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
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
