Inhibitory Effect of MS-153 on Elevated Brain Glutamate Level Induced by Rat Middle Cerebral Artery Occlusion

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Abstract
Background and Purpose In this study we investigated the effects of a novel compound, MS-153 ([ R ]-[−]-5-methyl-1-nicotinoyl-2-pyrazoline), on elevated brain glutamate concentrations and cerebral infarct volume induced by middle cerebral artery (MCA) occlusion in the rat. Methods The rat MCA was occluded by a thrombus induced by a photochemical reaction between green light and the photosensitizer dye rose bengal, which causes endothelial injury followed by formation of a platelet- and fibrin-rich thrombus at the site of photochemical reaction; this method is routinely used in our laboratory to produce arterial occlusion in experimental animals. Extracellular glutamate concentration at the ischemic border zone was determined by a microdialysis technique. The size of cerebral infarction was measured by a histochemical technique 24 hours after MCA occlusion. MS-153 was administered at various doses as a continuous infusion for 24 hours, beginning 0 to 2 hours after MCA occlusion. Results At the ischemic border zone, the concentration of glutamate in the extracellular fluid increased by 40-fold after ischemia. At 3.13 mg/kg per hour, MS-153 reduced glutamate concentration ( P <.05) and also the size of ischemic cerebral infarction ( P <.05). Furthermore, the glutamate uptake inhibitor dl - threo -β-hydroxyaspartate reversed the effect of MS-153 on glutamate concentration. Conclusions The reduction in the size of cerebral infarction by MS-153 may be attributable to the inhibition of glutamate release or an increase in cellular glutamate uptake.