title: Effect of gap junction inhibition on intracerebral hemorrhage-induced brain injury in mice.
abstract: It has been reported that gap junction contributes to ischemic brain injury and gap junction inhibitors improve neurological outcome in ischemic brain injury models. In the present study, we investigated the effects of gap junction inhibitor, carbenoxolone, on mortality, neurological deficits and brain edema in mice with intracerebral hemorrhage. A total of 80 male CD-1 mice were divided into two parts with two end-points for this study. In part one, animals were divided into four groups: sham, vehicle treatment following intracerebral hemorrhage induction, low-dose carbenoxolone (33 mg/kg) treatment 1 hour after intracerebral hemorrhage induction and high-dose carbenoxolone (100 mg/kg) treatment 1 hour after intracerebral hemorrhage induction groups. Animals were euthanized after 24 hours. In part two, animals were divided into four groups: sham, vehicle treatment 1 hour after intracerebral hemorrhage induction, single high-dose of carbenoxolone treatment at 1 hour after intracerebral hemorrhage induction and three high-doses of carbenoxolone treatment 1, 24 and 48 hours respectively after intracerebral hemorrhage induction. Animals were euthanized after 72 hours. Intracerebral hemorrhage was induced by collagenase injection. Neurological deficits were evaluated using modified Garcia's neurological test, wire hanging and beam balance tests. Brain edema was measured by brain water content. Our results showed that intracerebral hemorrhage produced brain edema and neurological deficits in mice. Carbenoxolone treatment failed to reduce brain edema and neurological deficits. In fact, the high dose of carbenoxolone aggravated neurological deficits and increased mortality 72 hours after the treatment. In conclusion, inhibition of gap junction has no short-term neuroprotective effect on intracerebral hemorrhage-induced brain injury. Further studies are required to assess the long-term effects of gap junction inhibitors in intracerebral hemorrhage models.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda CA 92350, USA.
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.forename: Takumi
authors.initials: T
authors.lastname: Sozen
authors.forename: Reiko
authors.initials: R
authors.lastname: Tsuchiyama
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology / Q000401:mortality / Q000473:pathology; D002229:Carbenoxolone / Q000627:therapeutic use*; D002375:Catalepsy; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000150:complications*; D017364:Collagenases; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007839:Functional Laterality; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D009460:Neurologic Examination / Q000379:methods; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D017364:Collagenases; D002229:Carbenoxolone