Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats.
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 (PPARgamma) 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-Delta-12,14-prostaglandin J2 (PGJ2, 120 microg/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 PPARgamma ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARgamma 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 PPARgamma 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.
García-Bueno
Borja
B
Faculty of Medicine, Department of Pharmacology, University Complutense, Madrid, Spain.
Caso
Javier R
JR
Pérez-Nievas
Beatriz G
BG
Lorenzo
Pedro
P
Leza
Juan C
JC
D000255:Adenosine Triphosphate / Q000378:metabolism; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D003847:Deoxyglucose / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D000077154:Rosiglitazone; D013315:Stress, Psychological / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
D027322:Amino Acid Transport System X-AG; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C493398:Slc1a1 protein, rat; C493395:Slc1a2 protein, rat; D016708:Synaptophysin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C037112:9-deoxy-delta-9-prostaglandin D2; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D005947:Glucose; D015230:Prostaglandin D2; D003345:Corticosterone