期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：41
页码：E9668-E9677
DOI：10.1073/pnas.1803384115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Progesterone (P4) is a potent neuroprotectant and a promising therapeutic for stroke treatment. However, the underlying mechanism(s) remain unclear. Our laboratory recently reported that brain-derived neurotrophic factor (BDNF) is a critical mediator of P4’s protective actions and that P4-induced BDNF release from cortical astrocytes is mediated by a membrane-associated progesterone receptor, Pgrmc1. Here, we report that the microRNA (miRNA) let-7i is a negative regulator of Pgrmc1 and BDNF in glia and that let-7i disrupts P4-induced BDNF release and P4’s beneficial effects on cell viability and markers of synaptogenesis. Using an in vivo model of ischemia, we demonstrate that inhibiting let-7i enhances P4-induced neuroprotection and facilitates functional recovery following stroke. The discovery of such factors that regulate the cytoprotective effects of P4 may lead to the development of biomarkers to differentiate/predict those likely to respond favorably to P4 versus those that do not.
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