Effects of the lipid peroxidation inhibitor tirilazed mesylate (U-74006F) on gerbil brain eicosanoid levels following ischemia and reperfusion

The present study measured the production of eicosanoids in the gerbil brain durin 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 PGF_2α, 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-PGF_1α 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 PGF_2α 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 aafter 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. The effects of U-74006F on postreperfusion eicosanoid synthesis are consistent with the lipid antioxidant properties of this compound. In particular, the attenuation of leukotriene levels is most likelu a reflection of a decrease in postreperfusion lipid peroxidation, since lipid peroxides are potent activators of 5-lipoxygenase.