Axon regeneration and exercise-dependent plasticity after spinal cord injury

Ann N Y Acad Sci, 2013 · DOI: 10.1111/nyas.12052 · Published: April 1, 2013

Spinal Cord Injury Regenerative Medicine Rehabilitation

Simple Explanation

Meaningful recovery after spinal cord injury (SCI) requires a combination of therapeutic interventions. These include regenerative transplants, neurotrophic factors, elimination of inhibitory molecules, sensorimotor training, and muscle stimulation. Peripheral nerve grafts support axonal regeneration across incomplete cervical or complete thoracic transections. Matrix modulation with chondroitinase (ChABC) facilitates axonal extension beyond the graft-spinal cord interface. Exercise, such as wheel walking, bicycling, or step training, increases spinal cord levels of endogenous neurotrophic factors. This may facilitate elongation and synaptic activity of regenerating axons and plasticity of spinal neurons below the injury.

Study Duration

Not specified

Participants

Adult rats and adult cats

Evidence Level

Not specified

Key Findings

1
Peripheral nerve grafts (PNGs) can effectively bridge spinal cord lesions and promote axon regeneration. The target site can be treated to make it either more attractive or less inhibitory for the extension of axons beyond the distal end of the PNG.
2
Exercise after SCI leads to a significant increase in the distribution of synapsin around neurons in the intermediate gray and ventral horn of the lumbar spinal cord, indicating an effect on synaptic sites.
3
Exercise increases BDNF, NT3, NT4, and GDNF protein levels in the lumbar enlargement, as well as in upper lumbar and thoracic regions caudal to the lesion site.

Research Summary

Several thousand axons regenerate into PNGs yet only 10–15% of these appear to exit the graft when inhibitory proteoglycans in the spinal cord are digested prior to apposition of the distal graft end. Hind limb exercise of spinalized rats significantly increases the level of NTFs in spinal cord tissue both proximal and distal to an injury site, increases the expression of cFos in dorsal horn and intermediate gray neurons, promotes expression of molecules involved in regulation of protein synthesis and restores reflex activity of motoneurons. A key feature of this work will be to test whether repetitive stimulation of spinal cord circuitry will be beneficial in attracting axons to areas of the spinal cord affected by exercise.

Practical Implications

Combination Therapy Potential

Combining peripheral nerve grafts with exercise may enhance axonal regeneration and functional recovery after SCI.

Targeted Rehabilitation

Exercise can be used to create suitable target areas within the spinal cord for regenerating axons, enhancing synaptic connections.

Neurotrophic Factor Modulation

Exercise-induced increases in neurotrophic factors can be leveraged to promote neuronal survival and plasticity after SCI.

Study Limitations

1
The overall benefit of Chondroitinase treatment is not very compelling as the majority of axons remain in the transplant.
2
Only a small number of axons reach target areas and there is no convincing evidence of restoration of volitional control of movement.
3
The long-term consequences of the transient increase in neuron activity (cFos) with exercise are not clear.

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