-AKT and MAP kinase signaling pathways are involved in the mPRα-mediated progestogen neuroprotective action in SH-SY5Y cells. These findings suggest that mPRα could play a neuroprotective role in PD pathology and may be a promising target for the development of therapeutic strategies for PD prevention or management.

帕金森病（Parkinson’s disease, PD）是全球第二大常见的神经退行性疾病，目前的长期治疗方案仍不尽如人意。多项研究表明，雌性激素（尤其是雌激素）或可发挥神经保护作用，但孕激素的潜在作用尚不明确，且尚无研究探讨膜孕激素受体（membrane progesterone receptors, mPRs）在其中的潜在参与作用。本研究以SH-SY5Y细胞为研究对象，采用两种经典的帕金森病细胞模型造模手段——6-羟基多巴胺（6-hydroxydopamine, 6-OHDA）与1-甲基-4-苯基吡啶鎓（1-methyl-4-phenylpyridinium, MPP+），探究mPRs潜在的神经保护作用。研究结果显示，生理性孕激素受体激动剂孕酮以及特异性mPR激动剂Org OD 02-0，均能有效降低6-OHDA与MPP+诱导的SH-SY5Y细胞死亡；而核孕激素受体激动剂普美孕酮（promegestone, R5020）及GABAA受体激动剂蝇蕈醇（muscimol）则无此类保护效果。通过基因沉默技术与选择性药理学激动剂开展的实验证实，mPRα是介导本次观测到的神经保护效应的受体亚型。进一步实验表明，PI3K-AKT及丝裂原活化蛋白激酶（MAP kinase）信号通路参与了mPRα介导的孕激素神经保护作用过程。上述研究结果提示，mPRα或可在帕金森病的病理进程中发挥神经保护作用，有望成为帕金森病预防与治疗策略开发的潜在靶点。