title: Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.
abstract: Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Davidson
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Rout
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Guido
authors.initials: G
authors.lastname: Wassink
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Yuill
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Zhang
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Green
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.affiliation: Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001831:Body Temperature; D002545:Brain Ischemia / Q000188:drug therapy / Q000628:therapy*; D002470:Cell Survival; D002560:Cerebrovascular Circulation; D017630:Connexins / Q000037:antagonists & inhibitors*; D004569:Electroencephalography; D005260:Female; D005333:Fetus; D007036:Hypothermia, Induced; D007276:Injections, Intraventricular; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009836:Oligodendroglia / Q000473:pathology; D011247:Pregnancy; D012756:Sheep
chemical_list: D017630:Connexins; D018696:Neuroprotective Agents