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The Journal of Neuroscience, August 1, 1999, 19(15):6235-6247
Caspase-Dependent and -Independent Death of Camptothecin-Treated Embryonic Cortical Neurons
Leonidas Stefanis1, 2, David S. Park1, Wilma J. Friedman1, and Lloyd A. Greene1 Departments of 1 Pathology and 2 Neurology, Taub Center for Alzheimer's Disease Research and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032
This study investigates the mechanisms underlying death of cultured embryonic cortical neurons exposed to the DNA-damaging agent camptothecin and in particular the interdependence of the roles of cyclin-dependent kinases (Cdks), caspases, and mitochondrial function. Camptothecin evokes rapid neuronal death that exhibits nuclear features of apoptosis. This death is accompanied by loss of cytochrome c and mitochondrial transmembrane potential as well as by induction of caspase-3-like activity and caspase-2 processing. The Cdk inhibitor flavopiridol provides long-term rescue from death and prevents loss of cytochrome c and mitochondrial transmembrane potential as well as caspase activation and processing. General caspase inhibitors rescue neurons from this rapid apoptotic death but do not prevent them from undergoing delayed death in which nuclear features of apoptosis are absent. Moreover, the caspase inhibitors do not affect early cytochrome c release and delay but do not prevent the loss of transmembrane potential. Agents that directly disrupt mitochondrial function without inducing cytochrome c release lead to a caspase-independent death. These observations favor a model in which (1) DNA damage leads to Cdk activation, which lies upstream of release of cytochrome c and caspase activation; (2) cytochrome c release is caspase-independent and may occur upstream of caspase activation; (3) early apoptotic death requires caspases; and (4) delayed nonapoptotic death that occurs in the presence of caspase inhibitors is a consequence of prolonged loss of mitochondrial function. These findings shed light on the mechanisms by which DNA damage kills neurons and raise questions regarding the general utility of caspase inhibitors as neurotherapeutic agents.
Key words: apoptosis; mitochondria; cytochrome c; transmembrane potential; DNA damage; cell cycle
Copyright © 1999 Society for Neuroscience 0270-6474/99/19156235-13$05.00/0
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