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
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.