Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia.
The signal transducers and activators of transcription (STAT) proteins are a group of transcriptional factors. Among them, STAT5 initiates a pro-survival signaling cascade. So far, little has been known about the role of STAT5 in cerebral ischemia and reperfusion. This study examines the phosphorylation status of STAT5 in hippocampal CA1 in the early stage after transient global cerebral ischemia in rats. Our data show that the phosphorylation of STAT5 was increased in hippocampal CA1 at 1h and 3h ischemia. Taking advantage of the neuroprotective effect of erythropoietin (EPO) in CA1, we further demonstrated that the administration of EPO enhanced the phosphorylation of STAT5, with SATA5a being phosphorylated earlier. The enhanced phosphorylation of STAT5 in the EPO-treated group was accompanied by the upregulation of STAT5 downstream gene products, Bcl-xL and XIAP. Consequently, ischemic CA1 neuronal damage was attenuated by the administration of EPO. Both the enhancement of STAT5 phosphorylation and the neuroprotection rendered by EPO were blocked by Tyrphostin, a selective inhibitor for Janus kinase 2, which is an upstream kinase of STAT5. These findings suggest an association between the activation of STAT5 and CA1 neuronal survival after cerebral ischemia.
Zhang
Feng
F
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Wang
Suping
S
Cao
Guodong
G
Gao
Yanqin
Y
Chen
Jun
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000473:pathology*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
D018696:Neuroprotective Agents; D050799:STAT5 Transcription Factor; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D004921:Erythropoietin; D053614:Janus Kinase 2