Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation.
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.
Repici
M
M
Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, rue du Bugnon 9, Lausanne CH-1005, Switzerland.
Centeno
C
C
Tomasi
S
S
Forloni
G
G
Bonny
C
C
Vercelli
A
A
Borsello
T
T
D000818:Animals; D000831:Animals, Newborn; D053148:Caspase 3 / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology* / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D010455:Peptides / Q000008:administration & dosage*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; C478085:D-JNKI-1