Evaluation of potassium channel blockers, 4-aminpyridine and 4-aminpyridine-3-methanol, in combination with electrical neuromodulation for functional upper limb recovery following incomplete cervical spinal cord injury
Cervical spinal cord injury (SCI) is a traumatic condition where individuals lose crucial motor and sensory functions in their hands and arms. These deficits can be caused by myelin damage, which exposes juxtaparanodal potassium channels leading to large potassium effluxes and ultimately, shortened and decreased conduction. However, potassium channel blockers such as 4-aminopyridine (4-AP) and the novel derivative, 4-aminopyridine-3-methanol (4-AP-3-MeOH) prevent potassium ion leakage and increase conduction to improve motor function. Currently, it is possible to regain voluntary motor control and strength in the forelimbs and hands by using complementary electrical stimulation, pharmacological agents and training to transform dormant spinal circuitry into active states. Here, we evaluated the extent to which potassium channel blockers, 4-AP and 4-AP-3-MeOH enable functional forelimb ability when used in combination with spinal stimulation and motor training after incomplete cervical SCI. 4-AP restored reaching and grasping function and muscle activation in rats after two weeks of treatment. 4-AP-3-MeOH, however, did not lead to improve motor functioning or muscle activation. Both drugs decreased muscle activation latency and allowed for earlier muscle activation. Our findings suggest 4-AP synergistically works with spinal stimulation and training to enable spared circuitry following SCI and can be used acutely to restore forelimb function.