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3-Methylglutaric acid (3MGA) is an organic acid that accumulates in various organic acidemias whose patients present neurodegeneration events in children coursing with metabolic acidurias. Limited evidence describes the toxic mechanisms elicited by 3MGA in the brain. Herein, we explored the effects of 3MGA on different toxic endpoints in synaptosomal and mitochondrial-enriched fractions of adult rat brains to provide novel information on early mechanisms evoked by this metabolite. At 1 and 5 mM concentration, 3MGA increased lipid peroxidation, but decreased mitochondrial function only at 5 mM concentration. Despite less intense effects were obtained at 1 mM concentration, its co-administration with the kynurenine pathway (KP) metabolite and N-methyl-D-aspartate receptor (NMDAr) agonist, quinolinic acid (QUIN, 50 and 100 µM), produced toxic synergism on markers of oxidative stress and mitochondrial function. The toxicity of 3MGA per se (5 mM) was prevented by the cannabinoid receptor agonist WIN55,212-2 and the NMDAr antagonist kynurenic acid (KYNA), suggesting cannabinoid and glutamatergic components in the 3MGA pattern of toxicity. The synergic model (3MGA + QUIN) was also sensitive to KYNA and the antioxidant S-allylcysteine, but not to the nitric oxide synthase inhibitor L-nitroarginine methyl ester. These findings suggest various underlying mechanisms involved in the neurotoxicity of 3MGA that may possibly contribute to the neurodegeneration observed in acidemias.

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