Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia.
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.
Hetz
Claudio
C
Serono Pharmaceutical Research Institute, 14 chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.
Vitte
Pierre-Alain
PA
Bombrun
Agnes
A
Rostovtseva
Tatiana K
TK
Montessuit
Sylvie
S
Hiver
Agnes
A
Schwarz
Matthias K
MK
Church
Dennis J
DJ
Korsmeyer
Stanley J
SJ
Martinou
Jean-Claude
JC
Antonsson
Bruno
B
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology*; D016923:Cell Death; D002460:Cell Line; D002469:Cell Separation; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005434:Flow Cytometry; D005849:Gerbillinae; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000473:pathology; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008956:Models, Chemical; D009474:Neurons / Q000378:metabolism*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry; D015424:Reperfusion; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D008055:Lipids; D008081:Liposomes; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c