Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPAR[gamma] target gene involved in neuroprotection
Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous...
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| Veröffentlicht in: | Journal of cerebral blood flow and metabolism 2007-07, Vol.27 (7), p.1327 |
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| creator | Romera, Cristina Hurtado, Olivia Mallolas, Judith Pereira, Marta P Morales, Jesús R Romera, Alejandro Serena, Joaquín Vivancos, José Nombela, Florentino Lorenzo, Pedro Lizasoain, Ignacio Moro, Maria A |
| description | Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P |
| doi_str_mv | 10.1038/sj.jcbfm.9600438 |
| format | Article |
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Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P<0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARgamma transcriptional activity in neurons and astrocytes (122.1%+/-8.1% and 158.6%+/-22.6% of control PPARgamma transcriptional activity, n=6, P<0.05). Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.</description><identifier>ISSN: 0271-678X</identifier><identifier>EISSN: 1559-7016</identifier><identifier>DOI: 10.1038/sj.jcbfm.9600438</identifier><language>eng</language><publisher>London: Sage Publications Ltd</publisher><ispartof>Journal of cerebral blood flow and metabolism, 2007-07, Vol.27 (7), p.1327</ispartof><rights>Copyright Nature Publishing Group Jul 2007</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids></links><search><creatorcontrib>Romera, Cristina</creatorcontrib><creatorcontrib>Hurtado, Olivia</creatorcontrib><creatorcontrib>Mallolas, Judith</creatorcontrib><creatorcontrib>Pereira, Marta P</creatorcontrib><creatorcontrib>Morales, Jesús R</creatorcontrib><creatorcontrib>Romera, Alejandro</creatorcontrib><creatorcontrib>Serena, Joaquín</creatorcontrib><creatorcontrib>Vivancos, José</creatorcontrib><creatorcontrib>Nombela, Florentino</creatorcontrib><creatorcontrib>Lorenzo, Pedro</creatorcontrib><creatorcontrib>Lizasoain, Ignacio</creatorcontrib><creatorcontrib>Moro, Maria A</creatorcontrib><title>Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPAR[gamma] target gene involved in neuroprotection</title><title>Journal of cerebral blood flow and metabolism</title><description>Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P<0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARgamma transcriptional activity in neurons and astrocytes (122.1%+/-8.1% and 158.6%+/-22.6% of control PPARgamma transcriptional activity, n=6, P<0.05). Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.</description><issn>0271-678X</issn><issn>1559-7016</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNjctKxDAUhoMoWC97lwf37SSt6WVZZLyAi2HoYkBkiJ0zmZQ2qclp38D3toIP4Or_4P_gY-xO8ETwrFyFLunaz-OQVDnnD1l5xiIhZRUXXOTnLOJpIeK8KHeX7CqEjnNeZlJG7Ps1tCccTAujx9bZgyHjrLEaPM6o-gB0UgTPb41Yreu6SUH3E6lBEQJ5ZcPoPKEHE0CBdTP2sNnU23ethkF9ACmvkUCjRTB2dv2MhwXA4uTd6B1h-9u7YRfHpYW3f3vN7p_WzeNLvChfEwbad27ydrn2qaikyLOUZ_-SfgBNu1nO</recordid><startdate>20070701</startdate><enddate>20070701</enddate><creator>Romera, Cristina</creator><creator>Hurtado, Olivia</creator><creator>Mallolas, Judith</creator><creator>Pereira, Marta P</creator><creator>Morales, Jesús R</creator><creator>Romera, Alejandro</creator><creator>Serena, Joaquín</creator><creator>Vivancos, José</creator><creator>Nombela, Florentino</creator><creator>Lorenzo, Pedro</creator><creator>Lizasoain, Ignacio</creator><creator>Moro, Maria A</creator><general>Sage Publications Ltd</general><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20070701</creationdate><title>Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPAR[gamma] target gene involved in neuroprotection</title><author>Romera, Cristina ; Hurtado, Olivia ; Mallolas, Judith ; Pereira, Marta P ; Morales, Jesús R ; Romera, Alejandro ; Serena, Joaquín ; Vivancos, José ; Nombela, Florentino ; Lorenzo, Pedro ; Lizasoain, Ignacio ; Moro, Maria A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_2195163203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Romera, Cristina</creatorcontrib><creatorcontrib>Hurtado, Olivia</creatorcontrib><creatorcontrib>Mallolas, Judith</creatorcontrib><creatorcontrib>Pereira, Marta P</creatorcontrib><creatorcontrib>Morales, Jesús R</creatorcontrib><creatorcontrib>Romera, Alejandro</creatorcontrib><creatorcontrib>Serena, Joaquín</creatorcontrib><creatorcontrib>Vivancos, José</creatorcontrib><creatorcontrib>Nombela, Florentino</creatorcontrib><creatorcontrib>Lorenzo, Pedro</creatorcontrib><creatorcontrib>Lizasoain, Ignacio</creatorcontrib><creatorcontrib>Moro, Maria A</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Journal of cerebral blood flow and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Romera, Cristina</au><au>Hurtado, Olivia</au><au>Mallolas, Judith</au><au>Pereira, Marta P</au><au>Morales, Jesús R</au><au>Romera, Alejandro</au><au>Serena, Joaquín</au><au>Vivancos, José</au><au>Nombela, Florentino</au><au>Lorenzo, Pedro</au><au>Lizasoain, Ignacio</au><au>Moro, Maria A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPAR[gamma] target gene involved in neuroprotection</atitle><jtitle>Journal of cerebral blood flow and metabolism</jtitle><date>2007-07-01</date><risdate>2007</risdate><volume>27</volume><issue>7</issue><spage>1327</spage><pages>1327-</pages><issn>0271-678X</issn><eissn>1559-7016</eissn><abstract>Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P<0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARgamma transcriptional activity in neurons and astrocytes (122.1%+/-8.1% and 158.6%+/-22.6% of control PPARgamma transcriptional activity, n=6, P<0.05). Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.</abstract><cop>London</cop><pub>Sage Publications Ltd</pub><doi>10.1038/sj.jcbfm.9600438</doi></addata></record> |
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| title | Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPAR[gamma] target gene involved in neuroprotection |
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