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 th at global brain ischaemia due to cardiac arrest in man induces a rapid incr ease in the amount of neuronal and glial PARP that can be detected by immun ohistochemistry. 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 m orphological evidence of ischaemic damage, and used double immuno-labelling to investigate the types of cell that were affected. We found that global brain ischaemia did cause accumulation of poly(ADP-ribose), particularly du ring the first 2 days after cardiac arrest. The distribution of cells with accumulation of poly(ADP-ribose) corresponded in general to regions of isch aemic damage or immediately adjacent: neocortex. Double immunolabelling for poly(ADP-ribose) and MAP2 showed many of the cells with poly(ADP-ribose) a ccumulation to be neurons. Our findings are in keeping with experimental ev idence of a role for PARP in post-ischaemic necrosis and of the potential f or reducing ischaemic brain damage by the use of PARP inhibitors.