Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation

M Repici, C Centeno, S Tomasi, G Forloni, C Bonny, A Vercelli, T Borsello

Research output: Contribution to journalArticle

Abstract

The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. The d-retro-inverso form of c-Jun N-terminal kinase-inhibitor (D-JNKI1), a cell-permeable inhibitor of JNK, powerfully reduces neuronal death induced by permanent and transient ischemia, even when administered 6 h after the ischemic insult, offering a clinically relevant window. We investigated the JNK molecular cascade activation in rat cerebral ischemia and the effects of D-JNKI1 on this cascade. c-Jun activation starts after 3 h after ischemia and peaks at 6 h in the ischemic core and in the penumbra at 1 h and at 6 h respectively. The 6 h c-Jun activation peak correlates well with that of P-JNK. We also examined the activation of the two direct JNK activators, MAP kinase kinase 4 (MKK4) and MAP kinase kinase 7 (MKK7). MKK4 showed the same time course as JNK in both core and penumbra, reaching peak activation at 6 h. MKK7 did not show any significant increase of phosphorylation in either core or penumbra. D-JNKI1 markedly prevented the increase of P-c-Jun in both core and penumbra and powerfully inhibited caspase-3 activation in the core. These results confirm that targeting the JNK cascade using the TAT cell-penetrating peptide offers a promising therapeutic approach for ischemia, raising hopes for human neuroprotection, and elucidates the molecular pathways leading to and following JNK activation.

Original languageEnglish
Pages (from-to)40-49
Number of pages10
JournalNeuroscience
Volume150
Issue number1
DOIs
Publication statusPublished - 30 Nov 2007

Keywords

  • Animals
  • Animals, Newborn
  • Caspase 3/metabolism
  • Disease Models, Animal
  • Enzyme Activation/drug effects
  • Infarction, Middle Cerebral Artery/enzymology
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • Male
  • Peptides/administration & dosage
  • Proto-Oncogene Proteins c-jun/metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction/drug effects
  • Time Factors

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