Combined Regenerative and Rehabilitative Approach to Promote Autonomic Recovery after Spinal Cord Injury
Sachdeva R, Sangha A, Auyeung A, Hutton G, Gopaul R, Ramer M, Krassioukov A
University of British Columbia, Vancouver, BC, Canada
Introduction: Spinal cord injury (SCI) disrupts the crucial cardio-autonomic control and leads to life-threatening conditions such as autonomic dysreflexia (AD). During AD, the loss of supraspinal control along with the aberrant sprouting of nociceptive afferents within the spinal cord allows peripheral stimuli to instigate uncontrolled surges in blood pressure (BP). Therefore, in response to a stimulus (e.g. a distended bladder), BP can rise up to 300 mmHg causing seizures, stroke or even death.(1) Using high thoracic SCI in rats (that reliably develops AD),(2) we hypothesized that a combination approach could significantly mitigate AD severity by simultaneously promoting axonal regeneration(3) to restore the supraspinal vasomotor control as well as by reducing aberrant sprouting of nociceptive afferents.(2)
Methods: Adult male Wistar rats received a complete spinal transection (Tx) at 3rd thoracic segment. Treatment group received peripheral nerve grafts spanning the lesion, intrathecal delivery of chondroitinase enzyme and cycling exercise (beginning on day 5, 1 hr/day, 5 days/week). Appropriate control groups received Tx only or Tx and a single intervention. Weekly and terminal cardiovascular function [i.e. resting BP, heart rate and pressor response to colorectal distension (CRD)] was assessed using radiotelemetry at 8 weeks. Functional regeneration across the graft was determined using stimulus-linked neuronal activity below the lesion upon electrical stimulation above the lesion. Retrograde and anterograde neural tract tracing was performed to determine the neuronal origin and extent of growth of regenerating axons as well as immunohistochemistry for the sprouting of nociceptive (calcitonin gene related peptide positive) afferents.
Results: The combination approach leads to significant cardiovascular recovery compared to the untreated group. Specifically, in response to CRD, the treatment group shows 53.8% reduction in systolic BP elevation (77.8 vs. 37.7 mmHg, p<0.0001), 42.2% reduction in diastolic BP elevation (42.5 vs. 24.5 mmHg, p<0.001), 57.6% reduction in mean arterial pressure elevation (54.2 vs. 22.9 mmHg, p<0.001) as well as abolishment of CRD-induced bradycardia (-80.2 vs. +14.6 bpm, p=0.056). Synaptically driven activity of spinal cord neurons across the graft confirmed the functional re-connection of axons. The time course of recovery as well as the effect of graft transection on recovered function is being evaluated. The underlying mechanisms of recovery i.e. the supraspinal source of regenerating axons, extent of axon growth below the lesion and, extent of nociceptive sprouting etc. are also being investigated.
Conclusion: Combined neuro-regenerative and rehabilitative approach leads to significant autonomic recovery after SCI, which is likely mediated by vasomotor regeneration and afferent plasticity manipulation. Considering the significant advances in Schwann cell transplantation in humans with SCI(4) and the clinical feasibility of exercise,(5) this study holds significant potential in improving autonomic function and the quality of life after SCI.
Funding support: Rick Hansen Foundation (AVK), Heart and Stroke Foundation (AVK), Craig H. Neilsen Postdoctoral Fellowship (RS).
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