Our previous studies and the others have strongly suggested that
c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic
brain injury. Here we reported that Tat-JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), a smaller 11-mer
peptide corresponding to residues 153-163 of murine JIP-1 conjugated to Tat
peptide, perturbed the assembly of JIP-1-JNK3 complexes, thus inhibiting the activation of JNK3 induced by
ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. As a result, Tat-JBD diminished the increased phosphorylation of c-Jun (a nuclear substrate of JNK) and the increased expression of
Fas ligand induced by
ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. At the same time, through inhibiting phosphorylation of Bcl-2 (a cytosolic target of JNK) and the release of Bax from Bcl-2/Bax dimers, Tat-JBD attenuated Bax translocation to mitochondria and the release of
cytochrome c induced by
ischemia/reperfusion. Furthermore, the activation of caspase3 and hydrolyzation of
poly-ADP-ribose-polymerase induced by
brain ischemia/reperfusion were also significantly suppressed by preinfusion of the
peptide Tat-JBD. Importantly, Tat-JBD showed
neuroprotective effects on ischemic brain damage in vivo, and administration of the
peptide after
ischemia also achieved the same effects as preinfusion of the
peptide did. Thus, our findings imply that Tat-JBD induced neuroprotection against
ischemia/reperfusion in rat hippocampal CA1 region via inhibiting nuclear and non-nuclear pathways of JNK signaling. Taken together, these results indicate that
Tat-JBD peptide provides a promising therapeutic approach for ischemic
brain injury.