T. Watanabe et al., PROTECTIVE EFFECTS OF MCI-186 ON CEREBRAL-ISCHEMIA - POSSIBLE INVOLVEMENT OF FREE-RADICAL SCAVENGING AND ANTIOXIDANT ACTIONS, The Journal of pharmacology and experimental therapeutics, 268(3), 1994, pp. 1597-1604
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.-