Abstract 2505: Neuronal-specific Loss of p53 Function in Forebrain Neurons is Protective Against Ischemic Injury
The p53 gene is a key regulator of cell apoptosis. It has been suggested that p53 function is involved in cell death in stroke. p53 immunoreactivity has been detected in brain tissue derived from animal models of stroke. Pharmacological inhibition of p53 function leads to decreased ischemic damage in animal stroke models. In addition, a recent study has reported that the human Tp53 Arg72Pro polymorphism correlates with different functional prognosis in stroke patients. However, both the pharmacological inhibitor and genetic linkage studies do not address the question whether p53 function determines the outcome of stroke by directly regulating cell death in neurons. To address this question, we investigated the role of p53 in ischemia-induced neuronal cell death using forebrain neuron-specific ablation of the gene coding for the p53 gene in mice. By expressing Cre recombinase under the control of the Camkinase II promoter, we achieved a selective deletion of functional p53 protein in forebrain neurons. This strategy represents a significant advance because it permits an evaluation of p53 function in these specific cells, compared to non-selective effects of pharmacological inhibitors on multiple cell types in multiple anatomical regions. Effectiveness of specific p53 deletion in forebrain, but no other brain regions and other organs, was confirmed by PCR in Camkinase II -cre/LoxP p53 ko mice. Loss of the p53 gene in forebrain neurons did not lead to abnormal development of the cortex, as demonstrated by normal structure of the forebrain and neuronal cell numbers (NeuN positive cells) in ko mice. This suggests that p53 is not involved in the apoptosis which eliminates excess neurons during development. However, we found that loss of p53 in forebrain neurons in adult mice is protective against ischemic injury after stroke (MCAo). Locomotor behavior measured in automated activity chambers showed that Camkinase II -cre/LoxP p53 ko mice have less locomotor deficits compared to wt mice after MCAo. Therefore, our data suggest that loss of p53 function specifically in forebrain neurons can protect these cells from ischemic injury occurring after stroke and neuronal-specific inhibition of p53 might be a new treatment strategy for improved prognosis.
- © 2012 by American Heart Association, Inc.