Effect of AMPA receptor antagonist YM872 on cerebral hematoma size and neurological recovery in the intracerebral hemorrhage rat model

Eur J Pharmacol. 2003 Apr 25;467(1-3):95-101. doi: 10.1016/s0014-2999(03)01572-3.

Abstract

[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate (YM872 or zonampanel), an AMPA receptor antagonist, is in clinical development for acute ischemic cerebral infarction. Stroke patients are prone to have subsequent intracerebral hemorrhages. In order to predict potential adverse effects, YM872 was tested in a rat model with collagenase-induced intracerebral hemorrhage. The morphologically determined hematoma volumes after 24 h were compared between animal groups intravenously infused with 3600 U/kg/h heparin for 30 min, or with 20 or 40 mg/kg/h of YM872, or placebo for 4 h. Heparin enlarged hematoma volume, but neither dose of YM872 affected hematoma size. In a separate study, neurological deficits were scored at various days after intracerebral hemorrhage induction in animals with intravenous infusion for 24 h of 10 or 20 mg/kg/h YM872, or saline. The YM872 groups scored significantly better than the saline group at 14 days. These data suggest that YM872 does not exacerbate intracerebral hemorrhage and might accelerate recovery.

MeSH terms

  • Animals
  • Atrophy / chemically induced
  • Atrophy / pathology
  • Brain Edema / chemically induced
  • Brain Edema / drug therapy*
  • Brain Edema / pathology
  • Brain Infarction / chemically induced
  • Brain Infarction / drug therapy
  • Brain Infarction / pathology
  • Cerebral Hemorrhage / chemically induced
  • Cerebral Hemorrhage / drug therapy*
  • Cerebral Hemorrhage / pathology
  • Collagenases
  • Dose-Response Relationship, Drug
  • Hematoma / chemically induced
  • Hematoma / drug therapy*
  • Hematoma / pathology
  • Heparin / adverse effects
  • Imidazoles / adverse effects
  • Imidazoles / pharmacology*
  • Male
  • Quinoxalines / adverse effects
  • Quinoxalines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors*

Substances

  • Imidazoles
  • Quinoxalines
  • Receptors, AMPA
  • YM 872
  • Heparin
  • Collagenases