Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery
| Autor: | Kylie Calderon, Frankie G. Garcia, Helena W. Morrison, Crumpacker Rh, Danielle A. Becktel, Gonzalez S, Frank M. Longo, Marco A. Tavera-Garcia, Jennifer B. Frye, Tony T. Yang, Rick G. Schnellmann, Jacob C. Zbesko, Kristian P. Doyle, Thuy-Vi V. Nguyen |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
medicine.medical_treatment Morpholines Receptor Nerve Growth Factor chemistry.chemical_compound Mice Atrophy Internal medicine medicine Animals Isoleucine Vascular dementia Neurotransmitter Stroke Pharmacology Neurotransmitter Agents business.industry Neurodegeneration Glutamate receptor Brain Infarction Middle Cerebral Artery medicine.disease Glutathione Mice Inbred C57BL Endocrinology Neuroprotective Agents chemistry Chronic inflammatory response Molecular Medicine Stroke recovery business Glycolysis |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 380(2) |
| ISSN: | 1521-0103 |
| Popis: | 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 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 nest construction 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 STATEMENTThe 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. |
| Databáze: | OpenAIRE |
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