Corticospinal neuroplasticity and sensorimotor recovery in rats treated by infusion of neurotrophin-3 into disabled forelimb muscles started 24 h after stroke

Abstract

Stroke often leads to arm disability and reduced responsiveness to stimuli on the other side of the body. Neurotrophin-3 (NT3) is made by skeletal muscle during infancy but levels drop postnatally and into adulthood. It is essential for the survival and wiring-up of sensory afferents from muscle. We have previously shown that gene therapy delivery of human NT3 into the affected triceps brachii forelimb muscle improves sensorimotor recovery after ischemic stroke in adult and elderly rats. Here, to move this therapy one step nearer to the clinic, we set out to test the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after ischemic cortical stroke in adult rats. To simulate a clinically-feasible time-to-treat, twenty-four hours later rats were randomized to receive NT3 or vehicle by infusion into triceps brachii for four weeks using implanted minipumps. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory deficits on the affected forearm. There was no evidence of forepaw sensitivity to cold stimuli after stroke or NT3 treatment. MRI confirmed that treatment did not induce neuroprotection. Functional MRI during low threshold electrical stimulation of the affected forearm showed an increase in peri-infarct BOLD signal with time in both stroke groups and indicated that neurotrophin-3 did not further increase peri-infarct BOLD signal. Rather, NT3 induced spinal neuroplasticity including sprouting of the spared corticospinal and serotonergic pathways. Neurophysiology showed that NT3 treatment increased functional connectivity between the corticospinal tracts and spinal circuits controlling muscles on the treated side. After intravenous injection, radiolabelled NT3 crossed from bloodstream into the brain and spinal cord in adult mice with or without strokes. Our results show that delayed, peripheral infusion of neurotrophin-3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral, high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke.