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 (PPARg) 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-D-12,14-prostaglandin J 2 (PGJ 2 , 120 mg/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 PPARg ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARg 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 PPARg ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ 2 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.

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

“…Bcl-2), increases the defense mechanisms against oxidative stress, and mitochondrial damage. In fact, treatment with rosiglitazone increased neuronal glucose uptake, and restored brain ATP levels in stressed rats (48). Additionally, in our studies we observed that PPAR␥ activity is important for the normal function of the mitochondria.…”

BT‐11 improves stress‐induced memory impairments through increment of glucose utilization and total neural cell adhesion molecule levels in rat brains

“…The method described by Garcia-Bueno et al (2007) was used to induce restraint stress. Experiments were carried out during the light period of the circadian cycle.…”

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…15d-PGJ 2 is the proposed endogenous ligand for the gamma isoform of peroxisome proliferator-activated nuclear receptors (PPARγ), a transcription factor whose main effect is to mitigate inflammation by repressing the expression of proinflammatory mediators [6]. PPARγ may be also activated by the antidiabetic thiazolidinedione drugs, which exert anti-inflammatory, antiexcitotoxic, and proenergetic effects in the brains of stressed rats [7,8]. The antioxidant profile of 15d-PGJ 2 / PPARγ may be related to its ability to regulate the nuclear factor erythroid-related factor 2 (NRF2), in brain [9].…”