Brain Advance Access originally published online on December 5, 2005
Brain 2006 129(2):465-479; doi:10.1093/brain/awh700
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Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence
1 Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, 2 Department of Neurobiology and Biophysics, School of Life Science, University of Science and Technology of China, Hefei and 3 Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Correspondence to: Guang-Yi Zhang, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu, 221002 P.R. China E-mail: gyzhang{at}xzmc.edu.cn
It is well documented that N-methyl-D-aspartate and 
-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors play a pivotal role in ischaemic brain injury. Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6•PSD-95•MLK3 signalling module and subsequent c-Jun N-terminal kinase (JNK) activation. Here we investigate whether GluR6 mediated JNK activation is correlated with ischaemic brain injury. Our results show that cerebral ischaemia followed by reperfusion can enhance the assembly of the GluR6•PSD-95•MLK3 signalling module and JNK activation. As a result, activated JNK can not only phosphorylate the transcription factor c-Jun and up-regulate Fas L expression but can also phosphorylate 14-3-3 and promote Bax translocation to mitochondria, increase the release of cytochrome c and increase caspase-3 activation. These results indicate that GluR6 mediated JNK activation induced by ischaemia/reperfusion ultimately results in neuronal cell death via nuclear and non-nuclear pathways. Furthermore, the peptides we constructed, Tat-GluR6-9c, show a protective role against neuronal death induced by cerebral ischaemia/reperfusion through inhibiting the GluR6 mediated signal pathway. In summary, our results indicate that the KA receptor subunit GluR6 mediated JNK activation is involved in ischaemic brain injury and provides a new approach for stroke therapy.
Key Words: cerebral ischaemia; glutamate receptor 6 (GluR6); mixed lineage kinase-3 (MLK3); c-Jun N-terminalkinase (JNK); Tat protein
Abbreviations:
AMPA = -amino-3-hydroxy-5-methyl-4-isoxazole propionate; KA = kainate; IB = immunoblotting; IP = immunoprecipitation; NMDA = N-methyl-D-aspartate
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Received July 14, 2005. Revised October 3, 2005. Accepted October 26, 2005.
* These authors contributed equally to this work
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