Pathophysiology of acute cerebral ischemia

Excitotoxicity Membrane depolarization in response to disrupted cellular oxidative and energy production processes leading to damaging activity of secondary messengers 

Depolarization Local depolarization caused by focal hypoxia decompensates already threatened metabolism in penumbra and propagates ischemic damage 

Apoptosis Programed or ordered cell death mediated by caspase enzymes 

Apoptosis is programed cell death and differs from necrosis in that it results in minimal inflammation and release of genetic material. Although necrosis is the predominant process that follows acute ischemia, apoptosis is important after more minor injury, particularly within the ischemic penumbra. Apoptosis is executed by the production, activation and action of caspases, which are protein-cleaving enzymes that dismantle cytoskeleton proteins and enzymes responsible for cellular repair (Zhang et al. 2004). Neurons are particularly susceptible to caspase-mediated cell death after cerebral ischemia, as demonstrated by the reduction in infarct size by caspase inhibitors in experimental models. 

Around acutely infarcted brain, there is an ischemic penumbra (Astrup et al. 1981). Here the blood flow is low, function depressed and the oxygen extraction fraction high. In other words, there is viable tissue with misery perfusion where the needs of the tissue are not being met The tissue may die or recover, depending on the speed and extent of restoration of blood flow. This concept opens up the possibility of a therapeutic time window during which restoration of flow or neuronal protection from ischemic damage might prevent both immediate cell death and the recruitment of neurons for apoptosis (see Ch. 21). 

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