Stroke, Vol 24, 1212-1216, Copyright © 1993 by American Heart Association
TJ DeGraba, PT Ostrow and JC Grotta
BACKGROUND AND PURPOSE: One explanation for inconclusive results with
calcium channel blockers in human acute stroke trials may be incomplete
information about the time course of calcium-mediated ischemic neuronal
injury. This study explores the temporal relation between duration of focal
ischemia and the functional activity of increased intracellular calcium as
measured by calcium-calmodulin binding. METHODS: Calcium- calmodulin
binding, determined by immunohistochemical assay of free calmodulin, was
measured in 60 male spontaneously hypertensive rats after 2 minutes and
after 1, 2, 4, and 24 hours of permanent tandem common carotid and middle
cerebral artery occlusion, and after 1 and 2 hours of reversible middle
cerebral artery occlusion followed by 1 and 22 hours of reperfusion,
respectively. Light microscopic histological damage was measured after 1
hour of occlusion with 23 hours of reperfusion and after 24 hours of
occlusion. RESULTS: Significant loss of calmodulin staining in the core of
the infarction was noted by 1 hour and became maximal after 4 hours of
ischemia. No reversal of calmodulin staining loss was noted after
reperfusion following 1 and 2 hours of ischemia. Cortical necrosis seen by
light microscopy correlated well with the area of maximal
calcium-calmodulin binding. The border zone area, represented by a mild
loss of calmodulin staining surrounding the central core of maximal
binding, gradually decreased in size and became incorporated into the
central core after 4 hours of ischemia; it may represent an area of
reversible ischemia. CONCLUSIONS: Calcium-calmodulin binding correlates
with duration of focal ischemia, and histological neuronal necrosis
corresponds to the cortical areas displaying a significant loss of
calmodulin staining. Inasmuch as loss of calmodulin staining represents a
marker for calcium-mediated activity after ischemia, it suggests a window
of opportunity within 4 hours after acute stroke for therapeutic
intervention with calcium antagonists.
ARTICLES
Threshold of calcium disturbances after focal cerebral ischemia in rats. Implications of the window of therapeutic opportunity
Department of Neurology, University of Texas Medical School, Houston 77030.
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