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J. Biol. Chem., Vol. 280, Issue 52, 42960-42970, December 30, 2005

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Bax Channel Inhibitors Prevent Mitochondrion-mediated Apoptosis and Protect Neurons in a Model of Global Brain Ischemia^*

Claudio Hetz¶, Pierre-Alain Vitte, Agnes Bombrun, Tatiana K. Rostovtseva||, Sylvie Montessuit1, Agnes Hiver, Matthias K. Schwarz, Dennis J. Church, Stanley J. Korsmeyer, Jean-Claude Martinou1, and Bruno Antonsson2

From the Serono Pharmaceutical Research Institute, 14 chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland, the ^||Laboratory of Physical and Structural Biology, NICHD, National Institutes of Health, Bethesda, Maryland 20892, the Dana-Farber Cancer Institute and the Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, and the ^¶Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile

Ischemic injuries are associated with several pathological conditions, including stroke and myocardial infarction. Several studies have indicated extensive apoptotic cell death in the infarcted area as well as in the penumbra region of the infarcted tissue. Studies with transgenic animals suggest that the mitochondrion-mediated apoptosis pathway is involved in ischemia-related cell death. This pathway is triggered by activation of pro-apoptotic Bcl-2 family members such as Bax. Here, we have identified and synthesized two low molecular weight compounds that block Bax channel activity. The Bax channel inhibitors prevented cytochrome c release from mitochondria, inhibited the decrease in the mitochondrial membrane potential, and protected cells against apoptosis. The Bax channel inhibitors did not affect the conformational activation of Bax or its translocation and insertion into the mitochondrial membrane in cells undergoing apoptosis. Furthermore, the compounds protected neurons in an animal model of global brain ischemia. The protective effect in the animal model correlated with decreased cytochrome c release in the infarcted area. This is the first demonstration that Bax channel activity is required in apoptosis.

Received for publication, May 31, 2005 , and in revised form, September 16, 2005.

^* This work was supported by a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation (to C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. This paper is dedicated to Stanley J. Korsmeyer, who very regrettably passed away during the preparation of the manuscript.

¹ Present address: Dépt. de Biologie Cellulaire, Sciences III, 30 quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.

Deceased.

² To whom correspondence should be addressed. Tel.: 41-22-706-9802; Fax: 41-22-794-6965; E-mail: bruno.antonsson{at}serono.com.

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