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
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Part of this study was presented at the 9th International Symposium on Pharmacology of Cerebral Ischemia; Marburg, Germany; July 21–24, 2002.
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DOI: 10.1124/jpet.103.064246.
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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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