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. 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.
Siesjö
B K
BK
Laboratory for Experimental Brain Research, University of Lund, University Hospital, Sweden.
Zhao
Q
Q
Pahlmark
K
K
Siesjö
P
P
Katsura
K
K
Folbergrová
J
J
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D002546:Ischemic Attack, Transient / Q000378:metabolism
D005609:Free Radicals; D005971:Glutamates; D002118:Calcium