{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:26:25Z","timestamp":1792517185949,"version":"4.5.0"},"reference-count":57,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JNS"],"published-print":{"date-parts":[[2010,9]]},"abstract":"<jats:p>Microvascular failure largely underlies the damaging secondary events that accompany traumatic brain injury (TBI). Changes in capillary permeability result in the extravasation of extracellular fluid, inflammatory cells, and blood, thereby producing cerebral edema, inflammation, and progressive secondary hemorrhage (PSH). Recent work in rat models of TBI and stroke have implicated 2 ion transport proteins expressed in brain endothelial cells as critical mediators of edema formation: the constitutively expressed Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup>-2Cl<jats:sup>\u2013<\/jats:sup> cotransporter, NKCC1, and the trauma\/ischemia-induced SUR1-regulated NC<jats:sub>Ca-ATP<\/jats:sub> (SUR1\/TRPM4) channel. Whereas NKCC1 function requires adenosine 5\u2032-triphosphate (ATP), activation of SUR1\/TRPM4 occurs only after ATP depletion. This opposite dependence on intracellular ATP levels implies that one or the other mechanism will activate\/deactivate as ATP concentrations rise and fall during periods of ischemia\/reperfusion, resulting in continuous edema formation regardless of cellular energy status. Moreover, with critical ATP depletion, sustained opening of SUR1\/TRPM4 channels results in the oncotic death of endothelial cells, leading to capillary fragmentation and PSH. Bumetanide and glibenclamide are 2 well-characterized, safe, FDA-approved drugs that inhibit NKCC1 and the SUR1\/TRPM4 channel, respectively. When used alone, these drugs have provided documented beneficial effects in animal models of TBI- and ischemiaassociated cerebral edema and PSH. Given the mechanistic and temporal differences by which NKCC1 and the SUR1\/TRPM4 channel contribute to the pathophysiological mechanisms of these events, combination therapy with bumetanide and glibenclamide may yield critical synergy in preventing injury-associated capillary failure.<\/jats:p>","DOI":"10.3171\/2009.11.jns081052","type":"journal-article","created":{"date-parts":[[2009,12,25]],"date-time":"2009-12-25T15:34:51Z","timestamp":1261755291000},"page":"622-629","source":"Crossref","is-referenced-by-count":130,"title":["Molecular mechanisms of microvascular failure in central nervous system injury\u2014synergistic roles of NKCC1 and SUR1\/TRPM4"],"prefix":"10.3171","volume":"113","author":[{"given":"J. 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