| BackgroundImbalance of DNA damage and DNA repair can cause irreversible damage on neurons and finally result in neuronal apoptosis and death following focal cerebral ischemia-reperfusion, which is pivotal for the pathogenesis of brain injury in acute ischemic cerebrovascular diseases. Cerebral ischemia-reperfusion affects the oxygen supplies and perturbs energy metabolism. Neuronal injuries can be initiated by a number of mediators following cerebral ischemia-reperfusion and result in apoptosis and death. Among these oxygen-derived free radidicals are particularly focused on. Oxygen-derived free radidicals, which are major products of aerobic and arachidonic acid metabolism, lipid peroxidation, can initiate base mutagenesis and produce single- and double-DNA strand breaks. Corresponding to the DNA lesions, DNA repair process is initiated to maintain the genomic stability. On the condition that DNA lesions were not repaired promptly or thoroughly after cerebral ischemia-reperfusion, irreversible injury in neuron would befall. Delayed neuronal death (DND) and selective vulnerability in hippocampus CA1 neurons, which were important characters following ischemia-reperfusion, were also proved to be related with DNA damage and repair. Several investigators have clearly demonstrated that imbalance of DNA damage and DNA repair, which causes cell death, is essential for stroke and brain injury.As to the relationship between DNA repair-related proteins and cerebral ischemia-reperfusion injury, a majority of researchers concentrated on the temporal and spatial changes of DNA repair-related proteins and it's correlation with neuronal apoptosis following ischemia-reperfusion. It has been clearly shown that distinct neuronal apoptosis came after a markedly decrease of expression, or decline of activity of DNA repair-related proteins. Double-staining of DNA repair-related proteins and apoptosis marker demonstrated that DNA repair-related proteins positive cells were apoptosis marker negative and, on the contrary, apoptosis marker positive. Other studies also indicated that up-regulated expression and increased activity, which protected neuron from apoptosis,could be induced by sub-lethal cerebral ischemia or hypothermia treatment following ischemia. These evidence raise the possibility that the transcription, expression and activity of DNA repair-related proteins were somewhat interfered with concomitant DNA injuries following cerebral ischemia-reperfusion, which destroyed effective repair of DNA lesions and generated apoptosis and death.Proliferating-cell nuclear antigen (PCNA), a DNA repair-related protein, plays a multiple role in DNA repair in all eukaryotes. Tomasevic and his colleagues detected a constitutive expression of PCNA and it's mRNA in all neurons. They also demonstrated largely abolished nuclear PCNA immunoreactivity following normothermic ischemia in the vulnerable CA1 neurons, prior to cell death. In contrast, total PCNA protein content of this region, as measured by Western blotting, remained largely unchanged. In another study by Xu Guangrun and his colleagues, focal cerebral ischemia was induced by photochemistry in aged rats. They reported that no expression of PCNA protein and mRNA was detected at the core of the infarction after 24 hours following ischemia, whereas the expression of PCNA at the peri-ischemia area initiated at 4 hours, with significant up-regulation at 24 hours. These findings indicate that DNA repair processes are affected following ischemia-reperfusion accompanied altered PCNA expression and, ultimately, these changes of DNA repair system alter the outcome of injured neurons.Nevertheless, there are many issues still hanging in doubt on DNA damage and repair following focal cerebral ischemia-reperfusion. As to the studies mentioned above, researchers focused on the dynamic changes of PCNA mRNA and protein following ischemia, but they ignored the relationship between these changes and DNA damage. Then it's reasonable to explore relationships between the PCNA and DNA dam...
|
PDF Full Text Request