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

被引:161
作者
SIESJO, BK
ZHAO, Q
PAHLMARK, K
SIESJO, P
KATSURA, K
FOLBERGROVA, J
机构
[1] Laboratory for Experimental Brain Research, University of Lund, University Hospital, Lund
关键词
D O I
10.1016/0003-4975(95)00077-X
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Calcium is considered a mediator of ischemic brain damage whether this is due to global or forebrain ischemia or to focal ischemia. Supporting evidence is the translocation of extracellular calcium into cells during ischemia, the precipitous rise in the free cytosolic calcium concentration, and the role of calcium in activating lipases, proteases, kinases, phosphatases, and endonucleases in potentially harmful metabolic cascades. In vitro and in vivo experiments suggest that the main route of entry is through channels gated by glutamate receptors. These experiments led to the excitotoxic hypothesis of cell death. The in vitro experiments further support the role of calcium as a mediator of cell death. Both cell calcium overload and acidosis enhance the production of partially reduced oxygen species, thus predisposing to free radical-related damage. In transient global or forebrain ischemia, free radicals formed during reperfusion may contribute to a perturbed membrane function, leading to a sustained alteration of cell calcium metabolism with ultimate mitochondrial calcium overload. In focal ischemia (stroke), free radicals may be important mediators of the infarction process. Infarction can be regarded as a form of secondary damage, which is probably caused by microvascular dysfunction. Very likely, such dysfunction is triggered by upregulation of adhesion molecules such as ICAM-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 nitrones that act as free radical spin-traps ameliorate focal ischemic damage with a therapeutic window of many hours.
引用
收藏
页码:1316 / 1320
页数:5
相关论文
共 43 条
[11]  
Erecinska, Silver, Ions and energy in mammalian brain, Progress in Neurobiology, 43, pp. 37-71, (1994)
[12]  
Hansen, Effects of anoxia on ion distribution in the brain, Physiol Rev, 65, pp. 101-148, (1985)
[13]  
Silver, Erecinska, Intracellular and extracellular changes of [Ca<sup>2+</sup>] in hypoxia and ischemia in rat brain in vivo, The Journal of General Physiology, 95, pp. 837-866, (1990)
[14]  
Choi, Glutamate neurotoxicity and diseases of the nervous system, Neuron, 1, pp. 623-634, (1988)
[15]  
Siesjo, The role of calcium in cell death, Neurodegenerative disorders: mechanisms and prospects for therapy, pp. 35-39, (1991)
[16]  
Siesjo, Historical overview, Calcium, ischemia, and death of brain cells, 522, pp. 638-661, (1988)
[17]  
Kozuka, Smith, Siesjo, Preischemic hyperglycemia enhances postischemic depression of cerebral metabolic rate, J Cereb Blood Flow Metab, 9, pp. 478-490, (1989)
[18]  
Pulsinelli, Levy, Duffy, Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia, Ann Neurol, 11, pp. 499-509, (1982)
[19]  
Hossmann, Disturbances of cerebral protein synthesis and ischemic cell death, Neurobiology of ischemic brain damage, pp. 161-177, (1993)
[20]  
Thilmann, Xie, Kleihues, Kiessling, Persistent inhibition of protein synthesis precedes delayed neuronal death in post-ischemic gerbil hippocampus, Acta Neuropathologica, 71, pp. 88-93, (1989)