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Attenuation of p53 expression protects against focal ischemic damage in transgenic mice
R C Crumrine1, A L Thomas, P F Morgan
1Division of Pharmacology, Burroughs Wellcome Company, Research Triangle Park, NC 27709.
Abstract:
Apoptosis or programmed cell death may be involved in neuronal death in the cerebral cortex after a permanent focal ischemic insult. Studies indicate that protein p53 is a major determinant of the cellular mechanism that leads to programmed cell death. Wild-type C57 mice and two groups of transgenic C57 mice, one homozygous and the other heterozygous for a p53 null gene, were subjected to middle cerebral artery occlusion. As expected, the wild-type mice had a large, consistent infarct volume (22.11 +/- 4.59 mm3; n = 10). Both transgenic groups had significantly less ischemic damage than the wild-type control group. However, unexpectedly, the heterozygous group had the least amount of ischemic damage (16.12 +/- 1.71 mm3, n = 11; 27% reduction in infarct size). The ischemic damage in the homozygous group (18.72 +/- 3.48 mm3, n = 9) was significantly less than in the wild-type control (15% reduction in infarct size) but significantly more than in the heterozygous group. Thus, although the absence of p53 expression was protective, greater protection was afforded by reduced expression of p53. These data suggest that attenuated p53 expression may be protective after an ischemic event.
Insights
Reduced expression of protein p53 offers significant protection against brain damage following ischemic stroke. Even partial reduction in p53 levels provided greater neuroprotection than complete absence in mouse models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Neuronal death in the cerebral cortex after ischemic stroke may involve apoptosis (programmed cell death).
- Protein p53 is a key regulator of programmed cell death pathways.
Purpose of the Study:
- To investigate the role of protein p53 in neuronal death after focal cerebral ischemia.
- To determine the neuroprotective effects of p53 absence or reduction following ischemic insult.
Main Methods:
- Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion in wild-type and p53-deficient (homozygous and heterozygous) C57 mice.
- Infarct volume was measured to quantify ischemic brain damage.
Main Results:
- Wild-type mice exhibited significant infarct volumes.
- Both homozygous and heterozygous p53-deficient mice showed reduced ischemic damage compared to wild-type controls.
- Heterozygous mice (reduced p53 expression) demonstrated the greatest reduction in infarct size (27%), indicating enhanced neuroprotection compared to homozygous mice (15% reduction).
Conclusions:
- Absence of p53 expression confers neuroprotection against ischemic stroke.
- Attenuated or reduced expression of p53 provides greater protection than complete absence, suggesting a dose-dependent protective effect.
- Targeting p53 expression levels may represent a therapeutic strategy for mitigating brain damage after ischemic events.