Let-7i inhibition enhances progesterone-induced functional recovery in a mouse model of ischemia

Trinh Nguyen, Chang Su, Meharvan Singh

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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 brainderived 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.

Original languageEnglish
Pages (from-to)E9668-E9677
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number41
DOIs
StatePublished - 9 Oct 2018

Keywords

  • BDNF
  • Ischemic stroke
  • Let-7i
  • Pgrmc1
  • Progesterone

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