SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease.
Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study roles of JNK activity in neuronal apoptosis in this model, we blocked JNK activity in vivo using a specific inhibitor of JNK, SP600125. Our data showed that MPTP-induced phospho-c-Jun of substantial nigral neurons, caused apoptosis of dopaminergic neurons, and decreased the dopamine level in striatal area. We found that inhibiting JNK with SP600125 reduced the levels of c-Jun phosphorylation, protected dopaminergic neurons from apoptosis, and partly restored the level of dopamine in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK pathway is the major mediator of the neurotoxic effects of MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to treat PD.
Wang
Wenya
W
Department of Pharmacology, Zhongshan Medical College, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510089, China.
Shi
Leyu
L
Xie
Yuanbin
Y
Ma
Chi
C
Li
Wenming
W
Su
Xingwen
X
Huang
Shoujian
S
Chen
Ruzhu
R
Zhu
Zhenyu
Z
Mao
Zixu
Z
Han
Yifan
Y
Li
Mingtao
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology
D000873:Anthracenes; D004791:Enzyme Inhibitors; C432165:pyrazolanthrone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine