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Louis K. Chang and Eugene M. Johnson, Jr.

Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Eugene M. Johnson, Washington University School of Medicine, Dept. of Molecular Biology and Pharmacology, 660 South Euclid, Box 8103, St. Louis, MO 63110. Tel.: (314) 362-3926. Fax: (314) 747-1772. E-mail: ejohnson{at}pcg.wustl.edu

Opening of the permeability transition pore (PTP) has been implicated as an important mitochondrial event that occurs during apoptosis. We examined the role of the PTP in the well-characterized cell death of rat sympathetic neurons deprived of nerve growth factor (NGF) in vitro. Removal of NGF causes these neurons to undergo either a classic apoptotic cell death or, when treated with a broad-spectrum caspase inhibitor such as boc-aspartyl(OMe)-fluoromethylketone (BAF), a delayed, nonapoptotic cell death. The PTP inhibitor, cyclosporin A (CsA), blocked commitment-to-die in the presence of BAF, as defined by the ability of NGF readdition to rescue cells, but had little effect on commitment-to-die in the absence of BAF. CsA did not have trophic effects on BAF-saved cells, but did block the decrease in mitochondrial membrane potential. These data suggest that PTP opening is a critical event in caspase-independent, nonapoptotic (but not caspase-dependent, apoptotic) death of NGF-deprived rat sympathetic neurons.

Key Words: apoptosis; cytochrome c; mitochondria; permeability transition pore; programmed cell death

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