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

Neuroscience
A L Colín-GonzálezA Santamaría

Abstract

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 ant...Continue Reading

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Citations

Aug 22, 2018·Journal of Cellular Biochemistry·Gilian GuerreiroCarmen Regla Vargas
Mar 28, 2019·Nature Reviews. Neurology·Moacir Wajner
May 24, 2019·Journal of Inherited Metabolic Disease·Hanneke A HaijesNanda M Verhoeven-Duif
Oct 17, 2019·Frontiers in Neuroscience·Vanessa X Tan, Gilles J Guillemin

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