Pharmacologically inhibiting kinesin-5 activity with monastrol promotes axonal regeneration following spinal cord injury

Exp Neurol, 2015 · DOI: 10.1016/j.expneurol.2014.10.013 · Published: January 1, 2015

Spinal Cord Injury Biochemistry Regenerative Medicine & Stem Cells

Simple Explanation

Adult neurons have limited regrowth capacity after spinal cord injury (SCI), but some regeneration is possible with a permissive substrate like an injured peripheral nerve. However, axons often stall at the interface and fail to re-enter spinal cord tissue. Inhibiting kinesin-5, a motor protein, with monastrol, a pharmacological agent, boosts axon growth on inhibitory substrates in vitro. The study aimed to see if monastrol treatment after SCI improves functional axon regeneration. The study found that combining chondroitinase ABC (ChABC) with monastrol significantly improved axon regeneration. However, there were no further improvements in function, suggesting more treatments are needed to enhance the integration of regrown axons.

Study Duration

13 weeks

Participants

Adult female Sprague-Dawley rats (n=8 per group for behavioral testing, n=5 per group for electrical stimulation, n=3 per group for axon labeling)

Evidence Level

Not specified

Key Findings

1
Monastrol treatment, combined with ChABC, significantly enhanced axonal regeneration after spinal cord injury in rats.
2
Despite increased regeneration, monastrol treatment did not lead to significant improvements in locomotor function as measured by the BBB scoring system.
3
Electrical stimulation revealed no significant difference in c-Fos induction, indicating that the regenerated axons did not effectively integrate and form functional synapses.

Research Summary

The study investigates whether inhibiting kinesin-5 with monastrol can improve axonal regeneration after spinal cord injury (SCI) when combined with ChABC treatment. Monastrol enhanced axonal regeneration beyond a peripheral nerve graft in a rat model of SCI, but this did not translate to improved functional recovery. The findings suggest that while monastrol can promote anatomical regeneration, additional strategies are needed to facilitate the integration of regenerated axons and improve functional outcomes after SCI.

Practical Implications

Combinatorial Therapies

Monastrol has the potential to be a key component of a combinatorial strategy to improve outcomes of spinal cord injury.

Drug Development

Further research could determine if other similarly-acting drugs are more effective than monastrol at promoting growth.

Optimizing Monastrol Exposure

Optimizing the exposure of the injury site to monastrol for a more limited period of time might yield better functional outcomes.

Study Limitations

1
The study did not directly assess which specific population of fibers regenerated out of the graft.
2
The mechanism of improvement observed in BBB scores in both treatment groups is not fully clear.
3
The study used a complete transection model, which primarily assesses true regeneration but may not fully capture functionally-compensatory collateral sprouting.

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