Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence

• Published in: Brain (London, England : 1878) Vol. 129; no. 2; pp. 465 - 479
• Main Authors: Pei, Dong-Sheng, Wang, Xiao-Tian, Liu, Yong, Sun, Ya-Feng, Guan, Qiu-Hua, Wang, Wei, Yan, Jing-Zhi, Zong, Yan-Yan, Xu, Tian-Le, Zhang, Guang-Yi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.02.2006; Oxford Publishing Limited (England)
• Subjects: AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; Animals; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; c-Jun N-terminalkinase (JNK); Cells, Cultured; cerebral ischaemia; Gene Products, tat - genetics; Gene Products, tat - metabolism; GluK2 Kainate Receptor; glutamate receptor 6 (GluR6); Hippocampus - metabolism; IB = immunoblotting; Immunohistochemistry - methods; In Situ Nick-End Labeling; IP = immunoprecipitation; KA = kainate; Male; MAP Kinase Kinase Kinases; Mitogen-Activated Protein Kinase 10 - metabolism; Mitogen-Activated Protein Kinase Kinase Kinase 11; Mitogen-Activated Protein Kinase Kinases - metabolism; mixed lineage kinase-3 (MLK3); Neurons - metabolism; NMDA = N-methyl-d-aspartate; Patch-Clamp Techniques; Protein Engineering; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid - drug effects; Receptors, Kainic Acid - genetics; Receptors, Kainic Acid - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Signal Transduction; Tat protein
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awh700

It is well documented that N-methyl-D-aspartate and α-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.