Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

doi:10.1073/pnas.0530113100

Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

^*Epilepsy Research, Research 151, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, West Los Angeles, CA 90073; ^§Experimental Neurology Laboratories, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343; and ^†Department of Neurology and ^¶Brain Research Institute, David Geffen School of Medicine at the University of California, Room c-128, Los Angeles, CA 90095

Communicated by Philip Siekevitz, The Rockefeller University, New York, NY (received for review August 1, 2002)

Abstract

Hypoxic necrosis of dentate gyrus neurons in primary culture required the activation of an orderly cell death program independent of protein synthesis. Early mitochondrial swelling and loss of the mitochondrial membrane potential were accompanied by release of cytochrome c and followed by caspase-9-dependent activation of caspase-3. Caspase-3 and -9 inhibitors reduced neuronal necrosis. Calcium directly induced cytochrome c release from isolated mitochondria. Hypoxic neuronal necrosis may be an active process in which the direct effect of hypoxia on mitochondria may lead to the final common pathway of caspase-3-mediated neuronal death.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: jniquet{at}ucla.edu.
Abbreviations:

DG,

dentate gyrus;

PB-G,

phosphate buffer containing gelatin;

EM,

electron microscopy;

caspase-3a,

active fragment of caspase-3;

CHX,

cycloheximide