Gene-dosing effect and persistence of reduction in ischemic brain injury in mice lacking inducible nitric oxide synthase

Abstract

We investigated whether the reduction in ischemic brain injury in inducible nitric oxide synthase (iNOS) null mice is related to the iNOS gene copy number, and whether such protection is long lasting. The middle cerebral artery (MCA) was occluded in heterozygous (+/−) and homozygous (−/−) iNOS null mice, as well as in wild-type littermates (iNOS +/+). Four days after MCA occlusion, total infarct volume was reduced by 29% in iNOS −/− mice ( n=6; P<0.05) and by 14% in iNOS±mice ( n=8; P<0.05), compared to iNOS +/+ ( n=8). Ten days after MCA occlusion, total infarct volume was still reduced in iNOS +/− (−14%) and −/− mice (−21%; P<0.05 from iNOS +/+; n=8/group). These data indicate that the reduction in infarct volume is greater in iNOS −/− than in iNOS +/− mice and that the effect is stable in time. We conclude that the reduction in ischemic damage conferred by iNOS deletion exhibits a gene-dosing effect and that the protection is long lasting.