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Inhibitory Effect of MCI-186, a Free Radical Scavenger, on Cerebral Ischemia Following Rat Middle Cerebral Artery Occlusion

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Abstract

  • 1.

    In this study, we investigated the effect of a radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), on cerebral damage induced by rat middle cerebral artery (MCA) occlusion, and further measured the hydroxyl radical level at the ischemic border zone using a microdialysis technique.

  • 2.

    MCI-186, at a dose of 3 mg/kg per 30 min, was administerated as a continuous infusion two times for 30 min, starting 20 min and then 80 min after Rose Bengal injection.

  • 3.

    MCI-186 significantly (P<0.05) reduced size of cerebral damage 24 hr after MCA occlusion and significantly (P<0.05) reduced hydroxyl radical level.

Introduction

Reactive oxygen species are generated within brain tissue during ischemic injury (Demopoulos et al., 1980; Raichle 1983). However, the sources of reactive oxygen species implicated in ischemic injury have not yet been clearly identified. It has been proposed that the mechanism of oxygen free radical generation may include the stimulation of the xanthine–xanthine oxidase system in cerebral vessels (Betz 1985) and activation of neutrophils (Matsuo et al., 1995) and arachidonic acid metabolism (Simonian and Coyler, 1996). Free radical-induced lipid peroxidation, oxidation of proteins and nucleic acids may contribute to the neuronal injury after cerebral ischemia. Damage to the cell membrane, for example, may result in dysfunction of essential membrane activities.

MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly synthesized free radical scavenger, exerts beneficial free radical scavenging and antioxidant characteristics (Watanabe et al., 1994) and prevents the peroxidative vascular endothelial cell damage caused by hydroperoxyeicosatetraenoic acid (Watanabe et al., 1988) in in vitro study. Furthermore, MCI-186 has been tested in various different experimental models for evaluatuation of its protective effects in cerebral ischemia/reperfusion (Abe et al., 1988; Nishi et al., 1989; Nishi et al., 1989; Watanabe et al., 1988) and myocardial ischemia/reperfusion (Minhaz et al., 1996). Thus, it seems that the neuroprotective effects of MCI-186 are attributable to the inhibition of free radical production.

In this study, we investigated the effect of MCI-186 on ischemic damage using middle cerebral artery (MCA) thrombosis model in rats, and determined whether its effect might be responsible for hydroxyl radical scavenging action by the salicylate hydroxylation technique using microdialysis, which has been suggested as a chemical trap for potential hydroxyl radical formation (Fig. 1) (Floyd et al., 1984, Floyd et al., 1986; Morimoto et al., 1996).

Section snippets

Animal preparation

Male Wistar rats (SLC Experimental Animal Co., Ltd., Shizuoka, Japan), weighing 240–270 g, were anesthetized with a 1.5% halothane and oxygen gas mixture. Body temperature was maintained at 37.5°C with a heating pad (K-Module, Model K-20, America Pharmaseal Co.), and a catheter for the administration of Rose Bengal or other agents placed in the femoral vein. MCA occlusion caused by photochemically induced thrombosis in the rat has been described by Umemura et al. 1993Umemura et al. 1994Umemura

Amount of cerebral damage

The dorsolateral cortex and striatum were damaged in the control group. MCI-186 (3 mg/kg per 30 min) significantly (P<0.05) reduced the amount of cerebral damage in the cortex but not in the striatum (Fig. 2).

Measurement of 2.3-DHBA and inhibitory effect of MCI-186

The mean preischemic values for 2.3-DHBA concentration were 35.74±6.80 and 40.65±2.93 pmol/ml in the control group and the group treated with MCI-186, respectively, and there was no significant difference between the groups. After the MCA occlusion, the concentration of 2.3-DHBA increased

Discussion

In this study, thrombotic occlusion of the MCA was induced by photochemical reaction between Rose Bengal and green light, which caused endothelial injury followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of the photochemical reaction (Saniabadi et al., 1995). Using this model, we investigated if focal cerebral ischemia induced by the MCA occlusion results in an increase of hydroxyl radical generation in the ischemic border zone. The

Summary

  • 1.

    In this study, we investigated the effect of a radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), on cerebral damage induced by rat middle cerebral artery (MCA) occlusion, and also measured the hydroxyl radical level at the ischemic border zone using a microdialysis technique.

  • 2.

    The rat MCA was occluded by a thrombus induced by a photochemical reaction. The hydroxyl radical level at the ischemic border zone was determined as a concentration of 2.3-dihydroxybenzoic acid metabolized

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