Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein.
We used transgenic mice expressing a dominant negative mutation of interleukin-1 beta 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 beta levels, observed in ischemic wild-type brain at 30 min after reperfusion, were 77% lower in the mutant strain, indicating that proIL-1 beta 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.
Hara
H
H
Stroke and Neurovascular Regulation, Neurosurgical Service, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Fink
K
K
Endres
M
M
Friedlander
R M
RM
Gagliardini
V
V
Yuan
J
J
Moskowitz
M A
MA
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D020170:Caspase 1; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D003546:Cysteine Endopeptidases / Q000235:genetics*; D053938:DNA Fragmentation; D015870:Gene Expression; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D009154:Mutation; D009422:Nervous System Diseases / Q000209:etiology
D007375:Interleukin-1; D003546:Cysteine Endopeptidases; D020170:Caspase 1