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

Exp Neurol, 2021 · DOI: 10.1016/j.expneurol.2021.113605 · Published: April 1, 2021

Spinal Cord Injury Pharmacology Neurorehabilitation

Simple Explanation

After spinal cord injury (SCI), many individuals develop spasticity, a condition with involuntary movements and hyperreflexia. Current medications have side effects that decrease motoneuron excitability, impairing motor function. This study used a KCC2 enhancer, CLP257, to increase chloride extrusion in rats with chronic SCI. The results showed improvements in the rate-dependent depression of the H-reflex and reduced EMG responses to muscle stretch. The improvements from the drug mirrored those of exercise, suggesting that increasing KCC2 activity pharmacologically could be a promising approach to decrease spastic symptoms without the severe side effects of current medications.

Study Duration

5 weeks

Participants

Sprague Dawley rats

Evidence Level

Not specified

Key Findings

1
Increasing KCC2 activity with CLP257 improved the rate-dependent depression of the H-reflex in sedentary animals after chronic SCI, indicating improved reflex modulation.
2
CLP257 reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI, suggesting a reduction in hyperreflexia and muscle spasms.
3
Pharmacologically increasing KCC2 activity mimics the beneficial effects of exercise on spasticity symptoms after SCI.

Research Summary

This study investigates the effects of pharmacologically increasing KCC2 activity using CLP257 on spasticity symptoms after chronic SCI in rats. The study also explores how this pharmacological approach interacts with exercise. The key findings indicate that CLP257 improves reflex modulation and reduces EMG responses to muscle stretch, mirroring the effects of exercise. CLP257 also increased KCC2 membrane expression. The authors conclude that pharmacologically increasing KCC2 activity with CLPs is a promising new strategy to alleviate symptoms of spasticity in individuals with SCI.

Practical Implications

Therapeutic Potential

Pharmacologically increasing KCC2 activity could be a promising therapeutic strategy for reducing spasticity after SCI, especially for individuals unable to participate in exercise programs.

Reduced Side Effects

Restoring endogenous inhibition via KCC2 enhancement may avoid the severe side effects associated with current anti-spastic medications that depress overall excitability.

Combination Therapy

KCC2 enhancers may be used in tandem with exercise-based therapies without detrimental effects.

Study Limitations

1
The precise mechanism of action of CLPs remains unknown.
2
The study primarily focuses on electrophysiological measures; further studies are needed to assess functional motor improvements.
3
The effects of CLP257 on specific spinal interneuron populations require further investigation.

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