AUTHOR=Nguyen Huynh T. H. , Wood Rhiannon J. , Prawdiuk Alexa R. , Furness Sebastian G. B. , Xiao Junhua , Murray Simon S. , Fletcher Jessica L.
TITLE=TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Corpus Callosum
JOURNAL=Frontiers in Molecular Neuroscience
VOLUME=12
YEAR=2019
URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00205
DOI=10.3389/fnmol.2019.00205
ISSN=1662-5099
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.