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Age-dependent increase in ischemic brain injury in wild-type mice and in mice lacking the inducible nitric oxide
M Nagayama1, T Aber, T Nagayama
1Department of Neurology, University of Minnesota Medical School, Minneapolis, USA.
Abstract:
The authors investigated the influence of age on the outcome of cerebral ischemia in wild-type mice and in mice with a deletion of the inducible nitric oxide synthase (iNOS) gene. The middle cerebral artery was permanently occluded 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 sections 4 days after permanent middle cerebral artery occlusion. No differences in forebrain volume were found among wild-type and iNOS-null mice at the ages studied (P > 0.05). In C57BL/6 mice (n = 5 to 6/group), neocortical infarct volume corrected for swelling was 28 +/- 5 mm3 in 4-week-old mice, 28 +/- 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-type 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%). Neurologic deficit scores improved significantly between 24 and 96 hours in 4- and 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 did 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 cerebral artery is larger in older than in younger mice. However, the reduction in infarct volume observed in iNOS-null mice is age-dependent and is greatest at 1 to 2 months of age. Therefore, age is a critical variable in studies of focal cerebral ischemic damage, both in wild-type mice and in mouse mutants.
Insights
Age significantly impacts cerebral ischemia outcomes in mice. Inducible nitric oxide synthase (iNOS) gene deletion reduces infarct size, with the greatest protective effect observed in younger mice (4-8 weeks old).
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Focal cerebral ischemia, a leading cause of stroke, involves complex inflammatory pathways.
- Inducible nitric oxide synthase (iNOS) plays a role in inflammatory responses and tissue damage.
- The influence of age on the severity and outcome of cerebral ischemia is not fully understood.
Purpose of the Study:
- To investigate the effect of age on cerebral ischemia outcomes in wild-type and iNOS-null mice.
- To determine if iNOS deletion alters age-dependent susceptibility to ischemic brain injury.
Main Methods:
- Permanent middle cerebral artery occlusion was performed in wild-type and iNOS-null mice aged 4, 8, 16, and 24 weeks.
- Infarct volume was quantified 4 days post-occlusion using thionin-stained brain sections.
- Neurologic deficit scores were assessed to evaluate functional recovery.
Main Results:
- Infarct volume increased with age in both wild-type and iNOS-null mice.
- iNOS-null mice exhibited significantly smaller infarct volumes compared to wild-type controls at all ages.
- The protective effect of iNOS deletion was most pronounced in younger mice (4-8 weeks old), with greater reductions in infarct size and improved neurologic function.
Conclusions:
- Age is a critical factor influencing the extent of focal cerebral ischemic damage.
- iNOS deficiency confers protection against ischemic injury, but this effect is age-dependent.
- Younger mice (1-2 months) show the most significant benefit from iNOS deletion following middle cerebral artery occlusion.