Guan Q-H, Pei D-S, Zong Y-Y, Xu T-L, Zhang G-Y
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, China.
Neuroscience. 2006 May 12;139(2):609-27. doi: 10.1016/j.neuroscience.2005.11.067. Epub 2006 Feb 28.
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.
我们之前的研究以及其他研究都有力地表明，c-Jun氨基末端激酶（JNK）信号通路在缺血性脑损伤中起关键作用。在此我们报告，JNK相互作用蛋白-1（JIP-1）的Tat-JNK结合结构域（JBD），即与Tat肽偶联的对应于小鼠JIP-1第153 - 163位残基的较小11聚体肽，扰乱了JIP-1 - JNK3复合物的组装，从而抑制了易损海马CA1亚区缺血/再灌注诱导的JNK3激活。结果，Tat-JBD减少了易损海马CA1亚区缺血/再灌注诱导的c-Jun（JNK的核底物）磷酸化增加以及Fas配体表达增加。同时，通过抑制Bcl-2（JNK的胞质靶点）磷酸化以及Bax从Bcl-2/Bax二聚体中的释放，Tat-JBD减弱了缺血/再灌注诱导的Bax转位至线粒体以及细胞色素c的释放。此外，脑缺血/再灌注诱导的caspase3激活和聚ADP核糖聚合酶的水解也被肽Tat-JBD预注射显著抑制。重要的是，Tat-JBD在体内对缺血性脑损伤显示出神经保护作用，缺血后给予该肽也获得了与肽预注射相同的效果。因此，我们的研究结果表明，Tat-JBD通过抑制JNK信号的核途径和非核途径诱导对大鼠海马CA1区缺血/再灌注的神经保护作用。综上所述，这些结果表明Tat-JBD肽为缺血性脑损伤提供了一种有前景的治疗方法。
