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 Doyle, Kereshmeh Taravosh-Lahn, Egle Cekanaviciute, Alex Han, Jeremy Z. Goodman, Britta Jones, Deqiang Jing, Stephen M. Massa, Frank M. Longo, Marion S. Buckwalter

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 2012
Externally publishedYes

Fingerprint

Stroke
Ligands
Neurogenesis
Brain-Derived Neurotrophic Factor
tropomyosin kinase
Neurons
Nerve Growth Factor Receptor
Neuronal Plasticity
Gait
Neuroglia
Pharmaceutical Preparations
Cicatrix
Extremities
N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide
Therapeutics

Keywords

  • neurotrophin
  • small molecule
  • stroke recovery

ASJC Scopus subject areas

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

Cite this

Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. / Han, Jullet; Pollak, Julia; Yang, Tao; Siddiqui, Mohammad R.; Doyle, Kristian; Taravosh-Lahn, Kereshmeh; Cekanaviciute, Egle; Han, Alex; Goodman, Jeremy Z.; Jones, Britta; Jing, Deqiang; Massa, Stephen M.; Longo, Frank M.; Buckwalter, Marion S.

In: Stroke, Vol. 43, No. 7, 07.2012, p. 1918-1924.

Research output: Contribution to journalArticle

Han, J, Pollak, J, Yang, T, Siddiqui, MR, Doyle, K, Taravosh-Lahn, K, Cekanaviciute, E, Han, A, Goodman, JZ, Jones, B, Jing, D, Massa, SM, Longo, FM & Buckwalter, MS 2012, 'Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke', Stroke, vol. 43, no. 7, pp. 1918-1924. https://doi.org/10.1161/STROKEAHA.111.641878
Han, Jullet ; Pollak, Julia ; Yang, Tao ; Siddiqui, Mohammad R. ; Doyle, Kristian ; Taravosh-Lahn, Kereshmeh ; Cekanaviciute, Egle ; Han, Alex ; Goodman, Jeremy Z. ; Jones, Britta ; Jing, Deqiang ; Massa, Stephen M. ; Longo, Frank M. ; Buckwalter, Marion S. / Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. In: Stroke. 2012 ; Vol. 43, No. 7. pp. 1918-1924.
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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.",
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T1 - Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke

AU - Han, Jullet

AU - Pollak, Julia

AU - Yang, Tao

AU - Siddiqui, Mohammad R.

AU - Doyle, Kristian

AU - Taravosh-Lahn, Kereshmeh

AU - Cekanaviciute, Egle

AU - Han, Alex

AU - Goodman, Jeremy Z.

AU - Jones, Britta

AU - Jing, Deqiang

AU - Massa, Stephen M.

AU - Longo, Frank M.

AU - Buckwalter, Marion S.

PY - 2012/7

Y1 - 2012/7

N2 - 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.

AB - 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.

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