A NOVEL AMPA RECEPTOR ANTAGONIST, YM872, REDUCES INFARCT SIZE AFTER MIDDLE CEREBRAL-ARTERY OCCLUSION IN RATS

The neuroprotective effect of YM872 ([2.3-dioxo-7-(1 H-imidazol-1-yl) 6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) rec eptor antagonist with improved water solubility, was examined in a rat focal cerebral ischemia model. Rats were subjected to permanent middl e cerebral artery (MCA) occlusion using the intraluminal suture occlus ion method for 24 h. YM872 was intravenously infused for 4 h (20 and 4 0 mg/kg/h) or 24 h (10 and 20 mg/kg/h), starting 5 min after the MCA o cclusion, to investigate the effect of prolonged duration of the treat ment on infarct volume. In the 4 h infusion study, YM872 reduced the c ortical infarct volume by 48% at a dose of 40 mg/kg/h. YM872 did not s ignificantly reduce the infarct at 20 mg/kg/h for 4 h. In the 24 h inf usion study, however, YM872 markedly reduced the cortical infarct volu me by 62%, even at 20 mg/kg/h. The present study indicates that the ne uroprotective effect of YM872 is enhanced by extending the duration of treatment, and demonstrates the benefit of the prolonged treatment wi th AMPA antagonists following focal cerebral ischemia. YM872, a highly water soluble compound, is applicable to investigate the role of AMPA receptors in ischemic models without concern about nephrotoxicity and could be useful in the treatment of human stroke. (C) 1998 Elsevier S cience B.V. All rights reserved.