title: Neuroprotective effects of volume-regulated anion channel blocker DCPIB on neonatal hypoxic-ischemic injury.
abstract: OBJECTIVE
  To evaluate the role of swelling-induced activation of volume-regulated anion channels (VRACs) in a neonatal hypoxic-ischemic injury model using the selective VRAC blocker 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on5-yl) oxobutyric acid (DCPIB).
  
  
  METHODS
  Cerebral hypoxic-ischemic injury was induced in 7-day-old mouse pups with Rice-Vannucci method. Prior to the onset of ischemia, the animals were ip administered DCPIB (10 mg/kg). The animals were sacrificed 24 h afterwards, coronal sections of the brains were cut and the areas of infarct were examined using TTC staining and an image-analysis system. Cultured PC12 cells were subjected to oxygen-glucose deprivation (OGD) for 4 h. The cellular viability was assessed using Cell Counting Kit 8. Intracellular chloride concentration [Cl(-)](i) was measured using 6-methoxy-N-ethylquinolinium iodide.
  
  
  RESULTS
  DCPIB-treated mice showed a significant reduction in hemispheric corrected infarct volume (26.65%±2.23%) compared to that in vehicle-treated mice (45.52%±1.45%, P<0.001). DCPIB-treated mice also showed better functional recovery as they were more active than vehicle-treated mice at 4 and 24 h post injury. In cultured PC12 cells, DCPIB (10 μmol/L) significantly reduced OGD-induced cell death. Moreover, DCPIB (20 μmol/L) blocked hypotonic-induced decrease in [Cl(-)](i) in PC12 cells of both control and OGD groups.
  
  
  CONCLUSIONS
  The results further support the pathophysiological role of VRACs in ischemic brain injury, and suggest DCPIB as a potential, easily administrable agent targeting VRACs in the context of perinatal and neonatal hypoxic-ischemic brain injury.
authors.affiliation: Departments of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ammar
authors.initials: A
authors.lastname: Alibrahim
authors.forename: Li-yan
authors.initials: LY
authors.lastname: Zhao
authors.forename: Christine You-jin
authors.initials: CY
authors.lastname: Bae
authors.forename: Andrew
authors.initials: A
authors.lastname: Barszczyk
authors.forename: Christopher L F
authors.initials: CL
authors.lastname: Sun
authors.forename: Guan-lei
authors.initials: GL
authors.lastname: Wang
authors.forename: Hong-shuo
authors.initials: HS
authors.lastname: Sun
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002712:Chlorides / Q000032:analysis / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005947:Glucose / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats
chemical_list: C443139:4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid; D018118:Chloride Channels; D002712:Chlorides; D003517:Cyclopentanes; D007189:Indans; D018696:Neuroprotective Agents; D005947:Glucose; D010100:Oxygen