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

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 cel l death, whereas Bar promotes programmed cell death. Activated caspase-1 (i nterleukin-1 beta converting enzyme) and caspase-3 (Yama/Apopain/Cpp32) cle ave proteins that are important in maintaining cytoskeletal integrity and D NA repair, and activate deoxyribonucleases, producing cell death with morph ological features of apoptosis. To address the question of whether these Bc l-2 and caspase family members participate in the process of delayed neuron al death in humans, we examined brain tissue samples removed from adult pat ients during surgical decompression for intracranial hypertension in the ac ute phase after traumatic brain injury (n=8) and com pared these samples to brain tissue obtained at autopsy from non-trauma patients (n=6). An increa se in Bcl-2 but not Bcl-x(L) or Bax, cleavage of caspase-1, up-regulation a nd cleavage of caspase-3, and evidence for DNA fragmentation with both apop totic and necrotic morphologies were found in tissue from traumatic brain i njury patients compared with controls. These findings are the first to demo nstrate that programmed cell death occurs in human brain after acute injury , and identify potential pharmacological and molecular targets for the trea tment of human head injury.