Repetitive Passive Cycling Exercise in Combination With Serotonergic Agonist Therapy Improves Motor Recovery Following Experimental Spinal Cord Injury

Introduction: Serotonin supplied by brainstem-spinal neurons plays a role in locomotion that is lost after spinal cord injury. Serotonergic agonists such as the drug, mCPP, promote locomotor function following spinal cord injury by modulating the central pattern generator (spinal cord reflex) for primitive gait that exists distal to the injury zone. The effect of repetitive training of this reflex through passive cycling exercise following experimental spinal cord injury (mid-thoracic transection) in rats was studied.

Methods: 61 rats underwent mid-thoracic laminectomy and complete spinal cord transection, creating an approximately 2-3 mm defect. One third of rats further underwent transplantation of the injury zone with fibroblasts genetically designed to secrete BDNF and NT-3 (Brain derived nerve growth factor and Neurotropic Factor-3). One third underwent transplantation with unmodified fibroblasts, and the final third received an acellular transplant. Additionally animals were categorized by treatment protocol. Animals in Group 1 (n=18) received no exercise and no drug treatment. Animals in group 2 (n=20) received no exercise but were given the serotonin agonist mCPP once a month. Animals in group 3 (n=23) received intensive passive cycling exercise 5 days per week for one hour each day, and were adjunctively treated with mCPP once a month. The animals were studied behaviorally and scored for motor function (BBB) after two months and prior to sacrifice.

Results: No significant differences in hindlimb movement in an openfield situation (BBB) was found when animals were studied according to the type of transplant that they received. Differences in BBB score was noted, however, when animals were studied according to treatment protocol. The average BBB score for animals that received no cycling exercise and did not receive serotonergic agonist drug therapy was between 3-4. However, animals that received the drug therapy without exercise therapy had improved motor scores with an average BBB of 7. Those animals that received both passive cyling exercise and mCPP drug therapy had the most improvement in BBB score with an average of 9. Exercised animals were also more likely to use plantar paw placement and dorsal stepping.

Significance: After spinal cord injury, repeated exercise in the form of passive cycling has a positive effect on motor recovery in combination with serotonergic agonists. Serotonergic agonists have a significant positive effect by binding to receptors of the central pattern generator and thereby enhancing primitive motor reflexes below the level of injury. Repeated exercise does likely aid in the preservation of limb function, which in combination with drug therapy contributes to the improved motor outcome seen in this study. It is also possible, however, that repetitive passive exercise stimulates an up-regulation of serotonin receptors on neurons distal to the level of injury, and thereby enhances the effect of drug therapy.