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Scientific article
English

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

Published inThe Journal of pharmacology and experimental therapeutics, vol. 310, no. 1, p. 25-32
Publication date2004
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.

Keywords
  • Acetonitriles/pharmacology/therapeutic use
  • Animals
  • Benzothiazoles
  • Brain Ischemia/complications/etiology/prevention & control
  • Disease Models, Animal
  • Gerbillinae
  • JNK Mitogen-Activated Protein Kinases
  • Lipopolysaccharides/pharmacology
  • Mice
  • Mice, Inbred C3H
  • Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
  • Neuroprotective Agents/pharmacology/therapeutic use
  • Phosphorylation/drug effects
  • Rats
  • Rats, Wistar
  • Thiazoles/pharmacology/therapeutic use
  • Tumor Necrosis Factor-alpha/metabolism
Affiliation Not a UNIGE publication
Citation (ISO format)
CARBONI, Sonia et al. 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. In: The Journal of pharmacology and experimental therapeutics, 2004, vol. 310, n° 1, p. 25–32. doi: 10.1124/jpet.103.064246
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Article (Published version)
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ISSN of the journal0022-3565
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