In addition to paralysis, spinal cord injury (SCI) also results in alterations to reflex function. These alterations lead to debilitating involuntary muscle contractions or spasms that can interrupt purposeful movements, decrease overall safety, and cause skin breakdown. This proposal seeks to identify a specific pharmacological intervention that will minimize the debilitating spasms that develop following SCI and that can be quickly translated for use in human subjects. These abnormal prolonged muscle contractions, or spasms, can be initiated by sensory stimulation below the level of the injury and, currently, they are thought to be an abnormal presentation of prolonged neuronal depolarizations caused by calcium-mediated persistent inward currents (CaPICs) in the spinal cord. Normally, descending neuromodulatory pathways from the brainstem control these PICS, but after SCI, these pathways are disrupted. This disruption causes some neuromodulatory receptors in the spinal cord to become constitutively active and initiate long lasting depolarizations, or plateau potentials, of the spinal motor system in response to stimuli below the lesion. We know from prior studies that the CaPIC is controlled through an L-type calcium channel and we suspect that CaV1.3, a specific L-type calcium channel, mediates the CaPIC. However, we have had no tools to test this. Recently, a new and novel drug, SKP004C08, was developed for use in humans through the collaboration of the Surmeier and Silverman laboratories at Northwestern University and has been shown to specifically block the CaV1.3 calcium channel. Using this new CaV1.3 channel blocker, we aim to test that the CaV1.3 channel indeed mediates both normal PICs and the elevated PICs seen after spinal cord injury. Secondly, we aim to prove that modulating the activity of CaV1.3 can normalize motoneuron excitability, which will decrease the severity and duration of spasms in vivo and improved function overall post SCI.
|Effective start/end date||9/30/15 → 9/30/18|
- Craig H. Neilsen Foundation (338167)