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 PGF(2 alpha), TXB(2) and LTC(4) (P < 0.05 vs. sham for all three eicosanoids). LTB(4) also rose but not significantly. On the other hand, PGE(2) and 6-keto-PGF(1 alpha) tended to decrease during ischemia and at 5-min postreperfusion (P < 0.05 vs. sham for PGE(2)). 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(2 alpha) or TXB(2) but significantly blunted the elevations in LTC(4) and LTB(4). The postreperfusion decrease in PGE(2) was also attenuated. In the 10-min BCO global ischemia model, there was also an increase in each of the measured eicosanoids, except LTB(4), at 5 min after reperfusion. Pretreatment with U-74006F (10 mg/kg i.p. 10 min before ischemia) selectively decreased the rise in LTC(4) but did not significantly affect the other eicosanoids. In contrast, the antioxidant actually caused a significant enhancement of the postreperfusion increase in PGE(2) 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 likely a reflection of a decrease in postreperfusion lipid peroxidation, since lipid peroxides are potent activators of 5-lipoxygenase.