PROTECTIVE EFFECTS OF MCI-186 ON CEREBRAL-ISCHEMIA - POSSIBLE INVOLVEMENT OF FREE-RADICAL SCAVENGING AND ANTIOXIDANT ACTIONS

The anti-ischemic effects and a possible mechanism of a new antistroke agent, 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186), were studied. Pre ischemic treatment with MCI-186 (3 mg/kg i.v.) facilitated the recover y of electrocorticographic activity and prolonged survival time in glo bal complete ischemia of rats; MCI-186 (1 and 3 mg/kg i.v.) also mitig ated dysfunction of the blood-brain barrier and energy failure in hemi spheric embolization of rats. Postischemic treatment with MCI-186 (3 m g/kg i.v.) decreased cortical infarction in focal embolization of rats . MCI-186 (0.6-2.4 mM) inhibited the OH.-induced hydroxylation of sali cylate (maximal inhibition, 40.2%), but at 100 mu M it did not influen ce O-2(-) generation. MCI-186 inhibited the formation of linoleic acid conjugated dienes caused by OH. (IC50 = 32.0 mu M). Also, concurrent a dministration of MCI-186 (3-100 mg/kg i.v.) ameliorated hyperglycemia, hyperlipoperoxidemia and degranulation of beta-cells in alloxan (40 m g/kg i.v.)-treated rats. In addition, MCI-186 inhibited iron-dependent peroxidation in rat brain homogenates and mitochondrial homogenates ( IC50 = 15.0 and 2.3 mu M, respectively) and prevented iron-dependent p eroxidative disintegration of mitochondrial membranes (IC50 = 39.0 mu M). These findings suggest that MCI-186 has potent anti-ischemic actio ns and that its mechanism may be closely associated with beneficial an tioxidant activities.-