TY - JOUR T1 - AS601245 (1,3-Benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) Acetonitrile): A c-Jun NH<sub>2</sub>-Terminal Protein Kinase Inhibitor with Neuroprotective Properties JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 25 LP - 32 DO - 10.1124/jpet.103.064246 VL - 310 IS - 1 AU - Sonia Carboni AU - Agnes Hiver AU - Cedric Szyndralewiez AU - Pascale Gaillard AU - Jean-Pierre Gotteland AU - Pierre-Alain Vitte Y1 - 2004/07/01 UR - http://jpet.aspetjournals.org/content/310/1/25.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -