DELAYED REDUCTION OF ISCHEMIC BRAIN INJURY AND NEUROLOGICAL DEFICITS IN MICE LACKING THE INDUCIBLE NITRIC-OXIDE SYNTHASE GENE

Citation
C. Iadecola et al., DELAYED REDUCTION OF ISCHEMIC BRAIN INJURY AND NEUROLOGICAL DEFICITS IN MICE LACKING THE INDUCIBLE NITRIC-OXIDE SYNTHASE GENE, The Journal of neuroscience, 17(23), 1997, pp. 9157-9164
Citations number
57
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
02706474
Volume
17
Issue
23
Year of publication
1997
Pages
9157 - 9164
Database
ISI
SICI code
0270-6474(1997)17:23<9157:DROIBI>2.0.ZU;2-7
Abstract
Inducible nitric oxide synthase (iNOS), an enzyme that produces toxic amounts of nitric oxide, is expressed in a number of brain pathologies , including cerebral ischemia. We used mice with a null mutation of th e iNOS gene to study the role of iNOS in ischemic brain damage. Focal cerebral ischemia was produced by occlusion of the middle cerebral art ery (MCA). In wild-type mice, iNOS mRNA expression in the post-ischemi c brain begun between 24 and 48 hr peaked at 96 hr and subsided 7 d af ter MCA occlusion. iNOS mRNA induction was associated with expression of iNOS protein and enzymatic activity. In contrast, mice lacking the iNOS gene did not express iNOS message or protein after MCA occlusion. The infarct and the motor deficits produced by MCA occlusion were sma ller in iNOS knockouts than in wild-type mice (p < 0.05). Such reducti on in ischemic damage and neurological deficits was observed 96 hr aft er ischemia but not al 24 hr, when iNOS is not yet expressed in wild-t ype mice. The decreased susceptibility to cerebral ischemia in iNOS kn ockouts could not be attributed to differences in the degree of ischem ia or vascular reactivity between wild-type and knockout mice, These f indings indicate that iNOS expression is one of the factors contributi ng to the expansion of the brain damage that occurs in the post-ischem ic period. iNOS inhibition may provide a novel therapeutic strategy ta rgeted specifically at the secondary progression of ischemic brain inj ury.