1. ^*Stroke and Neurovascular Regulation, Neurosurgical Service and Neurology Department, Massachusetts General Hospital, Harvard Medical School, Charlestown, U.S.A.
2. ^†Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, and Neurosurgical Service, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, U.S.A.
3. ^‡Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, U.S.A.

Correspondence: Michael A Moskowitz, Stroke and Neurovascular Regulation, Neurosurgical Service and Neurology Department, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129

Received 13 January 1997; Revised 12 February 1997; Accepted 14 February 1997.

Abstract

We used transgenic mice expressing a dominant negative mutation of interleukin-1 converting enzyme (ICE) (C285G) in a model of transient focal ischemia in order to investigate the role of ICE in ischemic brain damage. Transgenic mutant ICE mice (n = 11) and wild-type littermates (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 temperature, and heart rate did not differ between groups when measured for up to 1 h after reperfusion. Increases in immunoreactive IL-1 levels, observed in ischemic wild-type brain at 30 min after reperfusion, were 77% lower in the mutant strain, indicating that proIL-1 cleavage is inhibited in the mutants. DNA fragmentation was reduced in the 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 might provide a useful therapeutic target in cerebral ischemia.