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bioRxiv · 10.1101/642918

TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain

Nguyen, H. T.·Wood, R. J.·Prawdiuk, A. R.·Furness, S. G.·Xiao, J.·Murray, S.·Fletcher, J.
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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 the cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after one-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.

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Nguyen, H. T., Wood, R. J., Prawdiuk, A. R., Furness, S. G., Xiao, J., Murray, S., Fletcher, J.. 2019-05-21. TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain. https://doi.org/10.1101/642918

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