Bax channel inhibitors prevent mitochondrial-mediated apoptosis and protect neurons in a model of global brain ischemia

doi:10.1074/jbc.M505843200

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Papers In Press, published online ahead of print October 11, 2005
J. Biol. Chem, 10.1074/jbc.M505843200
Submitted on May 31, 2005
Accepted on October 11, 2005

Bax channel inhibitors prevent mitochondrial-mediated apoptosis and protect neurons in a model of global brain ischemia

Claudio Hetz, Pierre-Alain Vitte, Agnes Bombrun, Tatiana K. Rostovtseva, Sylvie Montessuit, Agnes Hiver, Matthias K. Schwarz, Dennis J. Church, Stanley J. Korsmeyer, Jean-Claude Martinou, and Bruno Antonsson

Protein Biochemistry, Serono Pharmaceutical Research Institute, Plan-les-Ouates, Geneva CH-1228

Corresponding Author: bruno.antonsson{at}serono.com

Abstract Ischemic injures 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 mitochondrial-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 prevent cytochrome c release from mitochondria, inhibit the decrease of the mitochondrial membrane potential and protect cells against apoptosis. The Bax channel inhibitors don’t affect the conformational activation of Bax, nor its translocation and insertion into the mitochondrial membrane in cells undergoing apoptosis. Furthermore, the compounds protect neurons in an animal model of global brain ischemia. The protective effect in the animal model correlates with decreased cytochrome c release in the infarcted area. This is the first demonstration that Bax-channel activity is required in apoptosis.

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