Elsevier

Neuroscience Letters

Volume 367, Issue 3, 9 September 2004, Pages 355-359
Neuroscience Letters

Indirubin-3′-oxime inhibits c-Jun NH2-terminal kinase: anti-apoptotic effect in cerebellar granule neurons

https://doi.org/10.1016/j.neulet.2004.06.044Get rights and content

Abstract

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-3β), 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 μM, 1.4 μM, and 1.0 μM, 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-3β 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-3β. Our studies give further supports for JNK-targeting strategy in preventing neuronal apoptosis.

Section snippets

Acknowledgments

Mingtao Li was supported by the National Natural Science Foundation of China: nos. 30170299 and 30370450; the Natural Science Foundation of Guangdong Province: nos. 010697, 021803, and 2003A3080402; and the major project grants from the Department of Science and Technology in Guangzhou: nos. 2002Z3-E4031 and 2003Z2-E4081. Zixu Mao was supported by NIH RO1 HD39446 and RO1 NS048254.

References (25)

  • Chinese Pharmacopoeia, vol. 1, People’s Health Publisher, Beijing, 1995, 741...
  • E.T. Coffey et al.

    c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons

    J. Neurosci.

    (2002)
  • Cited by (43)

    • Indirubin 3′-Oxime Inhibits Migration, Invasion, and Metastasis In Vivo in Mice Bearing Spontaneously Occurring Pancreatic Cancer via Blocking the RAF/ERK, AKT, and SAPK/JNK Pathways

      2019, Translational Oncology
      Citation Excerpt :

      In mouse fibroblast NIH/3T3, Indox inhibited the fibroblast growth factor-induced phosphorylation of ERK and AKT, but did not inhibit the phosphorylation of JNK and p38 MAPK [33]. Meanwhile, Indox has been reported to directly inhibit the activity of JNK1 and JNK3 in neuronal cells [34]. Similar to our findings, 5NO2Indox showed inhibitory effects on the phosphorylation of RAF-1, ERK, JNK, and c-Jun, thereby blocking the neoplastic transformation of mouse epidermal cells [35].

    • Indirubin, a bis-indole alkaloid binds to tubulin and exhibits antimitotic activity against HeLa cells in synergism with vinblastine

      2018, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Indirubin (INR) and its derivatives have shown anticancer effects on different cancer cell lines like PC3, HepG2, HCT116, HeLa, A549, NCI-H358, MDA-MB-468, and MDA-MB-435 [2,6–9]. Indirubin has been reported to modulate cellular targets like aryl hydrocarbon receptor [10,11], glycogen synthase kinase-3 [12], glycogen phosphorylase b [13], c-Jun N-terminal kinase [14], the Stat3 transcription factor [15], and DNA synthesis [2]. Inhibition of several kinases involved in cell division was reasoned for the possible G2/M phase arrest induced by indirubin and its analogues in cancer cells [2,7,8].

    View all citing articles on Scopus
    View full text