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Research ArticleArticle

Neuroprotective Efficacy of YM872, an α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptor Antagonist, after Permanent Middle Cerebral Artery Occlusion in Rats

Masayasu Takahashi, Jian Wei Ni, Sachiko Kawasaki-Yatsugi, Takashi Toya, Chikako Ichiki, Shin-Ichi Yatsugi, Kazuo Koshiya, Masao Shimizu-Sasamata and Tokio Yamaguchi
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 559-566;
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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Chikako Ichiki
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Shin-Ichi Yatsugi
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Kazuo Koshiya
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Masao Shimizu-Sasamata
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Tokio Yamaguchi
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Abstract

The neuroprotective efficacy of YM872, a novel, highly water-soluble α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, was investigated in rats subjected to permanent occlusion of the left middle cerebral artery. The rats were assessed either histologically or neurologically 24 hr or 1 wk after ischemia. YM872 was intravenously infused for either 4 or 24 hr at dose rates of 0 to 20 mg/kg/hr starting 5 min after ischemia to examine the effect of prolonged treatment. YM872 was then infused at 20 mg/kg/hr beginning 0 to 4 hr after ischemia to determine the efficacy time window. Additionally, a 20 mg/kg/hr dose rate of YM872 was infused for 4 hr in single day- or 5-day repetitive-administrations to evaluate long-term benefits of the drug. YM872 significantly reduced infarct volume in both 4- and 24-hr treatment groups measured 24 hr after ischemia. No difference was observed in the degree of protection between length of infusion. Significant neuroprotection was maintained even when drug administration was delayed up to 2 hr after ischemia. A single YM872-administration significantly improved neurological deficit and reduced infarct volume (30%, P < .01) measured 1 wk after ischemia. YM872 treatment did not induce such adverse effects as physiological changes, serious behavioral abnormalities or nephrotoxicity. These data suggest that the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor plays a crucial role in the progression of neuronal damage in the early phase of ischemia and that YM872 may be useful in treating acute ischemic stroke.

Footnotes

  • Send reprint requests to: Dr. Masao Shimizu-Sasamata, Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

  • Abbreviations:
    AMPA
    α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
    ANOVA
    analysis of variance
    MABP
    mean arterial blood pressure
    MCA
    middle cerebral artery
    NBQX
    2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline
    NMDA
    N-methyl-d-aspartate
    TTC
    2,3,5-triphenyltetrazolium hydrochloride
    VSCC
    voltage-sensitive calcium channel
    YM90K
    6-(1H-imidazol-1-yl)-7-nitro-2,3(1H, 4H)-quinoxalinedione monohydrochloride
    [Ca++]i
    intracellular Ca++concentration
    • Received April 30, 1998.
    • Accepted June 17, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Neuroprotective Efficacy of YM872, an α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptor Antagonist, after Permanent Middle Cerebral Artery Occlusion in Rats

Masayasu Takahashi, Jian Wei Ni, Sachiko Kawasaki-Yatsugi, Takashi Toya, Chikako Ichiki, Shin-Ichi Yatsugi, Kazuo Koshiya, Masao Shimizu-Sasamata and Tokio Yamaguchi
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 559-566;

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Research ArticleArticle

Neuroprotective Efficacy of YM872, an α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptor Antagonist, after Permanent Middle Cerebral Artery Occlusion in Rats

Masayasu Takahashi, Jian Wei Ni, Sachiko Kawasaki-Yatsugi, Takashi Toya, Chikako Ichiki, Shin-Ichi Yatsugi, Kazuo Koshiya, Masao Shimizu-Sasamata and Tokio Yamaguchi
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 559-566;
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