CALCIUM, ENERGY-METABOLISM AND THE DEVELOPMENT OF SELECTIVE NEURONAL LOSS FOLLOWING SHORT-TERM CEREBRAL-ISCHEMIA

Short-term cerebral ischemia results in the delayed loss of specific n euronal subpopulations. This review discusses changes in energy metabo lism and Ca2+ distribution during ischemia and recirculation and consi ders the possible contribution of these changes to the development of selective neuronal loss. Severe ischemia results in a rapid decline of ATP content and a subsequent large movement of Ca2+ from the extracel lular to the intracellular space. Similar changes are seen in tissue s ubregions containing neurons destined to die and those areas largely r esistant to short-term ischemia, although differences have been observ ed in Ca2+ uptake between individual neurons. The large accumulation o f intracellular Ca2+ is widely considered as a critical initiating eve nt in the development of neuronal loss but, as yet, definitive evidenc e has not been obtained. The increased intracellular Ca2+ content acti vates a number of additional processes including lipolysis of phosphol ipids and degradation or inactivation of some specific proteins, all o f which could contribute to altered function on restoration of blood f low to the brain. Reperfusion results in a rapid recovery of ATP produ ction. Cytoplasmic Ca2+ concentration is also restored during early re circulation as a result of both removal to the extracellular space and uptake into mitochondria. Within a few hours of recirculation, subtle increases in intracellular Ca2+ and a reduced capacity for mitochondr ial respiration have been detected in some ischemia-susceptible region s. Both of these changes could potentially contribute to the developme nt of neuronal loss. More pronounced alterations in Ca2+ homeostasis, resulting in a second period of increased mitochondrial Ca2+, develop with further recirculation in ischemia-susceptible regions. The availa ble evidence suggests that these increases in Ca2+, although developin g late, are likely to precede the irreversible loss of neuronal functi on and may be a necessary contributor to the final stages of this proc ess.