PT - JOURNAL ARTICLE AU - Jing Pan AU - Gang Wang AU - Hong-Qi Yang AU - Zhen Hong AU - Qin Xiao AU - Ru-Jing Ren AU - Hai-Yan Zhou AU - Li Bai AU - Sheng-Di Chen TI - K252a Prevents Nigral Dopaminergic Cell Death Induced by 6-Hydroxydopamine through Inhibition of Both Mixed-Lineage Kinase 3/c-Jun NH<sub>2</sub>-Terminal Kinase 3 (JNK3) and Apoptosis-Inducing Kinase 1/JNK3 Signaling Pathways AID - 10.1124/mol.107.038463 DP - 2007 Dec 01 TA - Molecular Pharmacology PG - 1607--1618 VI - 72 IP - 6 4099 - http://molpharm.aspetjournals.org/content/72/6/1607.short 4100 - http://molpharm.aspetjournals.org/content/72/6/1607.full SO - Mol Pharmacol2007 Dec 01; 72 AB - 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. The American Society for Pharmacology and Experimental Therapeutics