The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis.
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.
Department of Surgical Intensive Care Unit, The First Affiliated Hospital, Medical College, Zhejiang University, Qingchun Road 79, Hangzhou, 310003, People's Republic of China.
Guo-Bin
GB
Wang
Yun-Lan
YL
Ni
Xin-Ping
XP
Zhou
Wei-Fang
WF
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002432:Cecum / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004644:Emotions / Q000187:drug effects; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008026:Ligation; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011677:Punctures; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; D004921:Erythropoietin; D000068817:Epoetin Alfa; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases