Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade

Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1 beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatize d brain tissue. Reduction of tissue injury and free radical production foll owing brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also con ferred by pharmacological inhibition of caspase-1 by intracerebroventricula r administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Al a-Asp-chloromethylketone or the non-selective caspase inhibitor N-benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces t rauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1 beta converting enyzme-like ca spases and free radical production pathways, implicating free radical produ ction as a downstream mediator of the caspase cell death cascade. (C) 1999 IBRO. Published by Elsevier Science Ltd.