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

Neuroscience. 2007 Nov 30;150(1):40-9. doi: 10.1016/j.neuroscience.2007.08.021. Epub 2007 Aug 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Caspase 3 / metabolism*
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Infarction, Middle Cerebral Artery / enzymology*
  • Infarction, Middle Cerebral Artery / prevention & control*
  • 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


  • Peptides
  • Proto-Oncogene Proteins c-jun
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 3
  • D-JNKI-1