Blockade of gap junctions in vivo provides neuroprotection after perinatal global ischemia.
OBJECTIVE
We investigated the contribution of gap junctions to brain damage and delayed neuronal death produced by oxygen-glucose deprivation (OGD).


METHODS
Histopathology, molecular biology, and electrophysiological and fluorescence cell death assays in slice cultures after OGD and in developing rats after intrauterine hypoxia-ischemia (HI).


RESULTS
OGD persistently increased gap junction coupling and strongly activated the apoptosis marker caspase-3 in slice cultures. The gap junction blocker carbenoxolone applied to hippocampal slice cultures before, during, or 60 minutes after OGD markedly reduced delayed neuronal death. Administration of carbenoxolone to ischemic pups immediately after intrauterine HI prevented caspase-3 activation and dramatically reduced long-term neuronal damage.


CONCLUSIONS
Gap junction blockade may be a useful therapeutic tool to minimize brain damage produced by perinatal and early postnatal HI.
de Pina-Benabou
Mara H
MH
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
Szostak
Vanessa
V
Kyrozis
Andreas
A
Rempe
David
D
Uziel
Daniela
D
Urban-Maldonado
Marcia
M
Benabou
Salomon
S
Spray
David C
DC
Federoff
Howard J
HJ
Stanton
Patric K
PK
Rozental
Renato
R
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D017209:Apoptosis; D001921:Brain / Q000196:embryology*; D002229:Carbenoxolone / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002450:Cell Communication; D017630:Connexins / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D017629:Gap Junctions / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology; D007511:Ischemia / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009410:Nerve Degeneration; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011419:Propidium / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000897:Anti-Ulcer Agents; D017630:Connexins; D018696:Neuroprotective Agents; D009707:Nucleosomes; D012333:RNA, Messenger; D011419:Propidium; D004247:DNA; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005947:Glucose; D002229:Carbenoxolone; D010100:Oxygen