6 CLINICAL NEUROSCIENCES UPDATE SUMMER 2018 For decades, most of the preclinical scientific research on acute ischemic stroke and traumatic brain injury (TBI) focused on protecting or preserving neurons. However, in day-to-day neurocritical care, most of the efforts spent on managing patients with severe forms of brain injury—large hemispheric infarction (LHI) and brain contusions—are directed toward managing cerebral edema, brain swelling, and elevated intracranial pressure (ICP). Cerebral edema and elevated ICP add insult to injury by further compromising the already damaged brain and, in the worst cases, by directly causing brain death. The available “tools” for countering edema, brain swelling and elevated ICP are antiquated and inadequate, consisting simply of osmotherapeutics (mannitol and hypertonic saline) and decompressive craniectomy. At present, there are no strategies for targeting molecular mechanisms of brain edema. Bench-to-Bedside The story of glyburide (also known as glibenclamide) in ischemic stroke and TBI is a classic example of “bench to bedside” research—a fundamental, basic-science discovery whose potential clinical applicability was recognized early on, and has since advanced to clinical trials. The target of glyburide, the SUR1- TRPM4 channel, was discovered by serendipity nearly two decades ago while doing single channel patch clamp experiments on astrocytes from rat brain. It was quickly appreciated that this channel was unique, although it would take several years before the channel was characterized molecularly. Early on, it was recognized that the SUR1-TRPM4 channel plays a major role in edema formation. Cerebral ischemia and trauma induce subtle changes in the endothelial cells that line the blood vessels of the brain, causing them to express SUR1-TRPM4 channels. When these channels open, endothelial cells swell, thereby compromising the critical barrier function they normally perform. This results in edema formation and brain swelling, and can lead to secondary hemorrhage (in stroke, called hemorrhagic transformation; in TBI, called contusion blossoming). New work in stroke has shown that the SUR1-TRPM4 channel physically co-assembles with and regulates STROKE OF INSIGHT Clinician-scientist Dr. J Marc Simard recounts the work done by him and his colleagues in developing a novel therapy that targets brain swelling—a common cause of fatality in severe stroke and brain trauma. A Professor of Neurosurgery, Pathology and Physiology at the University of Maryland School of Medicine, J Marc Simard, MD, PhD is a board-certified clinical neurosurgeon as well as an active researcher—the consummate example of today’s physician-scientist.