Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain contusion

J. Marc Simard, Michael Kilbourne, Orest Tsymbalyuk, Cigdem Tosun, John Caridi, Svetlana Ivanova, Kaspar Keledjian, Grant Bochicchio, Volodymyr Gerzanich

Research output: Contribution to journalArticlepeer-review

Abstract

An important but poorly understood feature of traumatic brain injury (TBI) is the clinically serious problem of spatiotemporal progression ("blossoming") of a hemorrhagic contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the contusion. In untreated rats, PSH was characterized by progressive enlargement of the contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic contusions, and point to SUR1 as a potential therapeutic target in TBI.

Original languageEnglish (US)
Pages (from-to)2257-2267
Number of pages11
JournalJournal of Neurotrauma
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Keywords

  • Contusion
  • Glibenclamide
  • Hemorrhage
  • Sulfonylurea receptor 1
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

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