Mechanisms of Delayed Cell Death Following Focal Cerebral Ischemia

The morphological hallmarks of neuronal cell death following focal cerebral ischemia are cell shrinkage and nuclear condensation. These features are found in brain areas affected by immediate and delayed cell death. Accordingly, the mechanisms leading to ischemic cell death seem to be very similar whether or not affected cells are located in the infarct core where blood flow is almost absent or in the ischemic penumbra where collateral blood flow may keep cells alive for several hours (Astrup et al. 1981). For many years it remained unclear how ischemia causes the morphological findings described above. Nuclear condensation is the morphological sequel of DNA damage, which usually occurs in a highly regulated manner during programmed cell death. That nuclear condensation following cerebral ischemia was the result of DNA damage and endonuclease activation was finally demonstrated by Linnik et al. and Charriaut-Merlangue et al, respectively, more than 10 years ago (Linnik et al. 1995; Charriaut-Marlangue et al. 1996). This finding triggered intense search for the upstream signaling responsible for post-ischemic endo-nuclease activation, which was finally believed to be the activation of caspase-3 (Namura et al. 1998). Namura and colleagues showed constitutive expression of inactive caspase-3 in neurons throughout the brain, most prominently in neuronal perikarya within piriform cortex and, most importantly, caspase-like enzyme activity in ischemic brain 30-60 min after reperfusion following 2 h MCAo. Active caspase-3 was detected in ischemic neurons at the time of reperfusion by immuno-histochemistry. DNA laddering and TUNEL-positive cells as indicators of DNA fragmentation were detected 6-24 h after reperfusion (Namura et al. 1998). Further proof for the role of active caspase-3 for ischemic cell death came in the same year from experiments from the same laboratory using pan-caspase and caspase-3 specific

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