title: Inhibition of the Sur1-Trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage.
abstract: OBJECTIVE
  Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning.
  
  
  METHODS
  We used Förster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Förster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation and tumor necrosis α overexpression as measures of barrier dysfunction and neuroinflammation, and we assessed spatial learning and memory on days 7 to 19.
  
  
  RESULTS
  Sur1-Trpm4 channels were upregulated in humans and rats with SAH. In rats, inhibiting Sur1 using antisense or the selective Sur1 inhibitor glibenclamide reduced SAH-induced immunoglobulin G extravasation and tumor necrosis α overexpression. In models with entorhinal SAH, rats treated with glibenclamide for 7 days after SAH exhibited better platform search strategies and better performance on incremental and rapid spatial learning than vehicle-treated controls.
  
  
  CONCLUSIONS
  Sur1-Trpm4 channels are upregulated in humans and rats with SAH. Channel inhibition with glibenclamide may reduce neuroinflammation and the severity of cognitive deficits after SAH.
authors.affiliation: From the Departments of Neurosurgery (C.T., D.B.K., M.S.K., S.K.W., V.G., J.M.S.), Pathology (R.M., R.J.C., J.M.S.), and Physiology (J.M.S.), University of Maryland School of Medicine, Baltimore; and Department of Pathology, Western Michigan University School of Medicine, Kalamazoo, MI (J.L.d.J.).
authors.forename: Cigdem
authors.initials: C
authors.lastname: Tosun
authors.forename: David B
authors.initials: DB
authors.lastname: Kurland
authors.forename: Rupal
authors.initials: R
authors.lastname: Mehta
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.forename: Joyce L
authors.initials: JL
authors.lastname: deJong
authors.forename: Min Seong
authors.initials: MS
authors.lastname: Kwon
authors.forename: Seung Kyoon
authors.initials: SK
authors.lastname: Woo
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D013345:Subarachnoid Hemorrhage / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D064233:Sulfonylurea Receptors / Q000037:antagonists & inhibitors*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C577509:Abcc8 protein, rat; D064233:Sulfonylurea Receptors; D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat; D005905:Glyburide
keywords: cognition; memory; subarachnoid hemorrhage; sulfonylurea receptor; transient receptor potential melastatin 4