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 (BDNF) stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B (TrkB) and p75 neurotrophin (p75NTR) receptors. However, BDNF 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 TrkB would promote neurogenesis and functional recovery after stroke.
Four-month-old mice were trained on motor tasks prior to stroke. After stroke, functional test results were used to randomize mice into two equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for ten weeks.
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.
A small molecule agonist of TrkB improves functional recovery from stroke and increases neurogenesis when administered beginning three days after stroke. These findings provide proof-of-concept that targeting of TrkB 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.