Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection
Version of Record online: 13 JAN 2003
Journal of Neurochemistry
Volume 84, Issue 3, pages 566–575, February 2003
How to Cite
Chen, R.-W., Qin, Z.-H., Ren, M., Kanai, H., Chalecka-Franaszek, E., Leeds, P. and Chuang, D.-M. (2003), Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection. Journal of Neurochemistry, 84: 566–575. doi: 10.1046/j.1471-4159.2003.01548.x
- Issue online: 13 JAN 2003
- Version of Record online: 13 JAN 2003
- Received August 29, 2002; revised manuscript received October 18, 2002; accepted October 21, 2002.
- lithium neuroprotection;
- p53 phosphorylation
In rat cerebellar granule cells, glutamate induced rapid activation of c-Jun N-terminal kinase (JNK) and p38 kinase to phosphorylate c-Jun (at Ser63) and p53 (at Ser15), respectively, and a subsequent marked increase in activator protein-1 (AP-1) binding that preceded apoptotic death. These glutamate-induced effects and apoptosis could largely be prevented by long-term (7 days) pretreatment with 0.5–2 mm lithium, an antibipolar drug. Glutamate's actions could also be prevented by known blockers of this pathway, MK-801 (an NMDA receptor blocker), SB 203580 (a p38 kinase inhibitor) and curcumin (an AP-1 binding inhibitor). The concentration- and time-dependent suppression of glutamate's effects by lithium and curcumin correlated well with their neuroprotective effects. These results suggest a prominent role of JNK and p38, as well as their downstream AP-1 binding activation and p53 phosphorylation in mediating glutamate excitotoxicity. Moreover, the neuroprotective effects of lithium are mediated, at least in part, by suppressing NMDA receptor-mediated activation of the mitogen-activated protein kinase pathway.