title: Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase (JNK) via nuclear and non-nuclear pathways.
abstract: 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.
authors.affiliation: Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, China. gyzhang@xzmc.edu.cn
authors.forename: Q-H
authors.initials: QH
authors.lastname: Guan
authors.forename: D-S
authors.initials: DS
authors.lastname: Pei
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Zong
authors.forename: T-L
authors.initials: TL
authors.lastname: Xu
authors.forename: G-Y
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013347:Subcellular Fractions / Q000187:drug effects; D048069:Tumor Necrosis Factors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D015696:Gene Products, tat; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; C548497:Tat-JBD peptide; D048069:Tumor Necrosis Factors; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases