Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury

Molecular Therapy, 2017 · DOI: http://dx.doi.org/10.1016/j.ymthe.2017.08.011 · Published: December 1, 2017

Spinal Cord Injury Regenerative Medicine Neurorehabilitation

Simple Explanation

After a spinal cord injury, the severed axons in the central nervous system (CNS) fail to regenerate robustly, leading to permanent functional deficits. This study explores a combinatorial approach to overcome these obstacles by promoting axonal regeneration. The researchers combined peripheral nerve grafts, transduction of neurons to express constitutively active Rheb (caRheb), and digestion of growth-inhibitory chondroitin sulfate proteoglycans using chondroitinase ABC (ChABC) to promote axonal regeneration after cervical spinal cord injury. The study found that combining caRheb expression and ChABC treatment significantly potentiates the formation of synapses in the host spinal cord and improves the animals’ ability to use the affected forelimb, thus enhancing functional axonal regeneration following a cervical SCI.

Study Duration

24 Weeks

Participants

Adult female Fischer 344 rats (150–200 g)

Evidence Level

Not specified

Key Findings

1
Expressing caRheb in neurons post-SCI results in more axons regenerating across a ChABC-treated distal graft interface into caudal spinal cord than either treatment alone.
2
caRheb+ChABC treatment significantly potentiates the formation of synapses in the host spinal cord.
3
The animals’ ability to use the affected forelimb improved with caRheb+ChABC treatment.

Research Summary

This study investigates a combinatorial approach to promote axonal regeneration after cervical spinal cord injury (SCI). The approach involves transplanting a peripheral nerve graft (PNG), expressing constitutively active Rheb (caRheb), and digesting chondroitin sulfate proteoglycans (CSPGs) with chondroitinase ABC (ChABC). The researchers found that expressing caRheb in neurons post-SCI resulted in a modest increase in axonal regeneration across a ChABC-treated distal graft interface. More significantly, caRheb+ChABC treatment potentiated synapse formation and improved forelimb function. The study concludes that this combination strategy enhances functional axonal regeneration following a cervical SCI, suggesting it may elucidate the basis for a treatment strategy to promote functional recovery after SCI.

Practical Implications

Therapeutic Potential

The combination of caRheb expression and ChABC treatment may offer a novel therapeutic strategy for promoting functional recovery after cervical spinal cord injury.

Synergistic Effects

The study highlights the importance of targeting both intrinsic axonal growth potential and extrinsic inhibitory factors for effective regeneration.

Synaptic Integration

Enhancing synapse formation of regenerating axons can improve functional outcomes after SCI.

Study Limitations

1
The study was conducted on adult female Fischer 344 rats, and the results may not be directly applicable to other populations or species.
2
The relatively short post-grafting survival period (1 month for some analyses) may have limited the observation of axonal regeneration into the PNG after caRheb expression.
3
Further studies are needed to determine the long-term effects and safety of prolonged mTOR activation in the CNS.

Your Feedback

Was this summary helpful?

Back to Spinal Cord Injury