Neuronal accumulation of poly(ADP-ribose) after brain ischaemia

Animal and in vitro studies suggest that overactivation of poly(ADP-ribose) polymerase (PARP) in response to oxidative DNA damage makes a substantial contribution to cell death after brain ischaemia. We have recently shown that global brain ischaemia due to cardiac arrest in man induces a rapid increase in the amount of neuronal and glial PARP that can be detected by immunohistochemistry. In the present study we sought evidence of a corresponding increase in the amount of poly(ADP-ribose) within the brain, as this would confirm PARP activation and imply resulting consumption of NAD+. We also studied the distribution of poly(ADP-ribose) accumulation in relation to morphological evidence of ischaemic damage, and used double immunolabelling to investigate the types of cell that were affected. We found that global brain ischaemia did cause accumulation of poly(ADP-ribose), particularly during the first 2 days after cardiac arrest. The distribution of cells with accumulation of poly(ADP-ribose) corresponded in general to regions of ischaemic damage or immediately adjacent neocortex. Double immunolabelling for poly(ADP-ribose) and MAP2 showed many of the cells with poly(ADP-ribose) accumulation to be neurons. Our findings are in keeping with experimental evidence of a role for PARP in post-ischaemic necrosis and of the potential for reducing ischaemic brain damage by the use of PARP inhibitors.