A novel AMPA receptor antagonist, YM872, reduces infarct size after middle cerebral artery occlusion in rats

Brain Res. 1998 May 18;793(1-2):39-46. doi: 10.1016/s0006-8993(98)00108-5.

Abstract

The neuroprotective effect of YM872 ([2.3-dioxo-7-(1H-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) receptor antagonist with improved water solubility, was examined in a rat focal cerebral ischemia model. Rats were subjected to permanent middle cerebral artery (MCA) occlusion using the intraluminal suture occlusion method for 24 h. YM872 was intravenously infused for 4 h (20 and 40 mg/kg/h) or 24 h (10 and 20 mg/kg/h), starting 5 min after the MCA occlusion, to investigate the effect of prolonged duration of the treatment on infarct volume. In the 4 h infusion study, YM872 reduced the cortical infarct volume by 48% at a dose of 40 mg/kg/h. YM872 did not significantly reduce the infarct at 20 mg/kg/h for 4 h. In the 24 h infusion study, however, YM872 markedly reduced the cortical infarct volume by 62%, even at 20 mg/kg/h. The present study indicates that the neuroprotective effect of YM872 is enhanced by extending the duration of treatment, and demonstrates the benefit of the prolonged treatment with 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.

MeSH terms

  • Animals
  • Arterial Occlusive Diseases / drug therapy*
  • Arterial Occlusive Diseases / pathology
  • Blood Gas Analysis
  • Body Temperature
  • Brain / blood supply
  • Brain / drug effects
  • Brain Ischemia / drug therapy
  • Brain Ischemia / pathology
  • Cerebral Arteries / pathology*
  • Cerebral Infarction / drug therapy*
  • Cerebral Infarction / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Infusions, Intravenous
  • Kidney / pathology
  • Male
  • Neuroprotective Agents
  • Quinoxalines / administration & dosage
  • Quinoxalines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors*
  • Time Factors

Substances

  • Imidazoles
  • Neuroprotective Agents
  • Quinoxalines
  • Receptors, AMPA
  • YM 872