CEP11004, a novel inhibitor of the mixed lineage kinases, suppresses apoptotic death in dopamine neurons of the substantia nigra induced by 6-hydroxydopamine
CEP11004, a novel inhibitor of the mixed lineage kinases, suppresses apoptotic death in dopamine neurons of the substantia nigra induced by 6-hydroxydopamine
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DOI：
10.1046/j.1471-4159.2003.02176.x
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发表时间：
2004-01-01
影响因子：
4.7
通讯作者：
Burke, RE
中科院分区：
文献类型：
--
作者：
Ganguly, A;Oo, TF;Burke, RE
大量证据表明，导致c-jun磷酸化的激酶级联在介导程序性细胞死亡中起着重要的信号传导作用。我们之前已经证明c-jun在体内黑质多巴胺神经元诱导凋亡的模型中被磷酸化。为了确定这种反应的普遍性和功能意义，我们在6-羟多巴胺诱导多巴胺神经元凋亡的模型中，研究了一种新型混合谱系激酶抑制剂CEP11004的c-jun磷酸化和对细胞死亡的影响。我们发现总c-jun和ser73磷酸化的c-jun的表达在该模型中增加，并且两者都与凋亡形态学共定位。在1.0和3.0 mg/kg剂量下，CEP11004抑制凋亡的水平分别为对照值的44%和58%。它还将酶9的激活形式的阳性谱的数量抑制到大约相等的水平。在这些模型中，CEP11004显著抑制纹状体多巴胺能纤维的损失，仅为对照水平的22%。我们得出结论，c-jun磷酸化是活多巴胺神经元凋亡的一个普遍特征，混合谱系激酶在这些神经元中作为细胞死亡的上游介质发挥功能作用。
There is much evidence that the kinase cascade which leads to the phosphorylation of c-jun plays an important signaling role in the mediation of programmed cell death. We have previously shown that c-jun is phosphorylated in a model of induced apoptotic death in dopamine neurons of the substantia nigra in vivo. To determine the generality and functional significance of this response, we have examined c-jun phosphorylation and the effect on cell death of a novel mixed lineage kinase inhibitor, CEP11004, in the 6-hydroxydopamine model of induced apoptotic death in dopamine neurons. We found that expression of total c-jun and Ser73-phosphorylated c-jun is increased in this model and both colocalize with apoptotic morphology. CEP11004 suppresses apoptotic death to levels of 44 and 58% of control values at doses of 1.0 and 3.0 mg/kg, respectively. It also suppresses, to approximately equal levels, the number of profiles positive for the activated form of capase 9. CEP11004 markedly suppresses striatal dopaminergic fiber loss in these models, to only 22% of control levels. We conclude that c-jun phosphorylation is a general feature of apoptosis in living dopamine neurons and that the mixed lineage kinases play a functional role as up-stream mediators of cell death in these neurons.