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Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury
Journal article   Open access   Peer reviewed

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury

Jadwiga N Bilchak, Kyle Yeakle, Guillaume Caron, Dillon Malloy and Marie-Pascale Côté
Experimental neurology, v 338, pp 113605-113605
Apr 2021
DOI: https://doi.org/10.1016/j.expneurol.2021.113605
PMID: 33453210
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904648View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Animals Autonomic Dysreflexia - etiology Autonomic Dysreflexia - metabolism Muscle Spasticity - metabolism Rats Rats, Sprague-Dawley Spinal Cord - drug effects Spinal Cord - metabolism Spinal Cord Injuries - metabolism Symporters - metabolism Thiazolidines - pharmacology
After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca -dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals.

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#3 Good Health and Well-Being

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Web of Science research areas
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