DNA damage and repair in CNS injury

Reactive oxygen species (ROS) are free radicals that cause damage to many cellular components, including DNA. Since ROS are byproducts of normal metabolism, they are virtually always present. However, mammalian systems have evolved elaborate defense mechanisms, such as antioxidants, to remove ROS and reduce their levels. It has been shown that following CNS injury, ROS formation increases greatly, overwhelming defense mechanisms and damaging DNA. Fortunately, DNA damage can be repaired, however, the repair is error-prone with low fidelity. Mutations are common, leading to altered gene expression, genomic instability, and eventually apoptosis. P53 appears to be involved in many of these cellular processes. We present preliminary data supporting the contention that DNA damage and repair occurrs in a transgenic mouse model of forebrain ischemia, in which the reporter gene lacZ allows detection of DNA damage based on an increase in mutation frequency. Biochemical and molecular biology studies provide additional data supporting DNA damage and repair following forebrain ischemia and reperfusion.