Effects of an antistroke agent MCl-186 on cerebral arachidonate cascade.
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.
Watanabe
T
T
Pharmaceutical Laboratory, Yokohama Research Center, Mitsubishi Chemical Corporation, Japan.
Egawa
M
M
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001929:Brain Edema / Q000517:prevention & control; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D002867:Chromones / Q000494:pharmacology; D000077553:Edaravone; D016166:Free Radical Scavengers; D005849:Gerbillinae; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
D002867:Chromones; D016166:Free Radical Scavengers; D013481:Superoxides; D016718:Arachidonic Acid; C006312:FPL 55712; D000077553:Edaravone; D000983:Antipyrine