Neuroprotective effect of a novel AMPA receptor antagonist, YM90K, in rat focal cerebral ischaemia.
It has been reported that delayed treatment with alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor antagonists was able to more completely inhibit glutamate neurotoxicity than N-methyl-D-aspartate (NMDA) receptor antagonists. Therefore, we investigated the neuroprotective effect of YM90K, an AMPA receptor antagonist, on focal cerebral lesions induced by thrombotic middle cerebral artery (MCA) occlusion in rats, particularly in the early phase of the cerebral ischaemic lesions. The MCA was occluded by photochemical reaction between transmural green light and systemically administered Rose Bengal, which causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of photochemical reaction. The infarct size was measured at 24 and 72 h after the MCA occlusion by a histochemical technique. YM90K was administered at various doses as a continuous infusion for 4 h, beginning 0 to 3 h after the MCA occlusion. YM90K (10 and 20 mg/kg per h for 4 h continuous infusion), starting immediately after the MCA occlusion significantly (P < 0.05) reduced the infarct size at 24 h after MCA occlusion in a dose-dependent manner. Further, the agent showed the same efficacy at 72 h after. The inhibitory effect of YM90K (20 mg/kg per h) on the infarct size was the same when the drug was started immediately, 1, 2 and 3 h after MCA occlusion. In conclusion, the novel AMPA receptor antagonist YM90K was effective in the treatment of focal cerebral ischaemic lesions. Activation of AMPA receptor may play a key role in the development of cerebral infarct in the early phase of ischaemia in rats.
Umemura
K
K
Department of Pharmacology, Hamamatsu University School of Medicine, Japan. umemura@hama-med.ac.jp
Shimakura
A
A
Nakashima
M
M
D000818:Animals; D002536:Cerebral Arteries; D002540:Cerebral Cortex / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003342:Corpus Striatum / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione