title: Connexin hemichannel blockade improves outcomes in a model of fetal ischemia.
abstract: OBJECTIVE
  Connexin hemichannels can open during ischemia, resulting in loss of membrane potential, calcium influx, and release of glutamate. In this study, we tested the hypothesis that opening of hemichannels after cerebral ischemia may contribute to delayed evolution of injury.
  
  
  METHODS
  We infused a mimetic peptide that blocks connexin 43 hemichannels into the lateral ventricle of chronically instrumented fetal sheep in utero at 128 ± 1 days gestation (term is 147 days), starting 90 minutes after 30 minutes of severe ischemia induced by reversible bilateral carotid artery occlusion, for either 1 or 25 hours. Sheep were killed 7 days later.
  
  
  RESULTS
  Peptide infusion was associated with a graded improvement in recovery of electroencephalographic power after 7 days recovery, from -13 ± 1.9 dB (n = 7) after ischemia-vehicle to -9 ± 1.6 dB (n = 7) after ischemia-short infusion and -5 ± 1.6 dB after ischemia-long infusion (n = 6, p < 0.05). Peptide infusion was associated with reduced seizure activity after ischemia, less frequent status epilepticus (p < 0.05), and earlier return of sleep state cycling (p < 0.05). Ischemia-long infusion (but not ischemia-short infusion) was associated with improved survival of oligodendrocytes in intragyral and periventricular white matter (p < 0.05) and increased brain weight (p < 0.05). Ischemia-long infusion was associated with an intermediate estimate of surviving neurons in the parasagittal cortex of 2.9 ± 0.8 × 10(6), in comparison to sham control (4.3 ± 0.9 × 10(6)) or ischemia-vehicle (1.5 ± 0.4 × 10(6); p < 0.05 vs sham control).
  
  
  CONCLUSIONS
  These data support the hypothesis that opening of connexin hemichannels is a significant mediator of postischemic white and gray matter dysfunction and injury.
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Davidson
authors.forename: Colin R
authors.initials: CR
authors.lastname: Green
authors.forename: Louise F B
authors.initials: LF
authors.lastname: Nicholson
authors.forename: Simon J
authors.initials: SJ
authors.lastname: O'Carroll
authors.forename: Mhoyra
authors.initials: M
authors.lastname: Fraser
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.forename: Alistair Jan
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D002470:Cell Survival / Q000502:physiology; D018031:Connexin 43 / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D005260:Female; D005311:Fetal Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018390:Gene Targeting; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D011247:Pregnancy; D012640:Seizures / Q000517:prevention & control; D012756:Sheep; D012894:Sleep Stages / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D018031:Connexin 43; D010446:Peptide Fragments