Drug-Induced Hypothermia plus Glibenclamide for Rapid, In-Field Treatment of SCI
Abstract
The treatment of acute spinal cord injury to minimize long-term deficits remains an enormous unmet challenge. A common feature of acute spinal cord injury is that the injury site (the lesion) continues to expand and grow for several hours after the trauma. It stands to reason (and it has been proven in animal models) that treatments that halt lesion expansion can lead to better outcomes in terms of neurological and urological (bladder) function. For several decades, cooling of the body (therapeutic hypothermia) has been recognized to be beneficial in brain and spinal cord trauma, but numerous technical limitations severely reduce its use, and thus its impact. A revolution is underway in the field of body cooling, wherein cooling can now be induced using an intravenous infusion of a drug called dihydrocapsaicin, which is the ingredient in chili peppers that gives them their pungency. This innovative approach to body cooling has been evaluated in animal models of cardiac arrest and stroke, but has not yet been studied in brain or spinal cord trauma. For over a decade, we have known that the innovative approach to body cooling has been evaluated in animal models of cardiac arrest and drug glibenclamide, which has been routinely used for several decades to treat adult onset diabetes, can effectively prevent lesion expansion in animal models of spinal cord injury. In this project, we will study a rat model of severe cervical spinal cord injury and evaluate treatments with dihydrocapsaicin and glibenclamide. Our concept is that glibenclamide will reduce lesion expansion, and thereby allow body cooling to be more effective, because it will be acting on a smaller lesion. In Aim 1, we will compare body cooling obtained by conventional methods vs. body cooling obtained by dihydrocapsaicin infusion. Based on data from animal models of cardiac arrest and stroke, we expect that, in spinal cord injury, drug-induced cooling will be as effective as conventional cooling. If equivalent benefit can be demonstrated, this would be a tremendous advancement that in the future would allow body-cooling treatment of humans with spinal cord injury to be started in the field or during transport, instead of waiting, often several hours, for in-hospital treatment. In Aim 2, we will compare glibenclamide and cooling induced by dihydrocapsaicin, both alone and in combination. Based on data from animal models of stroke, we expect that, in spinal cord injury, the combination of the two will be superior to either one alone. Importantly, these innovative treatments could potentially be implemented soon in humans with spinal cord injury, given that the two drugs are known to be safe in humans, a clinical trial on conventional body cooling is anticipated soon from investigators at the Miami Project to Cure Paralysis, and an intravenous version of glibenclamide is about to be tested in a Phase 3 clinical trial in human stroke. Overall, the proposed work has immediate relevance to patients with acute spinal cord injury, in that minimizing expansion of the injury site by glibenclamide, and minimizing the harmful effects of the primary injury by body cooling is expected to enhance the recovery from SCI, and thus minimize neurological and urological deficits in these unfortunate patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810249
Entities
People
- J Marc Simard
Organizations
- United States Army
- University of Maryland, Baltimore