Neuroprotective effects of GluR6 antisense oligodeoxynucleotides on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region

• Published in: Journal of neuroscience research Vol. 82; no. 5; pp. 642 - 649
• Main Authors: Pei, Dong-Sheng, Guan, Qiu-Hua, Sun, Ya-Feng, Zhang, Qing-Xiu, Xu, Tian-Le, Zhang, Guang-Yi
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2005
• Subjects: Animals; Brain Ischemia - drug therapy; Brain Ischemia - genetics; Brain Ischemia - metabolism; Cell Death - drug effects; Cell Death - physiology; Cerebral Infarction - drug therapy; Cerebral Infarction - genetics; Cerebral Infarction - metabolism; cerebral ischemia; Disease Models, Animal; Disks Large Homolog 4 Protein; GluK2 Kainate Receptor; glutamate receptor 6 (GluR6); Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; Injections, Intraventricular; Intracellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Male; MAP Kinase Kinase Kinases; Membrane Proteins - metabolism; Mitogen-Activated Protein Kinase Kinase Kinase 11; Mitogen-Activated Protein Kinase Kinases - metabolism; mixed lineage kinase-3 (MLK3); Nerve Degeneration - drug therapy; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Neuroprotective Agents - pharmacology; Oligodeoxyribonucleotides, Antisense - pharmacology; Phosphorylation - drug effects; postsynaptic density protein 95 (PSD-95); Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid - drug effects; Receptors, Kainic Acid - genetics; Receptors, Kainic Acid - metabolism; Reperfusion Injury - drug therapy; Reperfusion Injury - genetics; Reperfusion Injury - metabolism
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.20669

To investigate whether the kainate (KA) receptors subunit GluR6 is involved in the neuronal cell death induced by cerebral ischemia followed by reperfusion, the antisense oligodeoxynucleotides (ODNs) of GluR6 were used to suppress the expression of GluR6 by intracerebroventricular infusion once per day for 3 days before ischemia. Transient brain ischemia was induced by four‐vessel occlusion in Sprague‐Dawley rats. The effects of GluR6 antisense ODNs on the phosphorylation of MLK3 and JNK and the interactions of MLK3 and PSD‐95 with GluR6 were examined by immunoprecipitation and immunoblotting. Our results show that GluR6 antisense ODNs can knock down the expression of GluR6 and suppress the assembly of the GluR6·PSD‐95·MLK3 signaling module and, therefore, inhibit JNK activation and phosphoralation of c‐jun. On the other hand, the GluR6 antisense ODNs also show a protective role against neuronal cell death induced by cerebral ischemia/reperfusion. Administration of GluR6 antisense ODNs once per day for 3 days before cerebral ischemia significantly decreased neuronal degeneration. In conclusion, our results demonstrate that kainate receptor subunit GluR6 plays an important role in neuronal death induced by cerebral ischemia followed by reperfusion. © 2005 Wiley‐Liss, Inc.