CALCIUM-RELATED DAMAGE IN ISCHEMIA

The objective of this hypothesis article is to review evidence support ing a role for calcium in mediating ischemic brain damage, and to pres ent data which puts mitochondrial dysfunction in the center of interes t. The assumptions/postulates put forward, relating to global/forebrai n and to focal ischemia, are as follows. (1) In brief ischemia of the global/forebrain type neuronal necrosis, particularly in the CA1 secto r of the hippocampus, is conspicuously delayed. It is postulated that the initial events during ischemia, and in the immediate recirculation period, lead to a perturbation of cell calcium homeostasis, with a gr adual postischemic rise in the free cytosolic calcium concentration (C a-i(2+)). When the latter reaches a certain limiting value mitochondri a start accumulating calcium. It is hypothesized that intramitochondri al calcium accumulation triggers a permeability transition of the inne r mitochondrial membrane (MPT), leading to production of reactive oxyg en species, release of calcium, and an increase in the cytosol calcium concentration of a potentially adverse nature. (2) If ischemia of thi s ''cardiac arrest'' type is prolonged, or complicated by preischemic hyperglycemia, neuronal necrosis is enhanced and pan-necrotic lesions appear. Such insults are known to cause rapidly developing mitochondri al failure, but the involvement of calcium has not yet been demonstrat ed. (3) In focal ischemia, core tissues probably suffer a metabolic in sult similar to that affecting brain tissues in global/forebrain ische mia. Thus, calcium influx and calcium overload of mitochondria are pre dictable, but available data only demonstrate rapidly developing, seco ndary energy failure, mitochondrial dysfunction, and enhanced influx o f Ca-45. Thus, although secondary mitochondrial failure has been prove d, a causative link between calcium influx and bioenergetic failure re mains to be proved. Perifocal, penumbral tissues are exposed to sponta neously occurring depolarisation waves, leading to cellular efflux of K+ and influx of Ca2+. The latter may lead to gradual mitochondrial ca lcium overload triggering a MPT, and cell death. Although conclusive e vidence has not yet been presented available results suggest a link be tween calcium influx, mitochondrial overload, and cell death.