Activation of the cerebral arachidonate (AA) cascade is one of the major causes of
edema and tissue injury in
cerebral ischemia, particularly after reperfusion. The cascade produces toxic
oxygen radicals responsible for peroxidative neurodegeneration and synthesizes, the potent edematous inducer,
leukotrienes. The present study was undertaken to evaluate the effect of MCl-186 (3-methyl-1-phenyl-pyrazolin-5-one), a radical scavenger and
antioxidant which has beneficial anti-ischemic actions, on the cerebral AA cascade. Postischemic treatment with MCl-186 (1.0 and 3.0 mg/kg i.v.) significantly inhibited the aggravation of cortical
edema seen 60 min after recirculation following 30 min of
ischemia in gerbils. An antilipoxygenase agent,
FPL-55712 (7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2- hydroxypropoxy]-4-oxo-8-propyl-4H-1-
benzopyran-2-
carboxylic acid, monosodium
salt; 10 mg/kg i.v.) or
AA-861 ((2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinon e; 60 mg/kg i.p.) was also effective in this model; however,
indomethacin (4 mg/kg i.p.), a
cyclooxygenase inhibitor, was ineffective. Concomitant treatment with MCl-186 (0.1-3.0 mg/kg i.v.) remarkably inhibited the swelling observed 24 hr after cortical infusion of AA (80 micrograms) in rats. Similarly, antilipoxygenase agents clearly inhibited the AA-induced
edema. Furthermore, postischemic treatment with MCl-186 (0.3-3.0 mg/kg i.v.) inhibited the facilitation of cerebral
leukotriene synthesis seen 15 min after recirculation following 30 min of
ischemia in gerbils. These findings suggest that the site of action of MCl-186 as an anti-ischemic agent may be closely associated with the cerebral AA cascade, especially the
lipoxygenase system, activated by
ischemia-reperfusion.