RT Journal Article
SR Electronic
T1 Subcutaneous Neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical stroke
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 427864
DO 10.1101/427864
A1 Denise Duricki
A1 Sotiris Kakanos
A1 Barbara Haenzi
A1 Christina Wayman
A1 Nora Bödecker
A1 Antje Vogelgesang
A1 Diana Cash
A1 Lawrence Moon
YR 2021
UL http://biorxiv.org/content/early/2021/08/06/427864.abstract
AB There is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation. Its level declines in muscle and other tissues postnatally. We show that levels of NT-3 in the bloodstream were low in humans with ischemia stroke relative to young healthy controls. Accordingly, we set out to determine whether subcutaneous delivery of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically feasible time frame via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke.Competing Interest StatementThe authors have declared no competing interest.