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.
Footnotes
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This work was supported by grants from the National Program of Basic Research (2006CB500706) of China, National Natural Science Fund (30471918, 30570637), Shanghai Key Project of Basic Science Research (04DZ14005), and Program for Outstanding Medical Academic Leader (LJ 06003).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.038463.
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ABBREVIATIONS: SNc, substantia nigra pars compacta; MAPK, mitogen-activated protein kinase; ASK1, apoptosis-inducing kinase 1; JNK, c-Jun N-terminal protein kinase; MLK, mixed lineage kinase; DMSO, dimethyl sulfoxide; IP, immunoprecipitation; TH, tyrosine hydroxylase; 6-OHDA, 6-hydroxydopaminergic; MOPS, 3-(N-morpholino)propanesulfonic acid; PI3K, phosphatidylinositol 3 kinase; MKK7, mitogen-activated protein kinase kinase 7; AP-1, activator protein 1; CP, caudate-putamen; FasL, Fas ligand; K252a, 9,1-epoxy-1H-diindolo(1,2,3-fg:3′,2′,1′-kl)pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, 2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-, methyl ester, (9-α,10-β,12-α)-; CEP1347, 9,12-epoxy-1H-diindolo(1,2,3-fg:3′,2′,1′-kl)pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, 5,16-bis((ethylthio)methyl)-2,3,9,10, 11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-, methyl ester, (9S-(9α,10β,12α))-; TH-IR, tyrosine hydroxylase immunoreactive.
- Received May 31, 2007.
- Accepted September 11, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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