Exercise and Peripheral Nerve Grafts as a Strategy To Promote Regeneration after Acute or Chronic Spinal Cord Injury

JOURNAL OF NEUROTRAUMA, 2017 · DOI: 10.1089/neu.2016.4640 · Published: May 15, 2017

Spinal Cord Injury Rehabilitation Regenerative Medicine & Stem Cells

Simple Explanation

Recovery of function is limited following spinal cord injury (SCI), due to primary trauma and necrosis, and secondary damage resulting in neurotoxicity, vascular dysfunction, inﬂammation, formation of the glial scar, demyelination, neurotoxicity, and apoptosis. Here we highlight two strategies, exercise and peripheral nerve grafts (PNGs), and the intersection of their mechanisms and evidence of combinatorial beneﬁts. Exercise appears to affect the intrinsic potential of neurons to regenerate after injury through upregulation of mediators of growth, asthe PTEN/mTOR pathway and RAGs such as GAP43, b-actin and neuritin.

Study Duration

5-12 weeks

Participants

Adult rats

Evidence Level

Not specified

Key Findings

1
Acute and chronically injured propriospinal neurons within the lumbar spinal cord displayed the greatest propensity for enhanced regeneration after exercise, which correlates with the direct sensory input to this region from exercised hindlimb muscles.
2
In the lumbar cord a signiﬁcant increase was seen in the number of neurons regenerating axons into the aPNG in both the acute exercise chronic PNG recipient group and the delayed exer-cise chronic PNG recipient group when compared with the non-exercised chronic PNG control group
3
Our ﬁnding that exercise seems to have a much more robust impact on regeneration in acutely injured neurons would suggest a critical time period after injury for the beneﬁcial effects of exercise.

Research Summary

Therapeutic interventions after spinal cord injury (SCI) routinely are designed to address multiple aspects of the primary and/or secondary damage that occurs. Exercise has a demonstrated efﬁcacy for post-SCI complications such as cardiovascular dysfunction, neuropathic pain, and chronic inﬂammation, yet there is little understanding of the mechanisms by which improvements might result from this non-invasive approach. Acute and chronically injured propriospinal neurons within the lumbar spinal cord displayed the greatest propensity for enhanced regeneration after exercise, which correlates with the direct sensory input to this region from exercised hindlimb muscles.

Practical Implications

Exercise Timing

Initiating exercise at shorter post-injury intervals (1–3 days) leads to exaggerated muscle fatigue, muscle degeneration, and generally diminished functional outcome.

Combination Therapy

Combining exercise with peripheral nerve grafts (PNGs) can additively enhance axonal regeneration and recovery after SCI.

Clinical Relevance

Exercise has the potential to facilitate regeneration in a therapeutically relevant time course, without the clinically limiting necessity to begin in the acute or subacute period after SCI.

Study Limitations

1
The study primarily focuses on animal models (rats), and the results may not directly translate to human SCI.
2
The study acknowledges that the exact molecular mechanisms by which exercise facilitates regeneration require further investigation.
3
The study points out that fewer than 10% of axons that enter these grafts typically extend beyond the distal end.

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