Toxic synergism between quinolinic acid and organic acids accumulating in glutaric acidemia type I and in disorders of propionate metabolism in rat brain synaptosomes: Relevance for metabolic acidemias.
The brain of children affected by organic acidemias develop acute neurodegeneration linked to accumulation of endogenous toxic metabolites like glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids. Excitotoxic and oxidative events are involved in the toxic patterns elicited by these organic acids, although their single actions cannot explain the extent of brain damage observed in organic acidemias. The characterization of co-adjuvant factors involved in the magnification of early toxic processes evoked by these metabolites is essential to infer their actions in the human brain. Alterations in the kynurenine pathway (KP) - a metabolic route devoted to degrade tryptophan to form NAD(+) - produce increased levels of the excitotoxic metabolite quinolinic acid (QUIN), which has been involved in neurodegenerative disorders. Herein we investigated the effects of subtoxic concentrations of GA, 3-OHGA, MMA and PA, either alone or in combination with QUIN, on early toxic endpoints in rat brain synaptosomes. To establish specific mechanisms, we pre-incubated synaptosomes with different protective agents, including the endogenous N-methyl-d-aspartate (NMDA) receptor antagonist kynurenic acid (KA), the antioxidant S-allylcysteine (SAC) and the nitric oxide synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME). While the incubation of synaptosomes with toxic metabolites at subtoxic concentrations produced no effects, their co-incubation (QUIN+GA, +3-OHGA, +MMA or +PA) decreased the mitochondrial function and increased reactive oxygen species (ROS) formation and lipid peroxidation. For all cases, this effect was partially prevented by KA and l-NAME, and completely avoided by SAC. These findings suggest that early damaging events elicited by organic acids involved in metabolic acidemias can be magnified by toxic synergism with QUIN, and this process is mostly mediated by oxidative stress, and in a lesser extent by excitotoxicity and nitrosative stress. Therefore, QUIN can be hypothesized to contribute to the pathophysiology of brain degeneration in children with metabolic acidemias.
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
A L
AL
Colín-González
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
A L
AL
Paz-Loyola
Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.
I
I
Serratos
Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
B
B
Seminotti
Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
C A J
CA
Ribeiro
Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
G
G
Leipnitz
Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
D O
DO
Souza
Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.
M
M
Wajner
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico. Electronic address: absada@yahoo.com.
A
A
Santamaría
D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000378:metabolism*; D004195:Disease Models, Animal; D005977:Glutarates / Q000378:metabolism* / Q000633:toxicity; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008764:Methylmalonic Acid / Q000378:metabolism / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000378:metabolism / Q000633:toxicity; D017378:Quinolinic Acid / Q000378:metabolism* / Q000633:toxicity; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
C108959:3-hydroxyglutaric acid; D005977:Glutarates; D018696:Neuroprotective Agents; D011422:Propionates; D017382:Reactive Oxygen Species; D008764:Methylmalonic Acid; D050770:Glutaryl-CoA Dehydrogenase; D017378:Quinolinic Acid; C035736:glutaric acid; C029658:propionic acid
cell damage; excitotoxicity; mitochondrial dysfunction; organic acidemias; oxidative stress; toxic synergism