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Molecular and Cellular Biochemistry

, Volume 385, Issue 1–2, pp 125–132 | Cite as

The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis

  • Guo-Bin Wang
  • Yun-Lan Ni
  • Xin-Ping Zhou
  • Wei-Fang ZhangEmail author
Article

Abstract

Sepsis is one of the most common causes of mortality in intensive care units. Although sepsis-associated encephalopathy (SAE) is reported to be a leading manifestation of sepsis, its pathogenesis remains to be elucidated. In this study, we investigated whether exogenous recombinant human erythropoietin (rhEPO) could protect brain from neuronal apoptosis in the model of SAE. We showed that application of rhEPO enhanced Bcl-2, decreased Bad in lipopolysaccharide treated neuronal cultures, and improved neuronal apoptosis in hippocampus of cecal ligation and peroration rats. We also found that rhEPO increased the expression of phosphorylated AKT, and the antiapoptotic role of rhEPO could be abolished by phosphoinositide 3-kinase (PI3K)/AKT inhibitor LY294002 or SH-5. In addition, systemic sepsis inhibited the hippocampal-phosphorylated mammalian target of rapamycin (mTOR) and p70S6K (downstream substrates of PKB/AKT signaling), which were restored by administration of exogenous rhEPO. Moreover, treatment with mTOR-signaling inhibitor rapamycin or transfection of mTOR siRNA reversed the neuronal protective effects of rhEPO. Finally, exogenous rhEPO rescued the emotional and spatial cognitive defects without any influence on locomotive activity. These results illustrated that exogenous rhEPO improves brain dysfunction by reducing neuronal apoptosis, and AKT/mTOR signaling is likely to be involved in this process. Application of rhEPO may serve as a potential therapy for the treatment of SAE.

Keywords

Sepsis Apoptosis rhEPO AKT/mTOR signaling Cognitive dysfunction Hippocampus 

Abbreviations

CLP

Cecal ligation and peroration

LPS

Lipopolysaccharide

mTOR

Mammalian target of rapamycin

MWM

Morris water maze

rhEPO

Recombinant human erythropoietin

SAE

Sepsis-associated encephalopathy

TUNEL

Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling

Notes

Conflict of interest

The authors have no financial conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Guo-Bin Wang
    • 1
  • Yun-Lan Ni
    • 1
  • Xin-Ping Zhou
    • 1
  • Wei-Fang Zhang
    • 1
    Email author
  1. 1.Department of Surgical Intensive Care UnitThe First Affiliated Hospital, Medical College, Zhejiang UniversityHangzhouPeople’s Republic of China

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