Age-dependent increase in ischemic brain injury in wild-type mice and in mice lacking the inducible nitric oxide synthase gene

The authors investigated the influence of age on the outcome of cerebral is chemia in wild-type mice and in mice with a deletion of the inducible nitri c oxide synthase (iNOS) gene. The middle cerebral artery was permanently oc cluded in iNOS-null mice and in wild-type (C57BL/6) controls aged 4, 8, 16, and 24 weeks. Infarct volume was determined in thionin-stained brain secti ons 4 days after permanent middle cerebral artery occlusion. No differences in forebrain volume were found among wild-type and iNOS-null mice at the a ges studied (P > 0.05). In C57BL/6 mice (n = 5 to 6/group), neocortical inf arct volume corrected for swelling was 28 +/- 5 mm(3) in 4-week-old mice, 2 8 +/- 3 at 8 weeks, 35 +/- 4 at 16 weeks, and 37 +/- 6 at 24 weeks (mean +/ - SD). iNOS-null mice (n = 5 to 6/group) had smaller infarcts than wild-typ e controls at all ages (P < 0.05). However, the magnitude of the reduction was greater in 4-week-old (-29% +/- 10%) or 8-week-old mice (-24% +/- 8%), than in 16-week-old (-14% +/- 10%) or 24-week-old mice (-11% +/- 6%). Neuro logic deficit scores improved significantly between 24 and 96 hours in 4- a nd 8-week-old iNOS-null mice compared with age-matched wild-type mice (P < 0.05). However, in 16- or 24-week-old iNOS-null mice, neurologic deficits d id not improve (P > 0.05). The authors conclude that in iNOS-/- and in wild -type mice, the size of the infarct produced by occlusion of the middle cer ebral artery is larger in older than in younger mice. However, the reductio n in infarct volume observed in iNOS-null mice is age-dependent and is grea test at 1 to 2 months of age. Therefore, age is a critical variable in stud ies of focal cerebral ischemic damage, both in wild-type mice and in mouse mutants.