K252a prevents nigral Dopaminergic cell death induced by 6-hydroxydopamine through inhibition of both mixed-lineage kinase 3/c-Jun NH2-terminal kinase 3 (JNK3) and apoptosis-inducing kinase 1/JNK3 signaling pathways
K252a prevents nigral Dopaminergic cell death induced by 6-hydroxydopamine through inhibition of both mixed-lineage kinase 3/c-Jun NH2-terminal kinase 3 (JNK3) and apoptosis-inducing kinase 1/JNK3 signaling pathways
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DOI：
10.1124/mol.107.038463
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发表时间：
2007-12-01
影响因子：
3.6
通讯作者：
Chen, Sheng-Di
中科院分区：
文献类型：
--
作者：
Pan, Jing;Wang, Gang;Chen, Sheng-Di
有大量研究表明，丝裂原活化蛋白激酶通路在6-羟基多巴胺（6-OHDA）诱导的大鼠黑质纹状体系统单侧损伤中起着关键作用。近年来的研究表明，混合谱系激酶3（MLK 3）和凋亡诱导激酶1（ASK 1）均参与了缺血诱导的神经元细胞死亡，而这一过程是由MLK 3/ c-Jun氨基末端激酶3（JNK 3）和ASK 1/JNK信号通路介导的。为了研究这些通路是否也与6-OHDA诱导的损伤相关，我们检测了6-OHDA大鼠中MLK 3、ASK 1和JNK 3的磷酸化。结果表明，MLK 3和ASK 1都可以激活JNK 3，然后通过其下游途径（即，核和非核途径）。K252 a具有广泛的作用，包括Trk抑制、MLK 3抑制以及通过与不同靶点的相互作用激活磷脂酰肌醇3激酶和促分裂原活化蛋白激酶激酶信号通路，并且是众所周知的神经保护化合物。我们发现K252 a对6-OHDA损伤诱导的多巴胺能神经元程序性死亡具有保护作用，并且K252 a治疗的6-OHDA大鼠模型的表型得到部分挽救。K252 a对MLK 3/JNK 3和ASK 1/JNK 3的抑制作用可能是6-OHDA损伤与应激激活激酶之间的联系。提示促凋亡MLK 3/JNK 3和ASK 1/JNK 3级联反应在6-OHDA损伤的多巴胺能神经元死亡中起重要作用。因此，JNK 3信号通路可能最终成为治疗帕金森病的新治疗方法的主要靶点，并且K252 a可能在帕金森病的治疗方面作为潜在的和重要的神经保护剂。
It is well documented that the mitogen-activated protein kinase pathway plays a pivotal role in rats with 6-hydroxydopamine (6-OHDA)-induced unilateral lesion in the nigrostriatal system. Our recent studies have shown that mixed-lineage kinase 3 (MLK3) and apoptosis-inducing kinase 1 (ASK1) are all involved in neuronal cell death induced by ischemia, which is mediated by the MLK3/ c-Jun NH2-terminal kinase 3 (JNK3) and ASK1/JNK signaling pathway. To investigate whether these pathways are correlated with 6-OHDA-induced lesion as well, we examined the phosphorylation of MLK3, ASK1, and JNK3 in 6-OHDA rats. The results showed that both MLK3 and ASK1 could activate JNK3 and then subsequently enhance the neuronal death through its downstream pathways (i.e., nuclear and non-nuclear pathway). K252a have wide-range effects including Trk inhibition, MLK3 inhibition, and activation of phosphatidylinositol 3 kinase and mitogen-activated protein kinase kinase signaling pathways through interactions with distinct targets and is a well known neuroprotective compound. We found that K252a could protect dopaminergic neurons against cell program death induced by 6-OHDA lesion, and the phenotypes of 6-OHDA rat model treated with K252a were partial rescued. The inhibition of K252a on the activation of MLK3/JNK3 and ASK1/JNK3 provided a link between 6-OHDA lesion and stress-activated kinases. It suggested that both proapoptotic MLK3/JNK3 and ASK1/JNK3 cascade may play an important role in dopaminergic neuronal death in 6-OHDA insult. Thus, the JNK3 signaling may eventually emerge as a prime target for novel therapeutic approaches to treatment of Parkinson disease, and K252a may serve as a potential and important neuroprotectant in therapeutic aspect in Parkinson disease.