B-RAFV600E Inhibitor Dabrafenib Attenuates RIPK3-Mediated Necroptosis and Promotes Functional Recovery after Spinal Cord Injury

Cells, 2019 · DOI: 10.3390/cells8121582 · Published: December 6, 2019

Simple Explanation

Spinal cord injury (SCI) leads to secondary damage, including neuronal loss, demyelination and axonal damage. The study investigates dabrafenib's ability to inhibit RIPK3-mediated necroptosis, a form of cell death, and promote recovery after SCI in mice. The researchers used a mouse model of spinal cord injury and treated the mice with dabrafenib. They observed that dabrafenib significantly inhibited RIPK3-mediated necroptosis, reducing secondary neural tissue damage. Dabrafenib treatment improved locomotor and sensory functions, and electrophysiological assessments confirmed enhanced functional recovery. This suggests dabrafenib could be a novel therapeutic strategy for SCI patients.

Study Duration

42 days

Participants

Adult female C57BL/6J mice (10–12 weeks of age)

Evidence Level

Not specified

Key Findings

1
Dabrafenib administration significantly inhibited RIPK3-mediated necroptosis in the injured spinal cord, reducing the expression of RIPK3 and phosphorylated MLKL (pMLKL).
2
Dabrafenib attenuated secondary neural tissue damage, including demyelination, neuronal loss, and axonal damage, following SCI.
3
The neuroprotective effect of dabrafenib dramatically improved the recovery of locomotor and sensory functions after SCI, as confirmed by behavioral and electrophysiological assessments.

Research Summary

This study investigates the therapeutic potential of dabrafenib, a B-RAFV600E inhibitor, in attenuating RIPK3-mediated necroptosis and promoting functional recovery after spinal cord injury (SCI) in a mouse model. The findings demonstrate that dabrafenib administration in the acute phase after SCI significantly inhibits RIPK3-MLKL signaling, reduces necrotic cell death, and attenuates secondary neural tissue damage. Importantly, dabrafenib treatment improves locomotor and sensory functions, preserves the central motor pathway, and enhances electrophysiological function in the injured spinal cord, suggesting its potential as a novel therapeutic strategy for SCI.

Practical Implications

Therapeutic Strategy

Dabrafenib could be a novel therapeutic strategy for treating patients with SCI by attenuating RIPK3-mediated necroptosis.

Drug Repositioning

Repurposing FDA-approved dabrafenib offers advantages for SCI treatment due to its existing safety profile and clinical data.

Neuroprotective Effect

Dabrafenib's neuroprotective effects include reducing demyelination, neuronal loss, and axonal damage, which contributes to improved functional recovery after SCI.

Study Limitations

1
The study did not perform in vitro analyses to confirm the biological effect of dabrafenib on spinal neurons or other neuronal cells.
2
The administration of dabrafenib might affect other molecular pathways to regulate neural tissue damage and functional outcomes following SCI.
3
Another SCI model lacking RIPK3 (e.g., RIPK3 knock-out) does weaken the case for RIPK3-mediated necroptosis attenuation by dabrafenib.

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