Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

Abstract

Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-Δ-12,14-prostaglandin J2 (PGJ2, 120 μg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARγ ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARγ ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARγ ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.