The aim of this study was to test whether poststroke
oral administration of a small molecule
p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of
stroke. Mice were administered
LM11A-31 for up to 12 weeks, beginning 1 week after
stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received
LM11A-31 were distinct from vehicle-treated mice by principal component analysis and had higher levels of
serotonin,
acetylcholine, and
dopamine in their ipsilateral hemisphere.
LM11A-31 treatment also improved redox homeostasis by restoring
reduced glutathione. It also offset a
stroke-induced reduction in glycolysis by increasing
acetyl-CoA. There was no effect on
cytokine levels in the
infarct. At 13 weeks after
stroke, adaptive immune cell infiltration in the
infarct was unchanged in LM11A-31-treated mice, indicating that
LM11A-31 does not alter the chronic inflammatory response to
stroke at the site of the
infarct. However, LM11A-31-treated mice had less brain
atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75NTR for preserving neuronal health and function during
stroke recovery. SIGNIFICANCE STATEMENT: The findings from this study introduce the
p75 neurotrophin receptor as a novel small molecule target for promotion of
stroke recovery. Given that
LM11A-31 is in clinical trials as a potential
therapy for
Alzheimer's disease, it could be considered as a candidate for assessment in
stroke or
vascular dementia studies.