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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00205

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

Huynh T. Nguyen1,  Rhiannon J. Wood1, Alexa R. Prawdiuk1,  Sebastian G. Furness2,  Junhua Xiao1, Simon S. Murray1 and  Jessica L. Fletcher1*
  • 1Department of Anatomy and Neuroscience, School of Biomedical Sciences, The University of Melbourne, Australia
  • 2Drug discovery biology, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Australia

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.

Keywords: oligodendrocyte, Brain-derived growth factor (BDNF), myelin, TrkB, remyelination, TrkB agonist, neurotrophin

Received: 19 May 2019; Accepted: 06 Aug 2019.

Edited by:

Jochen C. Meier, Technische Universitat Braunschweig, Germany

Reviewed by:

Albert I. Chen, Nanyang Technological University, Singapore
Elizabeth Hernández-Echeagaray, Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autonóma de México, Mexico  

Copyright: © 2019 Nguyen, Wood, Prawdiuk, Furness, Xiao, Murray and Fletcher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jessica L. Fletcher, The University of Melbourne, Department of Anatomy and Neuroscience, School of Biomedical Sciences, Melbourne, 3010, Victoria, Australia, jessica.fletcher@unimelb.edu.au