Null mutation of P53 attenuates hippocampal neuronal death in vivo following global ischemia in mice

Tumor suppressor gene p53 controls cell death after various stresses. However, the role of p53 in neuronal death after brain ischemia has been poorly understood. Here, we evaluated a direct causal link of p53 with neuronal death following global cerebral ischemia using p53 deficient mice. We used p53 mutant mice backcrossed for twelve generations to avoid bias in the genetic background. These mutants, as well as wild-type mice, were subjected to transient global ischemia by 3-vessel occlusion method, in which no difference in severity of ischemia was noted as evidenced by anoxic depolarization and cortical blood flow. The resulting neuronal death in the hippocampal CA1 sector was extensive in p53 wild-type mice: the surviving neuronal count was 9.3 ± 3.0 % of the normal control. However in mutant mice homozygous for p53, marked and significant attenuation of ischemic injury was observed, in which the neuronal count amounted to 61.3 ± 34.0 % (p < 0.0037). In wilt-typ mice, intense p53-like immunoreactivity was observed in hippocampal CA1 neurons at 12 hours after ischemia, and mRNA for Bax, a direct down stream target of p53, was also increased. These results indicated that p53 plays a crucial role in ischemic neuronal death in vivo, and suggest that this molecule could be a therapeutic target in neuronal death following cerebral ischemia.