title: The effect of a gap-junction blocker, carbenoxolone, on ischemic brain injury and cortical spreading depression.
abstract: Cortical spreading depression (CSD) has been shown to cause secondary cell loss in experimental models of brain injury and in patients, and blocking of CSD is a potential neuroprotective strategy. Here we tested the hypothesis that gap junctions affect CSD under physiological conditions as well as infarct development in a rat two-vein occlusion model suited to study pathophysiology of the penumbra (n = 71). We applied the gap junction blocker carbenoxolone (CBX) or saline intra-ventricularly. Interestingly, CBX temporarily increased systemic blood pressure and cortical blood flow (41% and 53%, 15 min after 250 μg CBX). We induced CSD with cortical microinjection of potassium chloride (KCl), counted how many spontaneous CSDs after CSD induction were elicited and measured the propagation velocity. After 250 μg CBX administration, significant 37.5 ± 6.5 additional CSDs were seen. CSD velocity increased significantly after 50 μg and 250 μg CBX. Occlusion of two adjacent cortical veins using Rose Bengal dye and fiberoptic illumination followed by 250 μg CBX or saline showed a significant more than doubling of infarct volumes 7 days after CBX. The current experiments provide evidence that CBX can accelerate the initiation and propagation of CSD suggesting opening of gap junctions is not required for CSD propagation. Blocking gap junctions worsens outcome from focal cerebral ischemia. Hence, measures intended to improve spatial buffering via astroglial gap junctions could have therapeutic potential in disease processes involving CSD.
authors.affiliation: Department of Neurosurgery, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tamura
authors.forename: B
authors.initials: B
authors.lastname: Alessandri
authors.forename: A
authors.initials: A
authors.lastname: Heimann
authors.forename: O
authors.initials: O
authors.lastname: Kempski
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000633:toxicity; D020520:Brain Infarction / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D002545:Brain Ischemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D002229:Carbenoxolone / Q000633:toxicity*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000897:Anti-Ulcer Agents; D002229:Carbenoxolone