Examining the effects of NKCC1 antagonist to modulate spinal network excitability
Funded in: 2020, 2021, 2022
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Problem: No pharmaceutical treatment found so far can effectively activate functionally dormant pathways in injured spinal cord and promote functional recovery
Target: Evaluating effects of applying Bumetanide, a clinical approved NKCC1 antagonist, to promote functional recovery
Goal: Generate bumetanide-based translatable results for functional recovery
Most human spinal cord injuries (SCI) are only anatomically incomplete, with both descending and ascending axons spared. However, over half of them completely lose muscle control and sensation below the injury level. This suggests that spared connections in the incompletely transected spinal cords are functionally dormant. In order to reactivate spared pathways, the main challenges are to understand the underlying mechanism and choose a translatable way to promote functional recovery post-SCI.
Previous studies have discovered that administration of CLP290, a K+-Cl- cotransporters 2 (KCC2) agonist, can restore stepping ability in complete paralyzed mice. Mechanistically, studies from the group showed that activating KCC2 corrects dysfunctional network excitability within spinal circuits and is sufficiently to promote observable functional recovery in SCI mice. All existing results support that KCC2 plays a key role in regulating network excitability together with Na+-K+-2Cl- cotransporter 1 (NKCC1), however the compound is constrained in clinical trials as no KCC2 agonists have been approved for human use. The hypothesis roots on an alternative compound, bumetanide, a clinical approved NKCC1 antagonist, to address the conflict. Based on preliminary data, bumetanide can actually reach better results, compared to KCC2 in terms of functional recovery in a translatable contusion SCI model.
In this proposed study, a translatable method is firstly developed to inhibit NKCC1. As a next step, the group will apply the same strategy in a clinically relevant SCI contusion injury model. In addition, to further promoting functional recovery, the scientists will apply 4-aminopyridine, a clinically used drug to treat multiple sclerosis, to enhance axon conduction in SCI mice.