Inhibitory effect of MS-153 on elevated brain glutamate level induced by rat middle cerebral artery occlusion.
OBJECTIVE
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-beta-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.
Umemura
K
K
Department of Pharmacology, Hamamatsu University School of Medicine, Japan. umemura@hama-med.ac.jp
Gemba
T
T
Mizuno
A
A
Nakashima
M
M
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002536:Cerebral Arteries; D002544:Cerebral Infarction / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D008297:Male; D009539:Nicotinic Acids / Q000494:pharmacology*; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar
C101692:5-methyl-1-nicotinoyl-2-pyrazoline; D009539:Nicotinic Acids; D005973:Glutamine; D018698:Glutamic Acid; D005998:Glycine