GLUTAMATE, CALCIUM, AND FREE-RADICALS AS MEDIATORS OF ISCHEMIC BRAIN-DAMAGE

Calcium is considered a mediator of ischemic brain damage whether this is due to global or forebrain ischemia or to focal ischemia. Supporti ng evidence is the translocation of extracellular calcium into cells d uring ischemia, the precipitous rise in the free cytosolic calcium con centration, and the role of calcium in activating lipases, proteases, kinases, phosphatases, and endonucleases in potentially harmful metabo lic cascades. In vitro and in vivo experiments suggest that the main r oute of entry is through channels gated by glutamate receptors. These experiments led to the excitotoxic hypothesis of cell death. The in vi tro experiments further support the role of calcium as a mediator of c ell death. Both cell calcium overload and acidosis enhance the product ion of partially reduced oxygen species, thus predisposing to free rad ical-related damage. In transient global or forebrain ischemia, free r adicals formed during reperfusion may contribute to a perturbed membra ne function, leading to a sustained alteration of cell calcium metabol ism with ultimate mitochondrial calcium overload. In focal ischemia (s troke), free radicals may be important mediators of the infarction pro cess. Infarction can be regarded as a form of secondary damage, which is probably caused by microvascular dysfunction. Very likely, such dys function is triggered by upregulation of adhesion molecules such as IC AM-1, microvascular ''plugging,'' and an inflammatory response at the blood-endothelial cell interface. The involvement of free radicals in this type of secondary damage is supported by results showing that nit rones that act as free radical spin-traps ameliorate focal ischemic da mage with a therapeutic window of many hours.