Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Abstract

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 1 hour and 3 hours 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.

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

“…11,16,17,31,32 Similarly, the activation of Stat5 by EPO has provided indirect evidence for a contribution of Stat5 in EPO neuroprotection both in animal models of cerebral ischaemia and in neuronal cultures exposed to oxidative stress. 6,[8][9][10] In a recent study, the EPO-induced Stat5 activity and neuroprotection was blocked by the JAK2 inhibitor, AG490. 9 However, AG490 is not completely specific to Stat5 and therefore inhibition of other signalling cascades downstream of JAK2, such as PI3K/ Akt, nuclear factor-kB or Ras/MAPK, cannot be fully excluded.…”

“…6,[8][9][10] In a recent study, the EPO-induced Stat5 activity and neuroprotection was blocked by the JAK2 inhibitor, AG490. 9 However, AG490 is not completely specific to Stat5 and therefore inhibition of other signalling cascades downstream of JAK2, such as PI3K/ Akt, nuclear factor-kB or Ras/MAPK, cannot be fully excluded. 6,7,11,14,15,17,31 Interestingly, the antiapoptotic effect of EPO in neuronal cell lines has been shown to require a combinatorial activation of Akt, Stat5 and MAPK.…”

“…3,4 Recent studies suggest a role for Stat5 in neuronal migration and axon guidance in the developing brain 3 and a novel therapeutic potential for constitutively active Stat5 in reducing axonal outgrowth defects in spinal muscular atrophy-like motor neurons. 5 Since activation of Stat5 in neurons accompanies the antiapoptotic and neuroprotective effects of EPO in vitro and in vivo, [6][7][8][9][10][11][12] Stat5 has been suggested to mediate the protective effects of EPO in neuronal cells. Nevertheless, the molecular mechanisms of EPO receptor (EPOR) activation in neurons are complex, as multiple neuroprotective signalling pathways are activated downstream of EPOR/JAK2.…”

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

“…Targeted genes, including the antiapoptotic protein Bcl-xL, have been implicated in vital cellular processes such as proliferation and survival. [13][14][15][16][17] Furthermore, retroviral transduction of JAK2 V617F into murine hematopoietic stem cells was recently shown to result in the development of a polycythemia-like phenotype. 7,18 The role of JAK2 V617F in splenic EMH has not been previously studied.…”

Neuroprotection in Animal Models of Global Cerebral Ischemia

“…Other Bashkatova et al, 2001Fang et al, 2010;Gaur & Kumar, 2010;Nanri et al, 1998;Pazos et al, 1999;Sinha et al, 2001;Warner et al, 2004. Human albumin Belayev et al, 1999 Cotena et al, 2008 ;Givehchian et al, 2010;Incagnioli et al, 2009;Zhang et al, 2007. Growth Factors BDNF D'Cruz et al, 2002Kiprianova et al, 1999aKiprianova et al, , 1999bLarsson et al, 1999;Popp et al, 2004 Asai et al, 2000;Baumann et al, 2009;Chopp et al, 1988;Colbourne & Corbett, 1994;Dong et al, 2001;Noguchi et al, 2011;Silasi & Colbourne, 2011;Webster et al, 2009;Zhang H. et al, 2010;Zhang Z, et al, 2001.…”