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Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection.
J Cereb Blood Flow Metab. 2007 Jul; 27(7):1327-38.JC

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.

Authors+Show Affiliations

Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17213861

Citation

Romera, Cristina, et al. "Ischemic Preconditioning Reveals That GLT1/EAAT2 Glutamate Transporter Is a Novel PPARgamma Target Gene Involved in Neuroprotection." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 27, no. 7, 2007, pp. 1327-38.
Romera C, Hurtado O, Mallolas J, et al. Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection. J Cereb Blood Flow Metab. 2007;27(7):1327-38.
Romera, C., Hurtado, O., Mallolas, J., Pereira, M. P., Morales, J. R., Romera, A., Serena, J., Vivancos, J., Nombela, F., Lorenzo, P., Lizasoain, I., & Moro, M. A. (2007). Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 27(7), 1327-38.
Romera C, et al. Ischemic Preconditioning Reveals That GLT1/EAAT2 Glutamate Transporter Is a Novel PPARgamma Target Gene Involved in Neuroprotection. J Cereb Blood Flow Metab. 2007;27(7):1327-38. PubMed PMID: 17213861.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection. AU - Romera,Cristina, AU - Hurtado,Olivia, AU - Mallolas,Judith, AU - Pereira,Marta P, AU - Morales,Jesús R, AU - Romera,Alejandro, AU - Serena,Joaquín, AU - Vivancos,José, AU - Nombela,Florentino, AU - Lorenzo,Pedro, AU - Lizasoain,Ignacio, AU - Moro,Maria A, Y1 - 2007/01/10/ PY - 2007/1/11/pubmed PY - 2007/10/5/medline PY - 2007/1/11/entrez SP - 1327 EP - 38 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J Cereb Blood Flow Metab VL - 27 IS - 7 N2 - 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. SN - 0271-678X UR - https://www.unboundmedicine.com/medline/citation/17213861/Ischemic_preconditioning_reveals_that_GLT1/EAAT2_glutamate_transporter_is_a_novel_PPARgamma_target_gene_involved_in_neuroprotection_ L2 - https://journals.sagepub.com/doi/10.1038/sj.jcbfm.9600438?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -