Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage

Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cl eaves inactive pro-IL-1 beta to active IL-1 beta The pro-inflammatory cytok ine IL-1 beta is implicated as a mediator of hypoxic-ischemic (HI) brain in jury, both in experimental models and in humans. ICE is a member of a famil y of ICE-Like proteases (caspases) that mediate apoptotic cell death in div erse tissues. The authors hypothesized that in neonatal mice with a homozyg ous deletion of ICE (ICE-KO) the severity of brain injury elicited by a foc al cerebral HI insult would be reduced, relative to wild-type mice. Paired litters of 9- to 10-day-old ICE-KO and wild-type mice underwent right carot id ligation, followed by 70 or 120 minutes of exposure to 10% O-2. In this neonatal model of transient focal cerebral ischemia followed by reperfusion , the duration of hypoxia exposure determines the duration of cerebral isch emia and the severity of tissue damage. Outcome was evaluated 5 or 21 days after lesioning; severity of injury was quantified by morphometric estimati on of bilateral cortical, striatal, and dorsal hippocampal volumes. In anim als that underwent the moderate HI insult (70-minute hypoxia), damage was a ttenuated in ICE-KO mice, when evaluated at 5 or 21 days post-lesioning. In contrast, in mice that underwent the more severe HI insult (120-minute hyp oxia), injury severity was the same in both groups. Reductions in intra-HI CBF, measured by laser Doppler flowmetry, and intra- and post-HI temperatur es did not differ be tween groups. These results show that ICE activity con tributes to the progression of neonatal HI brain injury in this model. Whet her these deleterious effects are mediated by proinflammatory actions of IL -1 beta and/or by pro-apoptotic mechanisms is an important question for fut ure studies.