[Cerebral ischemic cascade]

The pathophysiology of ischaemia depends on the residual cerebral blood flow. As a result, it is different in global ischaemia, when compared with focal ischaemia, where the centre area is surrounded with an area called an ischaemic penumbra. Ischaemia results from a sudden failure in the oxygen and glucose supply. Oxidative phosphorylation fails, a major event that is responsible for all the other reactions. Anaerobic metabolism produces lactate and H+. Cell membrane ionic pumps are inactivated, which results in a breakdown of ionic homeostasis. Ca++ and Na+ penetrate into the cells, as K+ is released. The energy failure causes an extracellular accumulation of excitatory amino-acids, thus eliciting a hyperstimulation of the NMDA receptors. These receptors are hyperactivated as a result of the deterioration in the control systems with, especially, the blockade of the NMDA receptor by Mg++. As a consequence, there is a massive entry of Ca++ into the cell, including a series of enzymatic reactions involving phospholipases, proteases and endonucleases. Reperfusion will cause toxic lesions by producing free radicals, due to the action of arachidonic acid, xanthine oxidase and nitric oxide. The decrease in cell energetic supplies, as well as the overactivation of enzymes and the production of free radicals, result in cell death.