title: JNK inhibitor protects dopaminergic neurons by reducing COX-2 expression in the MPTP mouse model of subacute Parkinson's disease.
abstract: Increasing evidence suggests that inflammation may be involved in the loss of dopaminergic neurons in Parkinson's disease (PD). Among inflammatory molecules, COX-2, a key kinase for the inflammatory response, has been suggested to play an important role in dopaminergic neuron loss in PD. However, the upstream molecular pathways of COX-2 expression remain uncertain. In the present study, we investigated the role of c-Jun [1] N-terminal kinase (JNK) in the process of COX-2 expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of subacute PD. Our data showed that MPTP induced a transient JNK activation of dopaminergic neurons, upregulated COX-2 expression in dopaminergic neurons, and caused the loss of dopaminergic neurons. We found that inhibiting JNK with SP600125, a special inhibitor of JNK, reduced the levels of c-Jun phosphorylation, blocked p-c-Jun translocation from the cytoplasm to the nucleus in dopaminergic neurons of substantia nigra, mitigated the loss of dopaminergic neurons, and improved motor function in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK signaling pathway may be the major upstream mediator of regulation of COX-2 expression induced by MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to PD.
authors: Department of Anatomy, North China Coal Medical University, Tangshan, 063000, China.
authors: Yongsheng
authors: Y
authors: Wang
authors: Yuxin
authors: Y
authors: Zhang
authors: Zifeng
authors: Z
authors: Wei
authors: Hui
authors: H
authors: Li
authors: Hongxia
authors: H
authors: Zhou
authors: Zhiyong
authors: Z
authors: Zhang
authors: Zuofeng
authors: Z
authors: Zhang
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009069:Movement Disorders / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011897:Random Allocation; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000873:Anthracenes; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; C432165:pyrazolanthrone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D004298:Dopamine