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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

Department of Neurology and Neuroscience Institute, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China (J.P., G.W., H.-Q.Y., Z.H., Q.X., R.-J.R., H.-Y.Z., L.B., S.-D.C.); and Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao-Tong University School of Medicine, Shanghai, China (J.P., H.-Q.Y., S.-D.C.)

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.

Address correspondence to: Dr. Sheng-Di Chen, Department of Neurology and Neuroscience Institute, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China. E-mail: chen_sd{at}medmail.com.cn