Effects of the lipid peroxidation inhibitor tirilazad mesylate (U-74006F) on gerbil brain eicosanoid levels following ischemia and reperfusion.
The present study measured the production of eicosanoids in the gerbil brain during early reperfusion after either a 3-h unilateral carotid occlusion (UCO, model of focal ischemia) or a 10-min bilateral carotid occlusion (BCO, model of global ischemia). Arachidonic acid (AA) metabolites were examined to determine if pretreatment with the 21-aminosteroid lipid peroxidation inhibitor U-74006F (tirilazad mesylate) could influence postreperfusion synthesis of brain eicosanoids. In the 3-h UCO focal ischemia model, there was an early (5-min) postreperfusion elevation in brain levels of PGF2 alpha, TXB2 and LTC4 (P < 0.05 vs. sham for all three eicosanoids). LTB4 also rose but not significantly. On the other hand, PGE2 and 6-keto-PGF1 alpha tended to decrease during ischemia and at 5-min postreperfusion (P < 0.05 vs. sham for PGE2). Pretreatment with known neuroprotective doses of U-74006F in this model (10 mg/kg i.p. 10 min before and again immediately upon reperfusion) did not affect the increase in PGF2 alpha or TXB2 but significantly blunted the elevations in LTC4 and LTB4. The postreperfusion decrease in PGE2 was also attenuated. In the 10-min BCO global ischemia model, there was also an increase in each of the measured eicosanoids, except LTB4, at 5 min after reperfusion. Pretreatment with U-74006F (10 mg/kg i.p. 10 min before ischemia) selectively decreased the rise in LTC4 but did not significantly affect the other eicosanoids. In contrast, the antioxidant actually caused a significant enhancement of the postreperfusion increase in PGE2 vs. vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Andrus
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Upjohn Company, Kalamazoo, MI 49001.
Taylor
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BM
Sun
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Hall
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ED
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D002339:Carotid Arteries; D003250:Constriction; D015777:Eicosanoids / Q000378:metabolism*; D005849:Gerbillinae; D015289:Leukotrienes / Q000378:metabolism; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008297:Male; D011281:Pregnatrienes / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism; D015424:Reperfusion; D013929:Thromboxane B2 / Q000378:metabolism
D015777:Eicosanoids; D015289:Leukotrienes; D008054:Lipid Peroxides; D011281:Pregnatrienes; D011453:Prostaglandins; D013929:Thromboxane B2; C053355:tirilazad