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(Stroke. 1995;26:1893-1900.)
© 1995 American Heart Association, Inc.

Articles

Inositol Trisphosphate, Polyphosphoinositide Turnover, and High-Energy Metabolites in Focal Cerebral Ischemia and Reperfusion

G.Y. Sun, PhD; J.-P. Zhang, BS; T.A. Lin, PhD; T.-N. Lin, PhD; Y.Y. He, MD C.Y. Hsu, MD, PhD

From the Biochemistry Department, University of Missouri, Columbia (G.Y.S., J.-P.Z., T.A.L.), and the Neurology Department, Washington University School of Medicine, St Louis (T.-N.L., C.C.H., C.Y.H.), Mo.

Correspondence to Dr Grace Y. Sun, M121 Medical Sciences Bldg, Biochemistry Department, University of Missouri, Columbia, MO 65212.

Background and Purpose Although the signaling pathway involving polyphosphoinositide (poly-PI) hydrolysis and release of inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] is an important mechanism for regulation of neuronal calcium homeostasis, the effect of cerebral ischemia-reperfusion on this calcium signaling pathway is not well understood. Because activity of this pathway is dependent on availability of ATP, this study is aimed at examining the poly-PI signaling pathway and high-energy metabolites in a rat stroke model.

Methods Focal cerebral ischemia in rats was induced by temporary occlusion of the right middle cerebral artery and both common carotid arteries. Levels of Ins(1,4,5)P₃ were determined by use of the radioreceptor binding assay. Poly-PI turnover in rat cortex was assessed with an in vivo protocol involving intracerebral injection of [³H]inositol and systemic administration of lithium. High-energy metabolites (ATP, ADP, and AMP) were analyzed by high-performance liquid chromatography.

Results Ischemia induced an increase in poly-PI turnover in the right middle cerebral artery cortex, but reperfusion led to a decline in this signaling activity. However, Ins(1,4,5)P₃ levels decreased during ischemia, and these levels were not restored if ischemic insults were longer than 30 minutes. ATP levels decreased to 26% of control during ischemia and recovered to 80% of control during the initial 4 hours of reperfusion; these changes were followed by a second phase of decline.

Conclusions Results show an important relationship between ischemia-induced depletion of high-energy metabolites and poly-PI signaling activity. However, the uncoupling between Ins(1,4,5)P₃ and ATP during reperfusion after severe ischemia suggests that metabolism of Ins(1,4,5)P₃ is more stringently regulated than ATP.

Key Words: adenosine triphosphate • cerebral ischemia, focal • gene expression • inositol 1,4,5-trisphosphate • reperfusion

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