YM872, a novel selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, reduces brain damage after permanent focal cerebral ischemia in cats.

Abstract

YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3, 4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate), a selective, potent and highly water-soluble competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, was investigated for its neuroprotective effect against focal cerebral ischemia in halothane-anesthetized cats. Cats were subjected to permanent occlusion of the left middle cerebral artery for 6 h, then sacrificed and examined histologically. The electroencephalogram and cerebral blood flow were monitored. Intravenous infusion of YM872 starting 10 min after the onset of ischemia at a rate of 2 mg/kg/h for 6 h markedly reduced the volume of ischemic damage by 61% (from 2604 +/- 202 mm3 of the cerebral hemisphere in saline-treated cats to 1025 +/- 277 mm3 in YM872-treated cats; P < .01), as assessed in 12 stereotaxically determined coronal sections. No significant differences were observed between YM872- and saline-treated cats concerning physiological variables including brain temperature. No precipitation of YM872 in the kidney was seen in any YM872-treated animal. The present data further support the notion that the AMPA receptor plays an important role in the progression of focal ischemic damage in a gyrencephalic model. This evidence for the neuroprotective efficacy of YM872 suggests its therapeutic potential in the treatment of acute stroke in humans.

• Authors: M Takahashi, J W Ni, S Kawasaki-Yatsugi, T Toya, S I Yatsugi, M Shimizu-Sasamata, K Koshiya, J I Shishikura, S Sakamoto, T Yamaguchi
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 284 Issue 2 Pg. 467-73 (Feb 1998) ISSN: 0022-3565 [Print] United States
• PMID: 9454786 (Publication Type: Journal Article)

Chemical References

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

Topics

• Animals
• Brain (blood supply)
• Brain Ischemia (drug therapy)
• Cats
• Cerebral Cortex (blood supply)
• Corpus Striatum (blood supply)
• Imidazoles (pharmacology)
• Male
• Neuroprotective Agents
• Quinoxalines (pharmacology)
• Receptors, AMPA (antagonists & inhibitors)
• Regional Blood Flow (drug effects)