PMID- 30237284
OWN - NLM
STAT- MEDLINE
DCOM- 20181106
LR  - 20190409
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 41
DP  - 2018 Oct 9
TI  - Let-7i inhibition enhances progesterone-induced functional recovery in a mouse 
      model of ischemia.
PG  - E9668-E9677
LID - 10.1073/pnas.1803384115 [doi]
AB  - 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.
FAU - Nguyen, Trinh
AU  - Nguyen T
AD  - Department of Pharmacology and Neuroscience, University of North Texas Health 
      Science Center, Fort Worth, TX 76107.
AD  - Institute for Healthy Aging, University of North Texas Health Science Center, 
      Fort Worth, TX 76107.
FAU - Su, Chang
AU  - Su C
AD  - Department of Pharmacology and Neuroscience, University of North Texas Health 
      Science Center, Fort Worth, TX 76107.
AD  - Institute for Healthy Aging, University of North Texas Health Science Center, 
      Fort Worth, TX 76107.
FAU - Singh, Meharvan
AU  - Singh M
AUID- ORCID: 0000-0002-8072-1769
AD  - Department of Pharmacology and Neuroscience, University of North Texas Health 
      Science Center, Fort Worth, TX 76107; Meharvan.Singh@unthsc.edu.
AD  - Institute for Healthy Aging, University of North Texas Health Science Center, 
      Fort Worth, TX 76107.
LA  - eng
GR  - P01 AG027956/AG/NIA NIH HHS/United States
GR  - T32 AG020494/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180920
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Membrane Proteins)
RN  - 0 (MicroRNAs)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (PGRMC1 protein, mouse)
RN  - 0 (Receptors, Progesterone)
RN  - 0 (mirnlet7 microRNA, mouse)
RN  - 4G7DS2Q64Y (Progesterone)
SB  - IM
MH  - Animals
MH  - Astrocytes/metabolism/pathology
MH  - Brain Ischemia/drug therapy/*metabolism/pathology
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cerebral Cortex/*metabolism/pathology
MH  - Disease Models, Animal
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - MicroRNAs/*antagonists & inhibitors/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Progesterone/*pharmacology
MH  - Receptors, Progesterone/metabolism
MH  - Recovery of Function/*drug effects
PMC - PMC6187141
OTO - NOTNLM
OT  - BDNF
OT  - Pgrmc1
OT  - ischemic stroke
OT  - let-7i
OT  - progesterone
COIS- Conflict of interest statement: The authors of this manuscript are coinventors on 
      a patent application (application no. PCT/US18/46456).
EDAT- 2018/09/22 06:00
MHDA- 2018/11/07 06:00
PMCR- 2019/04/09
CRDT- 2018/09/22 06:00
PHST- 2018/09/22 06:00 [pubmed]
PHST- 2018/11/07 06:00 [medline]
PHST- 2018/09/22 06:00 [entrez]
PHST- 2019/04/09 00:00 [pmc-release]
AID - 1803384115 [pii]
AID - 201803384 [pii]
AID - 10.1073/pnas.1803384115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9668-E9677. doi: 
      10.1073/pnas.1803384115. Epub 2018 Sep 20.