DNA repair and the p53 pathway in ischemic and traumatic brain injury

Abstract: Ischemic and traumatic brain damage are major causes of disability and death. While much effort has been spent to develop pharmacological treatments for these conditions, no neuroprotective drugs are in clinical use. Neuronal death following ischemia and trauma occurs in selected cell populations of the brain at various time points after the insult. It is believed that death of neurons are in part regulated through the expression of genes and proteins which regulate cellular viability. The tumor suppressor p53 has a central role in regulating the cell cycle and DNA repair processes following DNA damage and hypoxia. p53 can also initiate death-promoting mechanisms within cells. We studied the expression of p53, and the p53-regulated genes p21WAF1/Cip1, PAG608/Wig-1 and PCNA (a DNA repair factor) in a model of global forebrain ischemia in the rat. We also used mild intra-ischemic hypothermia (33°C) and ischemic preconditioning – two strategies that are known to protect neurons against ischemic damage – to study the expression of these genes and proteins in surviving neurons. We found that these mRNAs and proteins are induced in both ischemia-vulnerable hippocampal neurons, and cells that are resistant or protected by hypothermia or ischemic preconditioning. Rapid and transient activation of p53 and p53-regulated genes correlated with neuronal survival. In the second part of the study, we subjected genetically modified mice, which lacked p53 or the DNA repair factor XPA, to experimental brain trauma. Mice lacking p53 exhibited improved neuromotor recovery, compared to wild-type mice. In contrast, XPA-deficient animals recovered more slowly from neuromotor deficits, and exhibited impaired learning up to four weeks after brain injury. There was no difference in the histopathological outcome between wild-type and genetically modified animals. Together, our results suggest a modulatory role for the p53 pathway following ischemic and traumatic brain injury rahter than the previously proposed death-inducing role. The results also indicate for the first time that efficient repair of DNA may play an important role in recovery from neuromotor and cognitive deficits following traumatic brain injury.