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NEUROPHARMACOLOGY

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

Departments of Pharmacology (S.C., A.H., C.S., P.-A.V.) and Chemistry (P.G., J.-P.G.), Serono Pharmaceutical Research Institute, Geneva, Switzerland

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.

Address correspondence to: Dr. Pierre-Alain Vitte, Department of Pharmacology, Serono Pharmaceutical Research Institute, 14, Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland. E-mail: pierre-alain.vitte{at}serono.com

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