Aggravation of brain injury after transient focal ischemia in p53-deficient mice.
The transcriptional factor p53 is a regulatory protein which contributes to the preservation of tissue integrity by promoting either DNA repair or apoptosis. To establish the pathophysiological role of this protein in ischemia, we produced 1 h transient middle cerebral artery (MCA) occlusion in normal and in p53-deficient mice and investigated the resulting tissue damage by multiparametric imaging. Possible genetic influences on the angioarchitecture of the MCA territory and blood flow were examined by intravascular latex infusion and laser-Doppler flowmetry. Wild-type (p53(+/+)), heterozygous (p53(+/-)) and homozygous (p53(-/-)) mice deficient for the p53 gene did not differ in respect to angioarchitecture or the effect of vascular occlusion on blood flow and general physiological parameters. Twenty-four hours after 1 h MCA occlusion, mice revealed a gene dose-dependent decline in the size of metabolic disturbances (ATP depletion and inhibition of protein synthesis) and histological injury (Cresyl Violet staining). DNA fragmentations detected by terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) did not differ in the three groups and were only present in ATP-depleted tissue. Our findings suggest that after transient focal brain ischemia p53 prevents rather than aggravates brain injury, and that this effect is brought about by mechanisms that are unrelated to the pro-apoptotic properties of this gene.
Maeda
K
K
Max-Planck-Institute for Neurological Research, Department of Experimental Neurology, Gleueler Strasse 50, D-50931 Cologne, Germany.
Hata
R
R
Gillardon
F
F
Hossmann
K A
KA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020521:Stroke / Q000473:pathology / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate