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

J Neurochem. 2003 Feb;84(3):566-75. doi: 10.1046/j.1471-4159.2003.01548.x.

Abstract

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.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cells, Cultured
  • Cerebellum / cytology
  • DNA / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / toxicity
  • JNK Mitogen-Activated Protein Kinases
  • Lithium / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology
  • Phosphorylation / drug effects
  • Protein Binding / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Time
  • Transcription Factor AP-1 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Transcription Factor AP-1
  • Tumor Suppressor Protein p53
  • Glutamic Acid
  • DNA
  • Lithium
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases