Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke

Jullet Han, Julia Pollak, Tao Yang, Mohammad R. Siddiqui, Kristian P. Doyle, Kereshmeh Taravosh-Lahn, Egle Cekanaviciute, Alex Han, Jeremy Z. Goodman, Britta Jones, Deqiang Jing, Stephen M. Massa, Frank M. Longo, Marion S. Buckwalter

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48 Scopus citations

Abstract

Background and Purpose-Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke. Methods-Four-month-old mice were trained on motor tasks before stroke. After stroke, functional test results were used to randomize mice into 2 equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for 10 weeks. Results-LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. Conclusions-A small molecule agonist of tropomyosin-related kinase B improves functional recovery from stroke and increases neurogenesis when administered beginning 3 days after stroke. These findings provide proof-of-concept that targeting of tropomyosin-related kinase B alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as "pro-recovery" therapeutic agents for stroke.

Original languageEnglish (US)
Pages (from-to)1918-1924
Number of pages7
JournalStroke
Volume43
Issue number7
DOIs
StatePublished - Jul 1 2012

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Keywords

  • neurotrophin
  • small molecule
  • stroke recovery

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Han, J., Pollak, J., Yang, T., Siddiqui, M. R., Doyle, K. P., Taravosh-Lahn, K., Cekanaviciute, E., Han, A., Goodman, J. Z., Jones, B., Jing, D., Massa, S. M., Longo, F. M., & Buckwalter, M. S. (2012). Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke, 43(7), 1918-1924. https://doi.org/10.1161/STROKEAHA.111.641878