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Research ArticleNEUROPHARMACOLOGY

SEA0400, a Novel and Selective Inhibitor of the Na+-Ca2+ Exchanger, Attenuates Reperfusion Injury in the in Vitro and in Vivo Cerebral Ischemic Models

Toshio Matsuda, Naohisa Arakawa, Kazuhiro Takuma, Yoko Kishida, Yasushi Kawasaki, Masaki Sakaue, Kenzo Takahashi, Teisuke Takahashi, Taizo Suzuki, Tomomi Ota, Akiko Hamano-Takahashi, Michihito Onishi, Yu Tanaka, Kazuya Kameo and Akemichi Baba
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 249-256;
Toshio Matsuda
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Naohisa Arakawa
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Kazuhiro Takuma
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Yoko Kishida
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Yasushi Kawasaki
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Masaki Sakaue
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Kenzo Takahashi
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Teisuke Takahashi
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Taizo Suzuki
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Tomomi Ota
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Akiko Hamano-Takahashi
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Michihito Onishi
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Yu Tanaka
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Kazuya Kameo
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Akemichi Baba
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Abstract

The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 μM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.

Footnotes

  • This work was supported by a grant from the Ministry of Education, Sciences, Sports, and Culture of Japan.

  • Abbreviations:
    NCX
    Na+-Ca2+exchanger
    [Ca2+]i
    intracellular Ca2+ concentration
    KB-R7943
    2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
    DHP
    dihydropyridine
    SOCE
    store-operated Ca2+ entry
    ROS
    reactive oxygen species
    SEA0400
    2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline
    FCS
    fetal calf serum
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    H2DCF
    2′,7′-dichlorofluorescein diacetate
    MEM
    Eagle's minimum essential medium
    HBSS
    Hanks' balanced saline solution
    cNOS
    constitutive nitric-oxide synthetase
    CPA
    cyclopiazonic acid
    MCA
    middle cerebral artery
    NE
    norepinephrine
    LTB4
    leukotriene B4
    mACh
    muscarinic acetylcholine
    PAF
    platelet-activating factor
    • Received December 14, 2000.
    • Accepted March 23, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleNEUROPHARMACOLOGY

SEA0400, a Novel and Selective Inhibitor of the Na+-Ca2+ Exchanger, Attenuates Reperfusion Injury in the in Vitro and in Vivo Cerebral Ischemic Models

Toshio Matsuda, Naohisa Arakawa, Kazuhiro Takuma, Yoko Kishida, Yasushi Kawasaki, Masaki Sakaue, Kenzo Takahashi, Teisuke Takahashi, Taizo Suzuki, Tomomi Ota, Akiko Hamano-Takahashi, Michihito Onishi, Yu Tanaka, Kazuya Kameo and Akemichi Baba
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 249-256;

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Research ArticleNEUROPHARMACOLOGY

SEA0400, a Novel and Selective Inhibitor of the Na+-Ca2+ Exchanger, Attenuates Reperfusion Injury in the in Vitro and in Vivo Cerebral Ischemic Models

Toshio Matsuda, Naohisa Arakawa, Kazuhiro Takuma, Yoko Kishida, Yasushi Kawasaki, Masaki Sakaue, Kenzo Takahashi, Teisuke Takahashi, Taizo Suzuki, Tomomi Ota, Akiko Hamano-Takahashi, Michihito Onishi, Yu Tanaka, Kazuya Kameo and Akemichi Baba
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 249-256;
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