YM872, a Novel Selective α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Antagonist, Reduces Brain Damage after Permanent Focal Cerebral Ischemia in Cats
- Masayasu Takahashi,
- Jian Wei Ni,
- Sachiko Kawasaki-Yatsugi,
- Takashi Toya,
- Sin-Ichi Yatsugi,
- Masao Shimizu-Sasamata,
- Kazuo Koshiya,
- Jun-Ichi Shishikura,
- Shuichi Sakamoto and
- Tokio Yamaguchi
- Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 305, Japan
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 α-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.
Footnotes
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Send reprint requests to: Masayasu Takahashi, M.S., Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan.
- Abbreviations:
- AMPA
- α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
- CBF
- cerebral blood flow
- CGS19755
- cis-4-phosphonomethyl-2-piperidine carboxylic acid
- CSF
- cerebrospinal fluid
- d-CPP-ene
- d-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxilic acid
- EEG
- electroencephalogram
- HPLC
- high-performance liquid chromatography
- LDF
- laser Doppler flowmetry
- LY-293558
- (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid
- MCA
- middle cerebral artery
- NBQX
- 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline
- NMDA
- N-methyl-d-aspartate
- VSCC
- voltage-sensitive calcium channel
- YM90K
- [6-(1H-imidazol-1-yl)-7-nitro-2, 3(1H, 4H)-quinoxalinedione monohydrochloride
- MABP
- mean arterial blood pressure
- ANOVA
- analysis of variance
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- Received February 12, 1997.
- Accepted October 27, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
