Neuroprotective effects of GluR6 antisense oligodeoxynucleotides on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region.
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.
Pei
Dong-Sheng
DS
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, China.
Guan
Qiu-Hua
QH
Sun
Ya-Feng
YF
Zhang
Qing-Xiu
QX
Xu
Tian-Le
TL
Zhang
Guang-Yi
GY
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor
D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D018696:Neuroprotective Agents; D020319:Oligodeoxyribonucleotides, Antisense; D018092:Kainic Acid Receptors; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor; C501449:Dlg4 protein, rat