Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection
| Autor: | Florentino Nombela, Judith Mallolas, Jesús R Morales, Pedro Lorenzo, Ignacio Lizasoain, José Vivancos, Olivia Hurtado, María A. Moro, Alejandro Romera, Marta P. Pereira, Cristina Romera, Joaquín Serena |
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| Rok vydání: | 2007 |
| Předmět: |
Nervous system
Male Pyridines Blotting Western Peroxisome proliferator-activated receptor Gene Expression Glutamic Acid Pharmacology Response Elements Neuroprotection Rosiglitazone Downregulation and upregulation medicine Glutamate aspartate transporter Animals Hypoglycemic Agents RNA Messenger Rats Wistar Ischemic Preconditioning Promoter Regions Genetic Cells Cultured Chromatography High Pressure Liquid chemistry.chemical_classification Neurons biology Reverse Transcriptase Polymerase Chain Reaction Glutamate receptor Brain Infarction Middle Cerebral Artery Coculture Techniques Rats Inbred F344 Rats PPAR gamma medicine.anatomical_structure Neurology Biochemistry chemistry Excitatory Amino Acid Transporter 2 Metabotropic glutamate receptor Astrocytes Benzamides biology.protein Ischemic preconditioning Thiazolidinediones Neurology (clinical) Cardiology and Cardiovascular Medicine |
| Zdroj: | Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 27(7) |
| ISSN: | 0271-678X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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