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 language | English |
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Pages (from-to) | 40-49 |
Number of pages | 10 |
Journal | Neuroscience |
Volume | 150 |
Issue number | 1 |
DOIs | |
Publication status | Published - 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