Indirubin-3'-oxime inhibits c-Jun NH2-terminal kinase: anti-apoptotic effect in cerebellar granule neurons.
Previous studies have demonstrated that c-Jun NH2-terminal protein kinase (JNK) plays a crucial role in neuronal apoptosis. Here, we report that indirubin-3'-oxime, a known effective inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3-beta (GSK-3beta), has a significant inhibitory effect on JNK. Kinase assay showed that indirubin-3'-oxime directly inhibited the activity of all three isoforms of JNK (JNK1, and JNK3) in vitro, with half inhibition dose (IC50) of 0.8 microM, 1.4 microM, and 1.0 microM, respectively. In cerebellar granule neurons (CGNs), indirubin-3'-oxime blocked c-Jun phosphorylation induced by potassium withdrawal and prevented CGNs from apoptosis in a dose dependent manner. However, inhibitors of CDKs and GSK-3beta were ineffective in reducing c-Jun phosphorylation both in vitro and in vivo, suggesting that indirubin-3'-oxime prevents c-Jun phosphorylation independent of its inhibition on CDKs and GSK-3beta. Our studies give further supports for JNK-targeting strategy in preventing neuronal apoptosis.
Xie
Yuanbin
Y
Department of Pharmacology, Zhongshan Medical College, SUN Yat-sen University, No 74, Zhongshan Rd 2, Guangzhou 510080, China.
Liu
Yanling
Y
Ma
Chi
C
Yuan
Zhongmin
Z
Wang
Wenya
W
Zhu
Zhenyu
Z
Gao
Guoquan
G
Liu
Xianguo
X
Yuan
Hengxin
H
Chen
Ruzhu
R
Huang
Shoujian
S
Wang
Xuelan
X
Zhu
Xiaonan
X
Wang
Xuemin
X
Mao
Zixu
Z
Li
Mingtao
M
D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000633:toxicity; D051381:Rats
D000873:Anthracenes; D004791:Enzyme Inhibitors; D007211:Indoles; D010091:Oximes; C474021:indirubin-3'-monoxime; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D011188:Potassium