Neuroprotection against transient focal cerebral ischemia and oxygen-glucose deprivation by interference with GluR6-PSD95 protein interaction.
Previous studies have shown that KA receptor subunit GluR6 mediated c-Jun N-terminal protein kinase (JNK) signaling is involved in global ischemia injury. Our present study indicates that focal ischemic brain insult on rat middle cerebral artery occlusion (MACo) model enhances the assembly of the GluR6-PSD95-MLK3 module and facilitates the phosphorylation of JNK. Most importantly, a peptide containing the TAT protein transduction sequence, Tat-GluR6-9c, can perturb the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK7/4 and JNK. As result, the inhibition of JNK activation caused by Tat-GluR6-9c diminishes the phosphorylation of the transcription factor c-Jun, down-regulates FasL expression and attenuates bax translocation, release of cytochrome c and the activation of caspase-3. Furthermore, MCAo induced infract volume is reduced by intracerebroventricular injection of Tat-Glur6-9c. Oxygen-glucose-deprivation (OGD) cultured cortical neuronal cell also shows an improved cell viability by application of Tat-GluR6-9c. Taken together, our findings strongly suggest that GluR6-PSD95-MLK3 signaling module mediated activation of nuclear and non-nuclear pathways of JNK activation are involved in focal ischemia injury and OGD. Tat-GluR6-9c, the peptide we constructed, gives a new insight into the therapy for ischemic stroke.
Yu
Chang-Zhou
CZ
Research Center of Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu, People's Republic of China.
Li
Chong
C
Pei
Dong-Sheng
DS
Zong
Yan-Yan
YY
Shi
Qiong
Q
Wen
Xiang-Ru
XR
Guan
Qiu-Hua
QH
Hang
Dong
D
Hou
Xiao-Yu
XY
Zhang
Guang-Yi
GY
D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005947:Glucose / Q000172:deficiency*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*; D000097806:GluK2 Kainate Receptor
D000076122:Disks Large Homolog 4 Protein; D005947:Glucose; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010100:Oxygen; D018092:Kainic Acid Receptors; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D000097806:GluK2 Kainate Receptor; C501449:Dlg4 protein, rat