3-hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats.
A predominantly neurological presentation is common in patients with glutaric acidemia type I (GA-I). 3-hydroxyglutaric acid (3-OHGA), which accumulates in affected patients, has recently been demonstrated to play a central role in the neuropathogenesis of this disease. In the present study, we investigated the in vitro effects of 3-OHGA at concentrations ranging from 10 to 1000 microM on various parameters of the glutamatergic system, such as the basal and potassium-induced release of [3H]glutamate by synaptosomes, as well as on Na+-dependent [3H]glutamate uptake by synaptosomes and astrocytes and Na+-independent [3H]glutamate uptake by synaptic vesicles from cerebral cortex of 30-day-old Wistar rats. First, we observed that exposure of cultured astrocytes to 3-OHGA for 20 h did not reduce their viability. Furthermore, 3-OHGA significantly increased Na+-dependent [3H]glutamate uptake by astrocytes by up to 80% in a dose-dependent manner at doses as low as 30 microM. This effect was not dependent on the presence of the metabolite during the uptake assay, since it occurred even when 3-OHGA was withdrawn from the medium after cultured cells had been exposed to the acid for approximately 1 h. All other parameters investigated were not influenced by this organic acid, indicating a selective action of 3-OHGA on astrocyte transporters. Although the exact mechanisms involved in 3-OHGA-stimulatory effect on astrocyte glutamate uptake are unknown, the present findings contribute to the understanding of the pathophysiology of GA-I, suggesting that astrocytes may protect neurons against excitotoxic damage caused by 3-OHGA by increasing glutamate uptake and therefore reducing the concentration of this excitatory neurotransmitter in the synaptic cleft.
Frizzo
M E S
ME
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, CEP 900035-003, Brazil.
Schwarzbold
C
C
Porciúncula
L O
LO
Dalcin
K B
KB
Rosa
R B
RB
Ribeiro
C A J
CA
Souza
D O
DO
Wajner
M
M
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D005977:Glutarates / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
C108959:3-hydroxyglutaric acid; D005977:Glutarates; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid