ATTENUATION OF TRANSIENT FOCAL CEREBRAL ISCHEMIC-INJURY IN TRANSGENICMICE EXPRESSING A MUTANT ICE INHIBITORY PROTEIN

We used transgenic mice expressing a dominant negative mutation of int erleukin-1 beta converting enzyme (ICE) (C285G) in a model of transien t focal ischemia in order to investigate the role of ICE in ischemic b rain damage. Transgenic mutant ICE mice (n = 11) and wild-type litterm ates (n = 9) were subjected to 3 h of middle cerebral artery occlusion followed by 24 h of reperfusion. Cerebral infarcts and brain swelling were reduced by 44% and 46%, respectively. Neurological deficits were also significantly reduced. Regional CBF, blood pressure, core temper ature, and heart rate did not differ between groups when measured for up to 1 h after reperfusion. Increases in immunoreactive IL-1 beta lev els, observed in ischemic wild-type brain at 30 min after repel-fusion , were 77% lower in the mutant strain, indicating that proLL-1 beta cl eavage is inhibited in the mutants. DNA fragmentation was reduced in t he mutants 6 and 24 h after reperfusion. Hence, endogenous expression of an ICE inhibitor confers resistance to cerebral ischemia and brain swelling. Our results indicate that downregulation of ICE expression m ight provide a useful therapeutic target in cerebral ischemia.