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A small molecule p75(NTR) ligand protects neurogenesis after traumatic brain injury.

Authors: Shi, J  Longo, FM  Massa, SM 
Citation: Shi J, etal., Stem Cells. 2013 Nov;31(11):2561-74. doi: 10.1002/stem.1516.
Pubmed: (View Article at PubMed) PMID:23940017
DOI: Full-text: DOI:10.1002/stem.1516

The p75 neurotrophin receptor (p75(NTR)) influences the proliferation, survival, and differentiation of neuronal precursors and its expression is induced in injured brain, where it regulates cell survival. Here, we test the hypotheses that pharmacologic modulation of p75(NTR) signaling will promote neural progenitor survival and proliferation, and improve outcomes of traumatic brain injury (TBI). LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75(NTR) signaling modulator, significantly increased proliferation and survival, and decreased JNK phosphorylation, in hippocampal neural stem/progenitor cells in culture expressing wild-type p75(NTR), but had no effect on cells expressing a mutant neurotrophin-unresponsive form of the receptor. The compound also enhanced the production of mature neurons from adult hippocampal neural progenitors in vitro. In vivo, intranasal administration of LM11A-31 decreased postinjury hippocampal and cortical neuronal death, neural progenitor cell death, gliogenesis, and microglial activation, and enhanced long-term hippocampal neurogenesis and reversed spatial memory impairments. LM11A-31 diminished the postinjury increase of SOX2-expressing early progenitor cells, but protected and increased the proliferation of endogenous polysialylated-neural cell adhesion molecule positive intermediate progenitors, and restored the long-term production of mature granule neurons. These findings suggest that modulation of p75(NTR) actions using small molecules such as LM11A-31 may constitute a potent therapeutic strategy for TBI.

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RGD Object Information
RGD ID: 10414074
Created: 2015-12-02
Species: All species
Last Modified: 2015-12-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.