1. ¹Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
2. ²Department of Neurology, Hospital Universitario Doctor Josep Trueta, Girona, Spain
3. ³Hospital Clinico Universitario San Carlos, Madrid, Spain
4. ⁴Department of Neurology, Hospital Universitario La Princesa, Madrid, Spain

Correspondence: Dr O Hurtado, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain. E-mail: neurona@med.ucm.es

Received 17 April 2006; Revised 10 September 2006; Accepted 19 November 2006; Published online 10 January 2007.

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) , known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPAR 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 mol/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 PPAR transcriptional activity in neurons and astrocytes (122.1%8.1% and 158.6%22.6% of control PPAR transcriptional activity, n=6, P<0.05). Second, the PPAR 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 mol/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 PPAR leading to neuroprotection by increasing glutamate uptake.