α-Ketoadipic Acid and α-Aminoadipic Acid Cause Disturbance of Glutamatergic Neurotransmission and Induction of Oxidative Stress In Vitro in Brain of Adolescent Rats
Tissue accumulation of α-ketoadipic (KAA) and α-aminoadipic (AAA) acids is the biochemical hallmark of α-ketoadipic aciduria. This inborn error of metabolism is currently considered a biochemical phenotype with uncertain clinical significance. Considering that KAA and AAA are structurally similar to α-ketoglutarate and glutamate, respectively, we investigated the in vitro effects of these compounds on glutamatergic neurotransmission in the brain of adolescent rats. Bioenergetics and redox homeostasis were also investigated because they represent fundamental systems for brain development and functioning. We first observed that AAA significantly decreased glutamate uptake, whereas glutamate dehydrogenase activity was markedly inhibited by KAA in a competitive fashion. In addition, AAA and more markedly KAA induced generation of reactive oxygen and nitrogen species (increase of 2′,7′-dichloroflurescein (DCFH) oxidation and nitrite/nitrate levels), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione (GSH)) and aconitase activity. Furthermore, KAA-induced lipid peroxidation and GSH decrease were prevented by the antioxidants α-tocopherol, melatonin, and resveratrol, suggesting the involvement of reactive species in these effects. Noteworthy, the classical inhibitor of NMDA glutamate receptors MK-801 was not able to prevent KAA-induced and AAA-induced oxidative stress, determined by DCFH oxidation and GSH levels, making unlikely a secondary induction of oxidative stress through overstimulation of glutamate receptors. In contrast, KAA and AAA did not significantly change brain bioenergetic parameters. We speculate that disturbance of glutamatergic neurotransmission and redox homeostasis by KAA and AAA may play a role in those cases of α-ketoadipic aciduria that display neurological symptoms.
Keywordsα-Ketoadipic aciduria α-Ketoadipic acid α-Aminoadipic acid Glutamatergic neurotransmission Redox homeostasis Bioenergetics
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico #404883/2013-3, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul #2266-2551/14-2, Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul #PIBIC 27613, and Financiadora de Estudos e Projetos/Rede Instituto Brasileiro de Neurociência # 01.06.0842-00.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- Di Meo S, Reed TT, Venditti P, Victor VM (2016) Role of ROS and RNS sources in physiological and pathological conditions. Oxidative Med Cell Longev 2016:1245049Google Scholar
- Dominah GA, McMinimy RA, Kallon S, Kwakye GF (2017) Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington’s disease. Neurotoxicology. In pressGoogle Scholar
- Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill Inc, New YorkGoogle Scholar
- Fischer JC, Ruitenbeek W, Berden JA, Trijbels JMF, Veerkamp JH, Stadhouders AM, Sengers RCA, Janssen AJM (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clinica chimica acta; international journal of clinical chemistry 153(1):23–36CrossRefPubMedGoogle Scholar
- Frigerio F, Karaca M, De Roo M, Mlynarik V, Skytt DM, Carobbio S, Pajecka K, Waagepetersen HS, Gruetter R, Muller D, Maechler P (2012) Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission. J Neurochem 123(3):342–348CrossRefPubMedGoogle Scholar
- Goodman SI, Duran M (2014) Biochemical phenotypes of questionable clinical significance. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases, 1st edn. Springer, HeidelbergGoogle Scholar
- Halliwell B, Gutteridge JMC (2007) Measurement of reactive species. Free radicals in biology and medicine, 4th edn. Oxford University Press, OxfordGoogle Scholar
- Hoffmann GF, Kölker, S (2011) Cerebral organic acid disorders and other disorders of lysine catabolism. Inborn Metabolic Diseases, 5 edn., HeidelbergGoogle Scholar
- Huck S, Grass F, Hortnagl H (1984) The glutamate analogue alpha-aminoadipic acid is taken up by astrocytes before exerting its gliotoxic effect in vitro. The Journal of neuroscience : the official journal of the Society for Neuroscience 4(10):2650–2657Google Scholar
- Kolker S, Hoffmann GF, Schor DS, Feyh P, Wagner L, Jeffrey I, Pourfarzam M, Okun JG, Zschocke J, Baric I, Bain MD, Jakobs C, Chalmers RA (2003) Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 34(5):253–260CrossRefPubMedGoogle Scholar
- Leipnitz G, Seminotti B, Fernandes CG, Amaral AU, Beskow AP, da Silva LB, Zanatta A, Ribeiro CA, Vargas CR, Wajner M (2009) Striatum is more vulnerable to oxidative damage induced by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency as compared to liver. Int J Dev Neurosci 27(4):351–356CrossRefPubMedGoogle Scholar
- Sauer SW, Okun JG, Fricker G, Mahringer A, Muller I, Crnic LR, Muhlhausen C, Hoffmann GF, Horster F, Goodman SI, Harding CO, Koeller DM, Kolker S (2006) Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97(3):899–910CrossRefPubMedGoogle Scholar
- Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 14(5 Pt 1):2924–2932Google Scholar