INHIBITION OF INTERLEUKIN-1-BETA CONVERTING-ENZYME FAMILY PROTEASES REDUCES ISCHEMIC AND EXCITOTOXIC NEURONAL DAMAGE

The interleukin 1 beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and ne urodegenerative diseases, During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immun oreactive interleukin 1 beta (IL-1 beta) levels increased in ischemic mouse brain, Ischemic injury decreased after intracerebroventricular i njections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala -Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chlorometh ylketone, or a relatively selective inhibitor of CPP32-like caspases, zyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FM K decreased ICE-like cleavage products and tissue immunoreactive IL-1 beta levels in ischemic mouse brain and reduced tissue damage when adm inistered to rats as well. Only z-VAD.FMK and acetyl-Tyr r-Val-Ala-Asp -chloromethylketone reduced brain swelling, and nzyloxycarbonyl-Asp-Gl u-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced in crease in tissue IL-1 beta levels, The three cysteine protease inhibit ors significantly improved behavioral deficits, thereby showing that f unctional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death, Finally, we examined the effect of z-VAD,FiMK on excitotoxicity and found that it protected ag ainst alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain dam age, Thus, ICE-like and CPP32-like caspases contribute to mechanisms o f cell death in ischemic and excitotoxic brain injury and provide ther apeutic targets for stroke and neurodegenerative brain damage.