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Research ArticleNEUROPHARMACOLOGY

AS601245 (1,3-Benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) Acetonitrile): A c-Jun NH2-Terminal Protein Kinase Inhibitor with Neuroprotective Properties

Sonia Carboni, Agnes Hiver, Cedric Szyndralewiez, Pascale Gaillard, Jean-Pierre Gotteland and Pierre-Alain Vitte
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 25-32; DOI: https://doi.org/10.1124/jpet.103.064246
Sonia Carboni
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Agnes Hiver
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Cedric Szyndralewiez
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Pascale Gaillard
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Jean-Pierre Gotteland
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Pierre-Alain Vitte
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Abstract

Recent evidence suggests that activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Thus, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. In the current study, we report that a small molecule, AS601245 (1,3-benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) acetonitrile), which has been shown to inhibit the JNK signaling pathway, promotes cell survival after cerebral ischemia. In vivo, AS601245 (40, 60, and 80 mg/kg) administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and therefore by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection (6, 18, and 60 mg/kg) or as i.v. bolus (1 mg/kg) followed by an i.v. infusion (0.6 mg/kg/h) was also observed in rats after focal cerebral ischemia. These data suggest that the use of JNK inhibitors such as AS601245 may be a relevant strategy in the therapy of ischemic insults.

Footnotes

  • Part of this study was presented at the 9th International Symposium on Pharmacology of Cerebral Ischemia; Marburg, Germany; July 21–24, 2002.

  • DOI: 10.1124/jpet.103.064246.

  • ABBREVIATIONS: JNK, c-Jun NH2-terminal kinase; AP-1, activator protein-1; TNF, tumor necrosis factor; DND, delayed neuronal death; AS601245, 1,3-benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) acetonitrile; MK-801, (-)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine maleate; GST, glutathione S-transferase; PBS, phosphate-buffered saline; LPS, lipopolysaccharide; PBS-T, phosphate-buffered saline-1% Triton X-100; p-c-Jun, phospho-c-Jun; CCA, common carotid artery; ICA, internal carotid artery; MCA, middle cerebral artery; hJNK, human c-Jun NH2-terminal kinase.

    • Received December 11, 2003.
    • Accepted February 25, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleNEUROPHARMACOLOGY

AS601245 (1,3-Benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) Acetonitrile): A c-Jun NH2-Terminal Protein Kinase Inhibitor with Neuroprotective Properties

Sonia Carboni, Agnes Hiver, Cedric Szyndralewiez, Pascale Gaillard, Jean-Pierre Gotteland and Pierre-Alain Vitte
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 25-32; DOI: https://doi.org/10.1124/jpet.103.064246

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Research ArticleNEUROPHARMACOLOGY

AS601245 (1,3-Benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) Acetonitrile): A c-Jun NH2-Terminal Protein Kinase Inhibitor with Neuroprotective Properties

Sonia Carboni, Agnes Hiver, Cedric Szyndralewiez, Pascale Gaillard, Jean-Pierre Gotteland and Pierre-Alain Vitte
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 25-32; DOI: https://doi.org/10.1124/jpet.103.064246
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