In vitro effects of D-2-hydroxyglutaric acid on glutamate binding, uptake and release in cerebral cortex of rats.
Neurological dysfunction is common in patients with D-2-hydroxyglutaric aciduria (DHGA). However, the mechanisms underlying the neuropathology of this disorder are far from understood. In the present study, we investigated the in vitro effects of D-2-hydroxyglutaric acid (DGA) at various concentrations (0.1-1.0 mM) on various parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[3H]glutamate by synaptosomal preparations, Na(+)-dependent L-[3H]glutamate uptake by synaptosomal preparations and Na(+)-independent L-[3H]glutamate uptake by synaptic vesicles, as well as of Na(+)-independent and dependent L-[3H]glutamate binding to synaptic plasma membranes from cerebral cortex of male adult Wistar rats. We observed that DGA significantly increased synaptosomal L-[3H]glutamate uptake, without altering the other parameters. Although these findings do not support a direct excitotoxic action for DGA since the metabolite did not affect important parameters of the main neurotransmission system, they do not exclude a direct action of DGA on NMDA or other glutamate receptors. More comprehensive studies are therefore necessary to evaluate the exact role of DGA on neurotransmission.
Junqueira
Débora
D
Departamento de Bioqui;mica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil.
Brusque
Ana M
AM
Porciúncula
Lisiane O
LO
Rotta
Liane N
LN
Frizzo
Marcos E S
ME
Wyse
Angela T S
AT
Wannmacher
Clóvis M D
CM
Souza
Diogo O
DO
Wajner
Moacir
M
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D020739:Brain Diseases, Metabolic, Inborn / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000737:chemistry / Q000378:metabolism
D005977:Glutarates; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; C019417:alpha-hydroxyglutarate; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase