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Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury

Citation

Fletcher, JL and Dill, LK and Wood, RJ and Wang, S and Robertson, K and Murray, SS and Zamani, A and Semple, BD, Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury, Experimental Neurology, 339 pp. 1-15. ISSN 0014-4886 (2021) [Refereed Article]

Copyright Statement

Copyright 2021 Crown Copyright

DOI: doi:10.1016/j.expneurol.2021.113652

Abstract

Young children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with the partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts-the corpus callosum and external capsules-based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and post-mitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks post-injury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures.

Item Details

Item Type:Refereed Article
Keywords:BDNF, brain-derived neurotrophic factor, corpus callosum, external capsule, inflammation, LM22A-4, myelination, spectral confocal reflectance microscopy, tropomyosin-related kinase receptor
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Fletcher, JL (Dr Jessica Fletcher)
ID Code:147223
Year Published:2021
Web of Science® Times Cited:6
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-10-19
Last Modified:2021-11-03
Downloads:0

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