Rehabilitation Decreases Spasticity by Restoring Chloride Homeostasis through the Brain-Derived Neurotrophic Factor–KCC2 Pathway after Spinal Cord Injury

JOURNAL OF NEUROTRAUMA, 2020 · DOI: 10.1089/neu.2019.6526 · Published: March 15, 2020

Spinal Cord Injury Neuroplasticity Rehabilitation

Simple Explanation

Activity-based therapy is often used to help people recover after a spinal cord injury (SCI). This type of therapy can reduce muscle stiffness and spasms, which affect many individuals with SCI. This study found that exercise after SCI helps restore the balance of chloride in nerve cells, which reduces overexcitability and spasticity. This improvement relies on a protein called KCC2, which moves chloride out of the cells, and is regulated by brain-derived neurotrophic factor (BDNF). By identifying how exercise improves these symptoms, researchers can develop better treatments and rehabilitation strategies to help individuals with SCI regain motor function without the side effects of current medications.

Study Duration

4 Weeks

Participants

Adult female Sprague-Dawley rats

Evidence Level

Not specified

Key Findings

1
The activity-dependent increase in KCC2 functionally contributes to H-reﬂex recovery after spinal cord injury.
2
The exercise-induced increase in KCC2 expression is dependent on BDNF activity.
3
Blocking KCC2 or scavenging BDNF after SCI does not affect hyperreflexia in untrained animals, suggesting that the drugs' effects are linked to exercise-dependent recovery.

Research Summary

This study investigates the role of KCC2, a neuronal chloride extruder, and BDNF in mediating the beneficial effects of activity-based therapies on spasticity following spinal cord injury (SCI). The researchers found that exercise increases KCC2 expression in lumbar motoneurons, which reduces spinal hyperexcitability and improves reflex modulation. The study demonstrates that the activity-dependent increase in KCC2, triggered by exercise, requires BDNF to restore reflex modulation, highlighting the potential of chloride co-transporters as therapeutic targets for improving motor recovery after SCI.

Practical Implications

Therapeutic Target Identification

Chloride co-transporters, particularly KCC2, can be targeted to improve hyperreflexia after chronic SCI, especially for individuals with comorbidities delaying physical therapy.

Rehabilitation Strategy Optimization

Understanding the BDNF-KCC2 pathway can optimize rehabilitation programs to maximize functional recovery and reduce spasticity.

Pharmacological Intervention

This research supports the development of pharmacological interventions that facilitate chloride extrusion to restore endogenous inhibition without depressing overall excitability.

Study Limitations

1
The study was conducted on rats, and the results may not directly translate to humans.
2
The specific mechanisms by which KCC2 regulates BDNF levels are not fully elucidated.
3
The study focused on a complete spinal cord transection model, which may not fully represent the heterogeneity of human SCI.

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