Ischemic Preconditioning Reveals that GLT1/EAAT2 Glutamate Transporter is a Novel PPARγ 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.1327-1338
Hauptverfasser: 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
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container_issue 7
container_start_page 1327
container_title Journal of cerebral blood flow and metabolism
container_volume 27
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)γ, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARγ 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 μmol/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 PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P < 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]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 μmol/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 PPARγ leading to neuroprotection by increasing glutamate uptake.
doi_str_mv 10.1038/sj.jcbfm.9600438
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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)γ, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARγ 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 μmol/L, respectively, n = 6 to 12, P &lt; 0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P &lt; 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]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 μmol/l, respectively, n = 6 to 12, P &lt; 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. 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First, we found that the PPARγ 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 μmol/L, respectively, n = 6 to 12, P &lt; 0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P &lt; 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]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 μmol/l, respectively, n = 6 to 12, P &lt; 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. 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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)γ, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARγ 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 μmol/L, respectively, n = 6 to 12, P &lt; 0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P &lt; 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]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 μmol/l, respectively, n = 6 to 12, P &lt; 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 PPARγ leading to neuroprotection by increasing glutamate uptake.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><doi>10.1038/sj.jcbfm.9600438</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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title Ischemic Preconditioning Reveals that GLT1/EAAT2 Glutamate Transporter is a Novel PPARγ Target Gene Involved in Neuroprotection
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