Effects of L-2-hydroxyglutaric acid on various parameters of the glutamatergic system in cerebral cortex of rats.
L-2-Hydroxyglutaric acid (LGA) accumulates and is the biochemical hallmark of the neurometabolic disorder L-2-hydroxyglutaric aciduria (LHGA). Although this disease is predominantly characterized by severe neurological findings and pronounced cerebral atrophy, the pathomechanisms of brain injury are virtually unknown. In the present study, we investigated the effect of LGA (0.1-1 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 L-[3H]glutamate binding to synaptic plasma membranes from cerebral cortex of male adult Wistar rats. We observed that LGA significantly increased L-[3H]glutamate uptake into synaptosomes and synaptic vesicles, without altering synaptosomal glutamate release and glutamate binding to synaptic plasma membranes. Although more comprehensive studies are necessary to evaluate the exact role of LGA on neurotransmission, our findings do not support a direct excitotoxic action for LGA. Therefore, other abnormalities should be searched for to explain neurodegeneration of LHGA.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Débora
D
Junqueira
Ana M
AM
Brusque
Lisiane O
LO
Porciúncula
Liane N
LN
Rotta
Céar A J
CA
Ribeiro
Marcos E S
ME
Frizzo
Carlos S
CS
Dutra Filho
Clóvis M D
CM
Wannmacher
Angela T S
AT
Wyse
Diogo O
DO
Souza
Moacir
M
Wajner
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology*; D005977:Glutarates / Q000494:pharmacology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D005977:Glutarates; D009419:Nerve Tissue Proteins; C019417:alpha-hydroxyglutarate; D018698:Glutamic Acid; D012964:Sodium; D007770:L-Lactate Dehydrogenase; D011188:Potassium