Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats

Molecular Therapy, 2024 · DOI: https://doi.org/10.1016/j.ymthe.2024.01.029 · Published: April 1, 2024

Simple Explanation

Spasticity, a common issue after spinal cord injury (SCI), involves muscle spasms and stiffness. The study targets a protein called calpain1 in spinal motoneurons, which becomes overactive after SCI and contributes to these spasticity symptoms. Researchers used a gene therapy approach to reduce calpain1 levels in rats with SCI. By delivering a specific sequence (shRNA) targeting calpain1 directly into the spinal cord, they aimed to alleviate spasticity. The results showed that reducing calpain1 in motoneurons decreased muscle spasms, improved reflexes, and restored a key protein (KCC2) that helps control muscle excitability. This suggests a potential new strategy for treating spasticity in SCI patients.

Study Duration

7 weeks

Participants

42 adult Wistar Han female rats

Evidence Level

Not specified

Key Findings

1
Intrathecal delivery of AAV6-shRNA-CAPN1 effectively reduced calpain1 expression in lumbar motoneurons of rats with SCI.
2
Knockdown of calpain1 led to a significant decrease in muscle spasms, cocontractions, and hyperreflexia in SCI rats.
3
Calpain1 knockdown resulted in the upregulation of KCC2 membrane levels in SCI motoneurons, suggesting a restoration of inhibitory balance.

Research Summary

This preclinical study demonstrates that targeting calpain1 in spinal motoneurons via intrathecal administration of AAV6-GFP-shRNA-CAPN1 reduces hindlimb muscle spasticity in adult rats with spinal cord injury. The reduction in spasticity was evidenced by decreased muscle spasms, diminished hyperreflexia, and fewer muscle cocontractions, accompanied by a decrease in cytoplasmic calpain1 expression and an increase in KCC2 expression within the targeted motoneurons. The findings highlight the potential of gene therapy in neuromuscular rehabilitation post-SCI and lay the groundwork for further therapeutic developments in this domain.

Practical Implications

Therapeutic Target

Calpain1 is a viable therapeutic target for alleviating spasticity post-SCI.

Gene Therapy Potential

AAV6-mediated gene therapy is a promising method for delivering targeted treatments to spinal motoneurons.

Restoring Inhibitory Balance

Upregulating KCC2 expression can help restore the excitatory/inhibitory balance in motoneurons and reduce spasticity.

Study Limitations

1
Differences in calpain1 expression due to variations in the transcription/transduction processes within the flexor and extensor motor pools.
2
Extensor and flexor motor pools may respond differently to SCI.
3
The study focused on female rats, and results may differ in males.

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