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Calcium/calmodulin-dependent protein kinase II activity in focal ischemia with reperfusion in rats
S K Hanson1, J C Grotta, M N Waxham
1Department of Neurology, University of Texas Health Science Center at Houston.
Background And Purpose:
Evidence linking changes in calcium/calmodulin-dependent protein kinase II activity with ischemic cell death has been reported in animal models of global ischemia. The purpose of this study was to delineate the course of these changes after focal ischemia and to clarify the relation of changes in activity of calcium/calmodulin-dependent protein kinase II to the process of ischemic cell death.
Methods:
Change in calcium/calmodulin-dependent protein kinase II activity was evaluated in a rat model of focal ischemia after 5 minutes, 30 minutes, and 1 hour of tandem middle cerebral artery and common carotid artery occlusion both with and without reperfusion.
Results:
Calcium/calmodulin-dependent protein kinase II activity was significantly decreased after all three durations of ischemia followed by immediate decapitation compared with sham-operated animals, in both ischemic core and border-zone regions (P < .05 for all groups). Depression of activity occurred in a regionally graded fashion, with the most severe decrease in infarct core and progressively smaller decreases in samples moving out from the center, corresponding to the severity of histological injury later detected in infarct core and border-zone regions. There were only minor differences between the three durations of ischemia in the degree of enzyme depression noted in the more peripheral regions, indicating that the initial decrease in calcium/calmodulin-dependent protein kinase II activity is an early, sensitive marker for an ischemic insult. After reperfusion, the differences between the 5-minute group and longer periods of ischemia widened because of an increase toward baseline in the 5-minute group and a trend toward further decrease in the 30- and 60-minute groups.
Conclusions:
The extreme sensitivity of calcium/calmodulin-dependent protein kinase II to focal ischemia and the parallel temporal and regional changes in its activity to those of more delayed cell injury point to a potential role for this enzyme in the process of excitotoxic injury.