Attenuation of Transient Focal Cerebral Ischemic Injury in Transgenic Mice Expressing a Mutant ICE Inhibitory Protein

Author:

Hara Hideaki1,Fink Klaus1,Endres Matthias1,Friedlander Robert M.2,Gagliardini Valeria3,Yuan Junying3,Moskowitz Michael A.1

Affiliation:

1. Stroke and Neurovascular Regulation, Neurosurgical Service and Neurology Department, Massachusetts General Hospital, Harvard Medical School, Charlestown

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

3. Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, U.S.A.

Abstract

We used transgenic mice expressing a dominant negative mutation of interleukin-1β 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-1β levels, observed in ischemic wild-type brain at 30 min after reperfusion, were 77% lower in the mutant strain, indicating that proIL-1β 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 down-regulation of ICE expression might provide a useful therapeutic target in cerebral ischemia.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology

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