Evidence that glutaric acid reduces glutamate uptake by cerebral cortex of infant rats.
The role of excitotoxicity in the cerebral damage of glutaryl-CoA dehydrogenase deficiency (GDD) is under intense debate. We therefore investigated the in vitro effect of glutaric (GA) and 3-hydroxyglutaric (3-OHGA) acids, which accumulate in GDD, on [(3)H]glutamate uptake by slices and synaptosomal preparations from cerebral cortex and striatum of rats aged 7, 15 and 30 days. Glutamate uptake was significantly decreased by high concentrations of GA in cortical slices of 7-day-old rats, but not in cerebral cortex from 15- and 30-day-old rats and in striatum from all studied ages. Furthermore, this effect was not due to cellular death and was prevented by N-acetylcysteine preadministration, suggesting the involvement of oxidative damage. In contrast, glutamate uptake by brain slices was not affected by 3-OHGA exposure. Immunoblot analysis revealed that GLAST transporters were more abundant in the cerebral cortex compared to the striatum of 7-day-old rats. Moreover, the simultaneous addition of GA and dihydrokainate (DHK), a specific inhibitor of GLT1, resulted in a significantly higher inhibition of [(3)H]glutamate uptake by cortical slices of 7-day-old rats than that induced by the sole presence of DHK. We also observed that both GA and 3-OHGA exposure did not alter the incorporation of glutamate into synaptosomal preparations from cerebral cortex and striatum of rats aged 7, 15 and 30 days. Finally, GA in vivo administration did not alter glutamate uptake into cortical slices from 7-day-old rats. Our findings may explain at least in part why cortical neurons are more vulnerable to damage at birth as evidenced by the frontotemporal cortical atrophy observed in newborns affected by GDD.
Rosa
Rafael B
RB
Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Dalcin
Karina B
KB
Schmidt
Anna L
AL
Gerhardt
Daniéli
D
Ribeiro
César A J
CA
Ferreira
Gustavo C
GC
Schuck
Patricia F
PF
Wyse
Angela T S
AT
Porciúncula
Lisiane O
LO
Wofchuk
Susana
S
Salbego
Christianne G
CG
Souza
Diogo O
DO
Wajner
Moacir
M
D000111:Acetylcysteine / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism / Q000493:pharmacokinetics*; D005977:Glutarates / Q000008:administration & dosage* / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000378:metabolism
C108959:3-hydroxyglutaric acid; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D005971:Glutamates; D005977:Glutarates; C493392:Slc1a3 protein, rat; C020889:dihydrokainic acid; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid; D007608:Kainic Acid; D000111:Acetylcysteine