REDUCED ISCHEMIC BRAIN INJURY IN INTERLEUKIN-1-BETA CONVERTING ENZYME-DEFICIENT MICE

A variety of recent studies suggest a role for both inflammatory cytok ines such as interleukin-1 beta (IL-1 beta), and apoptosis in ischemic brain injury. Because IL-1 beta converting enzyme (ICE) is required f or the conversion of proIL-1 beta to its biologically active form. and has homology with proteins that regulate apoptosis in invertebrates, we studied the effect of cerebral ischemia on brain injury in mutant m ice deficient in the ICE gene (ICE knockout [KO] mice). Focal cerebral ischemia, produced by occlusion of the middle cerebral artery, result ed in brain edema (increased water and sodium content) at 4 hours and a histologically defined brain lesion at 24 hours. Both of these marke rs of brain injury were significantly reduced in the ICE KO mice as co mpared to wild-type C57BL16 mice. Regional cerebral blood flow, determ ined using the flow tracer, N-isopropyl [methyl 1,3-C-14] p-iodoamphet amine ((CIMP)-C-14), was similar in the two strains of mice, indicatin g that the reduced brain injury in the KO mice was not a result of a l esser degree of ischemia. These data show that ICE contributes to the development of ischemic brain damage, and that it plays a role at an e arly time in the pathologic process. Although the mechanism of this ef fect is uncertain, our results suggest that pharmacologic inhibition o f ICE may be a useful treatment for stroke.