Published Online
on September 22, 2005

A more recent version of this article appeared on October 1, 2005

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Submitted on March 24, 2005
Revised on May 17, 2005
Accepted on June 8, 2005

Blockade of Gap Junctions In Vivo Provides Neuroprotection After Perinatal Global Ischemia

Mara H. de Pina-Benabou; Vanessa Szostak; Andreas Kyrozis; David Rempe; Daniela Uziel; Marcia Urban-Maldonado; Salomon Benabou; David C. Spray; Howard J. Federoff; Patric K. Stanton; and Renato Rozental^*

From the Departments of Cell Biology and Anatomy (M.H.dP.-B., P.K.S., R.R.), Neurology (P.K.S.), Obstetrics (R.R.), Pediatrics, and Anesthesiology (R.R.), New York Medical College, Valhalla; Department of Physiology (M.H.dP.-B.), University of São Paulo, Brazil; Department of Neurology (V.S., A.K.) and Neurosciences (M.U.-M., D.C.S.), Albert Einstein College of Medicine, Bronx, NY; Department of Neurology (A.K.), Eginition Hospital, University of Athens, Greece; Department of Anatomy (D.U.), Federal University of Rio de Janeiro, Brazil; Division of Neurosurgery (S.B.), Beneficencia Portuguesa Hospital, Sao Paulo, Brazil; Aab Institute for Biomedical Sciences (D.R., H.J.F.), University of Rochester School of Medicine and Dentistry, New York.

^* To whom correspondence should be addressed. E-mail: r_rozental{at}nymc.edu.

Background and Purpose--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.

Key words: apoptosis • carbenoxolene • connexin • gap junction • ischemia

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