RESUMEN
Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 µmol g body weight-1, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.
Asunto(s)
Acetilcisteína/uso terapéutico , Neuronas Colinérgicas/efectos de los fármacos , Glutaratos/toxicidad , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/prevención & control , Neuroglía/efectos de los fármacos , Acetilcisteína/farmacología , Animales , Neuronas Colinérgicas/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Neuroglía/metabolismo , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Encéfalo/metabolismo , Glutaratos/metabolismo , Glutaril-CoA Deshidrogenasa/deficiencia , Ácido Quinolínico/metabolismo , Sinaptosomas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Glutaratos/toxicidad , Glutaril-CoA Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ácido Metilmalónico/metabolismo , Ácido Metilmalónico/toxicidad , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Propionatos/metabolismo , Propionatos/toxicidad , Ácido Quinolínico/toxicidad , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sinaptosomas/efectos de los fármacosRESUMEN
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) produces kidney damage in rats. Although many NDPS analogues have been screened as possible nephrotoxicants, the one-carbon homologue, N-(3,5-dichlorophenyl)glutarimide (NDPG), has not been evaluated. This study examined the nephrotoxic potential of NDPG and a putative metabolite, N-(3,5-dichlorophenyl)glutaramic acid (NDPGA). Male Fischer 344 rats (N = 3-4 per group) were administered a single i.p. injection in corn oil of NDPG or NDPGA (0.4 or 1.0 mmol/kg), NDPS (0.4 mmol/kg), or corn oil alone. Renal function was monitored for 48 h. In contrast to NDPS, NDPG and NDPGA did not significantly alter renal function or kidney morphology when compared to corn oil-treated controls. These experiments show that replacement of the succinimide ring in NDPS with a glutarimide ring abolishes toxicity.
Asunto(s)
Clorobencenos/toxicidad , Fungicidas Industriales/toxicidad , Glutaratos/toxicidad , Riñón/efectos de los fármacos , Piperidonas/toxicidad , Animales , Nitrógeno de la Urea Sanguínea , Clorobencenos/química , Evaluación Preclínica de Medicamentos , Fungicidas Industriales/química , Glutaratos/química , Riñón/patología , Riñón/fisiopatología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Piperidonas/química , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad , Succinimidas/química , Succinimidas/toxicidadRESUMEN
The acute toxicity of 3-hydroxy-3-methylglutaric acid (HMG) was studied in mice. The LD50 was shown to be 7.33 g/kg p.o. and 3.23 g/kg i.p. Subtoxic and pharmacological doses applied to mice and rats during gestation did not induce malformation of the foetuses and offspring and did not affect the reproductive performances of the dams. This compound is being investigated for its hypolipidemic activity.