title: 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.
abstract: 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.
authors.affiliation: Department of Neurology and Neuroscience Institute, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Hong-Qi
authors.initials: HQ
authors.lastname: Yang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
authors.forename: Qin
authors.initials: Q
authors.lastname: Xiao
authors.forename: Ru-Jing
authors.initials: RJ
authors.lastname: Ren
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D026121:Indole Alkaloids / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D002227:Carbazoles; D004298:Dopamine; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D020930:MAP Kinase Kinase Kinases; D048057:Mitogen-Activated Protein Kinase 10; D016627:Oxidopamine; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C049985:staurosporine aglycone