General Pharmacology: The Vascular System
General PapersInhibitory Effect of MCI-186, a Free Radical Scavenger, on Cerebral Ischemia Following Rat Middle Cerebral Artery Occlusion
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
References (31)
- et al.
Oxygen free radical involvement in ischemia and reperfusion injury to brain
Neurosci. Lett.
(1988) - et al.
Sensitive assay of hydroxy radical formation utilizing high pressure liquid chromatography with electrochemical detection phenol and salicylate hydroxylation products
J. Biochem. Biophys. Meth.
(1984) - et al.
Use of salicylate with high pressure liquid chromatography and electrochemical detection (LCED) as a sensitive measure of hydroxyl free radicals in adriamycin treated rats
J. Free Rad. Biol. Med.
(1986) - et al.
Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation
Free Rad. Biol. Med.
(1989) - et al.
Hydroxylation of salicylate as an assay for hydroxyl radicalsCautionary note
Free Rad. Biol. Med.
(1991) - et al.
Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in rat brain
Brain Res.
(1991) - et al.
Effect of 21-aminosteroid lipid peroxidation inhibitor, U74006F, in the rat middle cerebral artery occlusion model
Eur. J. Pharmac.
(1994) - et al.
Preventive effect of MCI-186 on 15-HPETE induced vascular endothelial cell injury in vitro
Prostagland. Leuk. Essential Fatty Acids
(1988) - et al.
Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger
Stroke
(1988) - et al.
The use of salicylate hydroxylation to detect hydroxy radical generation in ischemic and traumatic brain injury. Reversal by tirilazad mesylate (U-74006F)
Mol. Chem. Neuropathol.
(1993)
Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries
J. Neurochem.
Central nervous system trauma and stroke. I. Biochemical consideration for oxygen radical formation and lipid peroxidation
Free Rad. Biol. Med.
The free radical pathology and the microcirculation in the major central nervous system disorders
Acta Physiol. Scand.
Hydroxylation of salicylate by microsomal fractions and cytochrome P-450. Lack of production of 2.3-dihydroxybenzoate unless hydroxyl radical formation is permitted
Biochem. J.
Effect of indomethacin and a free radical scavenger on cerebral blood flow and edema after cerebral artery occlusion in cats
Stroke
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