Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence.

J. Claude Hemphill,Giuseppe Citerio,Raj K. Narayan,J. Marc Simard,Kevin N. Sheth,W. Taylor Kimberly,Josh Bell,Ruchira M. Jha,Juan Sahuquillo

doi:10.3390/ijms21020409

Abstract

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)—Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.

Highlights

The public health impact of traumatic brain injury (TBI) on death and disability is immense
We briefly summarize molecular studies of sulfonylurea receptor 1 (SUR1)-Transient receptor potential melastatin 4 (TRPM4), outlining the pathophysiology of this channel as it relates to cerebral edema and blood brain barrier (BBB) integrity
There is substantial preclinical and clinical evidence supporting a pivotal role of the SUR1TRPM4 pathway in cerebral edema development, contusion expansion, and outcome after TBI

Summary

Introduction

The public health impact of traumatic brain injury (TBI) on death and disability is immense. Characteristics of the primary injury are generally considered non-modifiable, reducing the impact of secondary injury has the potential to substantially improve outcomes after TBI. Existing multivariable TBI clinical outcome prediction models from large patient populations such as IMPACT (International Mission for Prognosis and Clinical Trial design in TBI) explain ~35% of outcome variability [2,3]. These models predominantly utilize non-modifiable injury characteristics (demographics, severity, motor score, pupillary reactivity with some added value from admission computed tomography (CT), laboratory values and second insults). More than 50% of TBI outcome variability may be related to host-response and secondary injury processes, providing tremendous opportunity for targeted intervention

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Conclusion