Modulation of the BK Channel During Acute Spinal Cord Injury is Neuroprotective

Spinal cord injury results in significant neuronal and glial cell death resulting in impaired neurological and motor function. While there are often surviving axonal tracts, these are frequently dysmyelinated or demyelinated. Key to this pathology is uncontrolled Ca 2+ entry, resulting in excitotoxicity and cell death. We propose that by activating mechanisms attenuating global depolarization and limiting Ca 2+ entry, we can reduce neuronal death and significantly improve neurological and motor function. To this effect, we previously demonstrated that the large‐conductance, voltage and Ca 2+ ‐activated K + (BK or Maxi K + ) channel is altered after SCI, and may play a part in the neuropathology of SCI. In this study, we set out to explore whether the use of a BK channel activator, Isopimaric acid (ISO), is neuroprotective post spinal cord injury. Wister rats received a 25‐g clip compression injury at the T7 levels for 1 min. One hour post‐surgery, they were administered ISO (120 μM), Ibeurotoxin (IbTx; 100nM), or a vehicle control via mini‐osmotic pump. Complete gait analysis was performed using two‐dimensional motion capture by filming rats on a weekly basis for 8 weeks. Compound Action Potentials (CAP) and high frequency conduction experiments were performed on spinal cords 8 weeks post surgery. Finally, the size of the injury site, loss of myelination, and cell death were assessed using immunohistochemistry (IHC). Complete gait analysis suggests that treatment with ISO improves motor function in our test model. ISO treated animals were able to recover gait function to a greater extent than IbTx and control animals. While the IbTx treated rats also demonstrated an improvement in complete gait function, their recovery was delayed and not of the same magnitude as ISO treated animals. This finding was further supported in our electrophysiology and IHC experiments. In our CAP experiments we find that there is a significant difference between all three groups. Additionally, we found preservation or re‐establishment of axonal tracts and myelination in our IHC experiments. In conclusion, activation of the BK channel during acute SCI may be a novel therapeutic target for acute spinal cord injury. Further studies are required to determine if modulation of the BK channel in chronic injury is beneficial for recovery, and to understand the mechanisms by which this ion channel may be working during spinal cord injury repair. Support or Funding Information Saskatchewan Health Research Foundation