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
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
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DOI：
10.1124/jpet.103.064246
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发表时间：
2004-07-01
影响因子：
3.5
通讯作者：
Vitte, PA
中科院分区：
文献类型：
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作者：
Carboni, S;Hiver, A;Vitte, PA
最近的证据表明，c-Jun氨基末端蛋白激酶（JNK）信号转导通路的激活可能在缺血诱导的细胞死亡中发挥作用。因此，防止JNK或c-Jun磷酸化的激活可能具有神经保护作用。在目前的研究中，我们报告了一种小分子，AS 601245（1，3-苯并噻唑-2-基（2-{[2-（3-吡啶基）乙基]氨基}-4嘧啶基）乙腈），它已被证明可以抑制JNK信号通路，促进脑缺血后的细胞存活。在体内，在短暂性全脑缺血的沙鼠模型中，腹腔注射AS 601245（40、60和80 mg/kg）可显著保护海马CA 1区神经元的延迟性丢失。这种作用是由JNK抑制介导的，因此是由c-Jun表达和磷酸化介导的。在大鼠局灶性脑缺血后，还观察到AS 601245通过i. p.注射（6、18和60 mg/kg）或i. v.推注（1 mg/kg）后i. v.输注（0.6 mg/kg/h）给药的显著神经保护作用。这些数据表明，使用JNK抑制剂如AS 601245可能是治疗缺血性损伤的相关策略。
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.