After cerebral artery occlusion, the extent of damage depends on the gradient of reduced blood flow in the respective supply area and time from onset. A complex pathophysiological cascade starts expanding, affecting brain cells over time and space.

There is a close association between delay from stroke onset to treatment with both tPA and ET and irreversible tissue damage—the ‘‘time-is-brain’’ rationale. Hence, timely reperfusion by reopening the occluded artery is the key to achieve better outcome. In contrast, despite promising results in animal models, neuroprotective attempts in humans have failed so far. While neuroprotection without reperfusion seems unlikely to be a successful strategy, the ‘‘freezing penumbra’’ concept, based on the assumption that salvageable tissue can be preserved by blocking the ischemic cascade until the blood supply is re-established remains under investigation. However, the early induction of secondary cell death in the penumbra would also probably require starting such treatments very quickly after arterial blockage.