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 erythropoie...
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| Veröffentlicht in: | Molecular and cellular biochemistry 2014-01, Vol.385 (1-2), p.125-132 |
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| creator | Wang, Guo-Bin Ni, Yun-Lan Zhou, Xin-Ping Zhang, Wei-Fang |
| description | 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. |
| doi_str_mv | 10.1007/s11010-013-1821-5 |
| format | Article |
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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.</description><identifier>ISSN: 0300-8177</identifier><identifier>EISSN: 1573-4919</identifier><identifier>DOI: 10.1007/s11010-013-1821-5</identifier><identifier>PMID: 24057122</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Analysis ; Animals ; Apoptosis ; Apoptosis - drug effects ; bcl-Associated Death Protein - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Biomedical research ; Brain - drug effects ; Brain - pathology ; Brain - physiopathology ; Cardiology ; Cecum - pathology ; Cognition - drug effects ; Emotions - drug effects ; Epoetin Alfa ; Erythrocytes ; Erythropoietin ; Erythropoietin - administration & dosage ; Erythropoietin - pharmacology ; Erythropoietin - therapeutic use ; Health aspects ; Hospitals ; Humans ; Infection ; Life Sciences ; Ligation ; Locomotives ; Male ; Medical Biochemistry ; Mitogens ; Neurons ; Neurons - drug effects ; Neurons - metabolism ; Neurons - pathology ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; Oncology ; Pathogenesis ; Phosphorylation - drug effects ; Proto-Oncogene Proteins c-akt - metabolism ; Punctures ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins - administration & dosage ; Recombinant Proteins - pharmacology ; Recombinant Proteins - therapeutic use ; Sepsis ; Sepsis - drug therapy ; Sepsis - pathology ; Sepsis - physiopathology ; Signal Transduction - drug effects ; Studies ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Molecular and cellular biochemistry, 2014-01, Vol.385 (1-2), p.125-132</ispartof><rights>Springer Science+Business Media New York 2013</rights><rights>COPYRIGHT 2014 Springer</rights><rights>Springer Science+Business Media New York 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-9aff5c73bcd487ae3bb61bf2612ff416250ff134d7ca40102a787e0851de35543</citedby><cites>FETCH-LOGICAL-c620t-9aff5c73bcd487ae3bb61bf2612ff416250ff134d7ca40102a787e0851de35543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11010-013-1821-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11010-013-1821-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27911,27912,41475,42544,51306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24057122$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Guo-Bin</creatorcontrib><creatorcontrib>Ni, Yun-Lan</creatorcontrib><creatorcontrib>Zhou, Xin-Ping</creatorcontrib><creatorcontrib>Zhang, Wei-Fang</creatorcontrib><title>The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis</title><title>Molecular and cellular biochemistry</title><addtitle>Mol Cell Biochem</addtitle><addtitle>Mol Cell Biochem</addtitle><description>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.</description><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>bcl-Associated Death Protein - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical research</subject><subject>Brain - drug effects</subject><subject>Brain - pathology</subject><subject>Brain - physiopathology</subject><subject>Cardiology</subject><subject>Cecum - pathology</subject><subject>Cognition - drug effects</subject><subject>Emotions - drug effects</subject><subject>Epoetin Alfa</subject><subject>Erythrocytes</subject><subject>Erythropoietin</subject><subject>Erythropoietin - administration & dosage</subject><subject>Erythropoietin - pharmacology</subject><subject>Erythropoietin - therapeutic use</subject><subject>Health aspects</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Infection</subject><subject>Life Sciences</subject><subject>Ligation</subject><subject>Locomotives</subject><subject>Male</subject><subject>Medical Biochemistry</subject><subject>Mitogens</subject><subject>Neurons</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Oncology</subject><subject>Pathogenesis</subject><subject>Phosphorylation - drug effects</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Punctures</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recombinant Proteins - administration & dosage</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Sepsis</subject><subject>Sepsis - drug therapy</subject><subject>Sepsis - pathology</subject><subject>Sepsis - physiopathology</subject><subject>Signal Transduction - drug effects</subject><subject>Studies</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0300-8177</issn><issn>1573-4919</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkl1rFDEUhoModq3-AG9kwBtvps3JxyR7uRS_sFCQ7XXIzJx0U2YmY5JR9t-bdatWUZEEEpLnPefk5CXkOdAzoFSdJwAKtKbAa9AMavmArEAqXos1rB-SFeWU1hqUOiFPUrqlBaYAj8kJE1QqYGxFrrc7rDYftufj9upjNdu8-2L31Yi9txlTNeESw2SHao4hY5f9Z6zQubJLVXAVxn3exTAHj9lPVZkJ5-TTU_LI2SHhs7v1lFy_eb29eFdfXr19f7G5rLuG0VyvrXOyU7zteqGVRd62DbSONcCcE9AwSZ0DLnrVWVGKZ1ZphVRL6JFLKfgpeXWMW8r7tGDKZvSpw2GwE4YlGRANA61BH9CXv6G3YYnlad8oaDgviX5SN3ZA4ycXcrTdIajZCMGF1pKyf1JcCi3XEnihzv5AldHj6LswofPl_Jew_yW4nwGOgi6GlCI6M0c_2rg3QM3BIeboEFMcYg4OMbJoXtz1YWnLN_9QfLdEAdgRSOVqusF4r1F_jfoVIK_Big</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Wang, Guo-Bin</creator><creator>Ni, Yun-Lan</creator><creator>Zhou, Xin-Ping</creator><creator>Zhang, Wei-Fang</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20140101</creationdate><title>The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis</title><author>Wang, Guo-Bin ; Ni, Yun-Lan ; Zhou, Xin-Ping ; Zhang, Wei-Fang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-9aff5c73bcd487ae3bb61bf2612ff416250ff134d7ca40102a787e0851de35543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - 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Academic</collection><jtitle>Molecular and cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Guo-Bin</au><au>Ni, Yun-Lan</au><au>Zhou, Xin-Ping</au><au>Zhang, Wei-Fang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis</atitle><jtitle>Molecular and cellular biochemistry</jtitle><stitle>Mol Cell Biochem</stitle><addtitle>Mol Cell Biochem</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>385</volume><issue>1-2</issue><spage>125</spage><epage>132</epage><pages>125-132</pages><issn>0300-8177</issn><eissn>1573-4919</eissn><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.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>24057122</pmid><doi>10.1007/s11010-013-1821-5</doi><tpages>8</tpages></addata></record> |
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| ispartof | Molecular and cellular biochemistry, 2014-01, Vol.385 (1-2), p.125-132 |
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| subjects | Analysis Animals Apoptosis Apoptosis - drug effects bcl-Associated Death Protein - metabolism Biochemistry Biomedical and Life Sciences Biomedical research Brain - drug effects Brain - pathology Brain - physiopathology Cardiology Cecum - pathology Cognition - drug effects Emotions - drug effects Epoetin Alfa Erythrocytes Erythropoietin Erythropoietin - administration & dosage Erythropoietin - pharmacology Erythropoietin - therapeutic use Health aspects Hospitals Humans Infection Life Sciences Ligation Locomotives Male Medical Biochemistry Mitogens Neurons Neurons - drug effects Neurons - metabolism Neurons - pathology Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Oncology Pathogenesis Phosphorylation - drug effects Proto-Oncogene Proteins c-akt - metabolism Punctures Rats Rats, Sprague-Dawley Recombinant Proteins - administration & dosage Recombinant Proteins - pharmacology Recombinant Proteins - therapeutic use Sepsis Sepsis - drug therapy Sepsis - pathology Sepsis - physiopathology Signal Transduction - drug effects Studies TOR Serine-Threonine Kinases - metabolism |
| title | The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis |
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