The TrkA agonist gambogic amide promotes neuroplasticity and recovery following ischemic stroke.

Abstract

Recovery from ischemic brain damage cause by stroke is limited unless treatments are implemented within a narrow time window to increase blood flow and reduce tissue damage to the affected area of the brain. Our laboratory has pioneered alternative approaches that are not restricted by a treatment window and involve stimulating neuroplastic mechanisms within uninjured areas of the brain to establish new compensatory neuronal connections that restore function. In this report, we tested if the small molecule TrkA agonist gambogic amide (GamAm) could stimulate neuroplasticity and recovery of function following stroke. Rats first were trained on the skilled forelimb reaching task and the horizontal ladder rung walking task and then underwent MCAO to result in an ischemic stroke in the motor cortex associated with the preferred forelimb. One week later they received four doses (one per day) of GamAm (2 mg/kg, i.p.). The rats underwent behavioral testing for eight weeks after which they received an injection of the anterograde neuronal tracer biotinylated dextran amine (BDA) into the contralesional motor cortex. Our results show that rats receiving GamAm displayed significant improvement over control vehicle-treated rats in both the skilled reaching and walking behavioral tasks. Analysis of BDA-positive axons revealed that GamAm treatment resulted in increased corticorubral plasticity to the deafferented red nucleus, an important area for motor control. These findings support a role for GamAm, and possibly other small molecule Trk agonists, as potential therapies for stimulating neuroplastic mechanisms to promote stroke recovery.