TY - JOUR
T1 - Effects of the lipid peroxidation inhibitor tirilazed mesylate (U-74006F) on gerbil brain eicosanoid levels following ischemia and reperfusion
AU - Andrus, Paula K.
AU - Taylor, Bruce M.
AU - Sun, Frank F.
AU - Hall, Edward D.
PY - 1994/10/3
Y1 - 1994/10/3
N2 - 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 PGF2α, 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-PGF1α 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 PGF2α 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.
AB - 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 PGF2α, 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-PGF1α 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 PGF2α 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.
KW - 21-Aminosteroid
KW - Leukotriene
KW - Prostaglandin
KW - Tirilazad mesylate
UR - http://www.scopus.com/inward/record.url?scp=0027963503&partnerID=8YFLogxK
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U2 - 10.1016/0006-8993(94)90871-0
DO - 10.1016/0006-8993(94)90871-0
M3 - Article
C2 - 7820653
AN - SCOPUS:0027963503
SN - 0006-8993
VL - 659
SP - 126
EP - 132
JO - Brain Research
JF - Brain Research
IS - 1-2
ER -