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. Preischemic treatment with MCI-186 (3 mg/kg i.v.) facilitated the recovery of electrocorticographic activity and prolonged survival time in global complete ischemia of rats; MCI-186 (1 and 3 mg/kg i.v.) also mitigated dysfunction of the blood-brain barrier and energy failure in hemispheric embolization of rats. Postischemic treatment with MCI-186 (3 mg/kg i.v.) decreased cortical infarction in focal embolization of rats. MCI-186 (0.6-2.4 mM) inhibited the OH.-induced hydroxylation of salicylate (maximal inhibition, 40.2%), but at 100 microM it did not influence O2- generation. MCI-186 inhibited the formation of linoleic acid-conjugated dienes caused by OH. (IC50 = 32.0 microM). Also, concurrent administration of MCI-186 (3-100 mg/kg i.v.) ameliorated hyperglycemia, hyperlipopeoxidemia and degranulation of beta-cells in alloxan (40 mg/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 microM, respectively) and prevented iron-dependent peroxidative disintegration of mitochondrial membranes (IC50 = 39.0 microM). These findings suggest that MCI-186 has potent anti-ischemic actions and that its mechanism may be closely associated with beneficial antioxidant activities.
Watanabe
T
T
Pharmaceuticals Laboratory I, Mitsubishi Kasei Corporation, Yokohama, Japan.
Yuki
S
S
Egawa
M
M
Nishi
H
H
D000496:Alloxan; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000517:prevention & control*; D000077553:Edaravone; D004621:Embolization, Therapeutic; D004734:Energy Metabolism / Q000187:drug effects; D016166:Free Radical Scavengers; D017665:Hydroxyl Radical; D007515:Islets of Langerhans / Q000187:drug effects; D015227:Lipid Peroxidation; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013481:Superoxides
D000975:Antioxidants; D016166:Free Radical Scavengers; D013481:Superoxides; D017665:Hydroxyl Radical; D000496:Alloxan; D000077553:Edaravone; D000983:Antipyrine