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Journal of Pharmacology and Experimental Therapeutics

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OtherNEUROPHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 467-473;
Masayasu Takahashi
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Jian Wei Ni
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Sachiko Kawasaki-Yatsugi
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Takashi Toya
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Sin-Ichi Yatsugi
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Masao Shimizu-Sasamata
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Kazuo Koshiya
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Jun-Ichi Shishikura
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Shuichi Sakamoto
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Tokio Yamaguchi
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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

  • 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
    • Received February 12, 1997.
    • Accepted October 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherNEUROPHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 467-473;

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OtherNEUROPHARMACOLOGY

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
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 467-473;
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