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Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury

ROBERT S. B. CLARK^*,,#1, PATRICK M. KOCHANEK^*,,#,**, MINZHI CHEN^*, SIMON C. WATKINS, DONALD W. MARION^**, JUN CHEN^||, RONALD L. HAMILTON^¶, J. ERIC LOEFFERT and STEVEN H. GRAHAM^||,**,

^* Departments of Anesthesiology and Critical Care Medicine,
Pediatrics,
Cell Biology and Physiology,
^§ Neurological Surgery,
^|| Neurology, and
^¶ Pathology, and the
^# Safar Center for Resuscitation Research and
^** Brain Trauma Research Center, University of Pittsburgh School of Medicine; and
Neurology Service (127), Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15260, USA

¹Correspondence: Robert S. B. Clark, M.D, Safar Center for Resuscitation Research, 3434 Fifth Avenue Pittsburgh, PA 15260. E-mail: clark{at}smtp.anes.upmc.edu

The bcl-2 and caspase families are important regulators of programmed cell death in experimental models of ischemic, excitotoxic, and traumatic brain injury. The Bcl-2 family members Bcl-2 and Bcl-x_L suppress programmed cell death, whereas Bax promotes programmed cell death. Activated caspase-1 (interleukin-1ß converting enzyme) and caspase-3 (Yama/Apopain/Cpp32) cleave proteins that are important in maintaining cytoskeletal integrity and DNA repair, and activate deoxyribonucleases, producing cell death with morphological features of apoptosis. To address the question of whether these Bcl-2 and caspase family members participate in the process of delayed neuronal death in humans, we examined brain tissue samples removed from adult patients during surgical decompression for intracranial hypertension in the acute phase after traumatic brain injury (n=8) and compared these samples to brain tissue obtained at autopsy from non-trauma patients (n=6). An increase in Bcl-2 but not Bcl-x_L or Bax, cleavage of caspase-1, up-regulation and cleavage of caspase-3, and evidence for DNA fragmentation with both apoptotic and necrotic morphologies were found in tissue from traumatic brain injury patients compared with controls. These findings are the first to demonstrate that programmed cell death occurs in human brain after acute injury, and identify potential pharmacological and molecular targets for the treatment of human head injury.—Clark, R. S. B., Kochanek, P. M., Chen, M., Watkins, S. C., Marion, D. W., Chen, J., Hamilton, R. L., Loeffert, J. E., Graham, S. H. Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury.

Key Words: apoptosis • Bax • Bclx_L • Cpp32 • interleukin-1ß converting enzyme

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