title: Role of SCH79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage.
abstract: OBJECTIVE
  Plasma thrombin concentration is increased after subarachnoid hemorrhage (SAH). However, the role of thrombin receptor (protease-activated receptor-1 [PAR-1]) in endothelial barrier disruption has not been studied. The aims of this study were to investigate the role of PAR-1 in orchestrating vascular permeability and to assess the potential therapeutics of a PAR-1 antagonist, SCH79797, through maintaining vascular integrity.
  
  
  METHODS
  SCH79797 was injected intraperitoneally into male Sprauge-Dawley rats undergoing SAH by endovascular perforation. Assessment was conducted at 24 hours after SAH for brain water content, Evans blue content, and neurobehavioral testing. To explore the role of PAR-1 activation and the specific mechanism of SCH79797's effect after SAH, Western blot, immunoprecipitation, and immunofluorescence of hippocampus tissue were performed. A p21-activated kinase-1 (PAK1) inhibitor, IPA-3, was used to explore the underlying protective mechanism of SCH79797.
  
  
  RESULTS
  At 24 hours after SAH, animals treated with SCH79797 demonstrated a reduction in brain water content, Evans blue content, and neurobehavioral deficits. SCH79797 also attenuated PAR-1 expression and maintained the level of vascular endothelial-cadherin, an important component of adherens junctions. Downstream to PAR-1, c-Src-dependent activation of p21-activated kinase-1 led to an increased serine/threonine phosphorylation of vascular endothelial-cadherin; immunoprecipitation results revealed an enhanced binding of phosphorylated vascular endothelial-cadherin with endocytosis orchestrator β-arrestin-2. These pathological states were suppressed after SCH79797 treatment.
  
  
  CONCLUSIONS
  PAR-1 activation after SAH increases microvascular permeability, at least, partly through a PAR-1-c-Src-p21-activated kinase-1-vascular endothelial-cadherin phosphorylation pathway. Through suppressing PAR-1 activity, SCH79797 plays a protective role in maintaining microvascular integrity after SAH.
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Yan
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.forename: Damon
authors.initials: D
authors.lastname: Klebe
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.forename: Basak
authors.initials: B
authors.lastname: Caner
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Fujii
authors.forename: Changman
authors.initials: C
authors.lastname: Zhou
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004220:Disulfides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009284:Naphthols / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors
chemical_list: D004220:Disulfides; D004791:Enzyme Inhibitors; C541795:IPA-3 compound; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D009284:Naphthols; D011758:Pyrroles; D011799:Quinazolines; D054462:p21-Activated Kinases; D010975:Platelet Aggregation Inhibitors
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