title: Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, P209, Stanford, CA 94305-5489, USA.
authors.forename: Jullet
authors.initials: J
authors.lastname: Han
authors.forename: Julia
authors.initials: J
authors.lastname: Pollak
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Siddiqui
authors.forename: Kristian P
authors.initials: KP
authors.lastname: Doyle
authors.forename: Kereshmeh
authors.initials: K
authors.lastname: Taravosh-Lahn
authors.forename: Egle
authors.initials: E
authors.lastname: Cekanaviciute
authors.forename: Alex
authors.initials: A
authors.lastname: Han
authors.forename: Jeremy Z
authors.initials: JZ
authors.lastname: Goodman
authors.forename: Britta
authors.initials: B
authors.lastname: Jones
authors.forename: Deqiang
authors.initials: D
authors.lastname: Jing
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
mesh_terms: D000818:Animals; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000627:therapeutic use; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke; D014335:Tropomyosin / Q000008:administration & dosage* / Q000737:chemistry; D020813:Receptor, trkB
chemical_list: D008024:Ligands; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D014335:Tropomyosin; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB