ABSTRACT
The aim of this study was to test whether post-stroke 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 glutamate, 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 following 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 nesting test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor 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.
Competing Interest Statement
Conflict of Interest: Dr. Longo is listed as an inventor on patents relating to LM11A-31 assigned to the University of North Carolina and the University of California, San Francisco. Dr Longo is a principal of, and has financial interest in PharmatrophiX, a company focused on the development of small molecule ligands for neurotrophin receptors that has licensed several of these patents.
List of nonstandard abbreviations
- Aβ
- Amyloid beta
- AD
- Alzheimer’s Disease
- AKT
- Ak strain transforming (RAC alpha serine/threonine-protein kinase)
- APP
- Amyloid precursor protein
- BDNF
- Brain derived neurotrophic factor
- Cdk5
- Cyclin dependent kinase 5
- ChAT
- Choline acetyl transferase
- DH Stroke
- Distal middle cerebral artery occlusion + hypoxia stroke
- dMCAO
- distal Middle cerebral artery occlusion
- FO
- Familiar object
- G-CSF
- Granulocyte-colony stimulating factor
- GM-CSF
- Granulocyte macrophage-colony stimulating factor
- GSH
- Reduced glutathione
- GSK3β
- Glycogen synthase kinase 3 beta
- GSSG
- Oxidized glutathione
- IFN-γ
- Interferon gamma
- IL
- Interleukin
- IP-10
- Interferon induced protein-10
- IRAK
- Interleukin-1 receptor associated kinase
- KC
- Keratinocytes derived chemokine
- MCP-1
- Monocyte chemoattractant protein-1
- MIP-1α
- Macrophage inflammatory protein-1 alpha
- MIP-1β
- Macrophage inflammatory protein-1 beta
- MIP-2
- Macrophage inflammatory protein-2
- NeuN
- Neuronal nuclei
- NFκB
- Nuclear factor kappa-light-chain-enhancer of activated B cells
- NGF
- Nerve growth factor
- NMDA
- N-methyl-D-aspartate
- NO
- Novel object
- NOR
- Novel object recognition
- OF
- Open field
- PCA
- Principal component analysis
- P75NTR
- p75 neurotrophin receptor
- PI3K
- Phosphoinositide 3 kinase
- RANTES
- Regulated on activation normal T cell expressed and secreted
- RI
- Recognition index
- SAB
- Spontaneous alternation behavior
- TCA
- Tricarboxylic acid
- TH
- Tyrosine hydroxylase
- Thy1
- Thymocyte differentiation antigen 1
- TNF-α
- Tumor necrosis factor-alpha
- TPA
- Tissue plasminogen activator
- UPLC-MS/MS
- Ultrahigh performance liquid chromatography/tandem mass spectrometry