Abstract
ObjectiveNeurotrophin‐3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke.MethodsRats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps.ResultsRadiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. 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 impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri‐infarct blood oxygenation level–dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways.InterpretationOur results show that delayed, peripheral infusion of NT3 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. ANN NEUROL 2019;85:32–46.
Highlights
NT3 protein is synthesized by muscle spindles[21] and NT3 can be transported from muscle to sensory ganglia and spinal motor neurons in nerves[6,14,16] as well as to the central nervous system (CNS) and peripheral nervous system (PNS) via the bloodstream.[22,23,24]
Loss of corticospinal tract (CST) axons was assessed at 8 weeks in the upper cervical spinal cord using PKCγ immunofluorescence.[35,36]
The magnetic resonance imaging (MRI) and PKCγ histology data indicate that there were no confounding pretreatment differences in mean infarct volumes and that NT3 did not act as a neuroprotective agent, as expected, based on our previous results[16] and given that treatment was initiated after the majority of cell death would have occurred
Summary
Neurotrophin-3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. Here, we tested the hypothesis that infusion of NT3 protein (14 kDa) into impaired forelimb muscles would improve sensorimotor recovery after stroke (ie, bypassing the need for gene therapy and spinal surgery) This is plausible because others have shown that a signal from muscle spindles can improve neuroplasticity of descending pathways and can enhance recovery after spinal cord lateral hemisection.[20] Notably, NT3 protein is synthesized by muscle spindles[21] and NT3 can be transported from muscle to sensory ganglia and spinal motor neurons in nerves[6,14,16] as well as to the CNS and peripheral nervous system (PNS) via the bloodstream.[22,23,24] Importantly, NT3 protein has excellent translational potential; phase I and II clinical trials have shown that repeated, systemic high doses of NT3 protein are well tolerated, safe, and effective in >200 humans with sensory and motor neuropathy (Charcot–Marie–Tooth type 1A)[25] or constipation including in people with spinal cord injury.[25,26] These studies pave the way for NT3 as a therapy for stroke in humans. We show in a blinded, randomized preclinical trial that treatment of impaired upper arm muscles with human NT3 protein reverses sensory and motor disability in rats when treatment is initiated in a clinically feasible timeframe (24 hours after stroke)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
