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) meta bolites were examined to determine if pretreatment with the 21-aminost eroid 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 e levation 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 signific antly. On the other hand, PGE(2) and 6-keto-PGF(1 alpha) tended to dec rease 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) bu t significantly blunted the elevations in LTC(4) and LTB(4). The postr eperfusion decrease in PGE(2) was also attenuated. In the 10-min BCO g lobal ischemia model, there was also an increase in each of the measur ed eicosanoids, except LTB(4), at 5 min after reperfusion. Pretreatmen t with U-74006F (10 mg/kg i.p. 10 min before ischemia) selectively dec reased the rise in LTC(4) but did not significantly affect the other e icosanoids. In contrast, the antioxidant actually caused a significant enhancement of the postreperfusion increase in PGE(2) vs. vehicle-tre ated animals. The effects of U-74006F on postreperfusion eicosanoid sy nthesis are consistent with the lipid antioxidant properties of this c ompound. In particular, the attenuation of leukotriene levels is most likely a reflection of a decrease in postreperfusion lipid peroxidatio n, since lipid peroxides are potent activators of 5-lipoxygenase.