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TrkB agonist LM22A-4 increases oligodendroglial populations during myelin repair in the corpus callosum

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Nguyen, HTH, Wood, RJ, Prawdiuk, AR, Furness, SGB, Xiao, J, Murray, SS and Fletcher, JL ORCID: 0000-0003-2009-0798 2019 , 'TrkB agonist LM22A-4 increases oligodendroglial populations during myelin repair in the corpus callosum' , Frontiers in Molecular Neuroscience , pp. 1-12 , doi: 10.3389/fnmol.2019.00205.

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Abstract

The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in a cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after 1-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

Item Type: Article
Authors/Creators:Nguyen, HTH and Wood, RJ and Prawdiuk, AR and Furness, SGB and Xiao, J and Murray, SS and Fletcher, JL
Keywords: oligodendrocyte, myelin, BDNF, multiple sclerosis, demyelinating disease, animal models
Journal or Publication Title: Frontiers in Molecular Neuroscience
Publisher: Frontiers Research Foundation
ISSN: 1662-5099
DOI / ID Number: 10.3389/fnmol.2019.00205
Copyright Information:

Copyright 2019 Nguyen, Wood, Prawdiuk, Furness, Xiao, Murray and Fletcher. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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