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

65 Citations (Scopus)

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 - Nov 30 2007

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JNK Mitogen-Activated Protein Kinases
Brain Ischemia
Caspase 3
Phosphotransferases
MAP Kinase Kinase Kinase 4
Ischemia
MAP Kinase Kinase 7
MAP Kinase Kinase 4
Cell-Penetrating Peptides
MAP Kinase Kinase Kinases
Brain Injuries
D-JNKI-1
Phosphorylation

Keywords

  • MAPK
  • middle cerebral artery occlusion
  • neuronal death
  • neuroprotection
  • TAT-permeable peptide

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation. / Repici, M.; Centeno, C.; Tomasi, S.; Forloni, G.; Bonny, C.; Vercelli, A.; Borsello, T.

In: Neuroscience, Vol. 150, No. 1, 30.11.2007, p. 40-49.

Research output: Contribution to journalArticle

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