title: The effect of WIN 55,212-2 suggests a cannabinoid-sensitive component in the early toxicity induced by organic acids accumulating in glutaric acidemia type I and in related disorders of propionate metabolism in rat brain synaptosomes.
abstract: Several physiological processes in the CNS are regulated by the endocannabinoid system (ECS). Cannabinoid receptors (CBr) and CBr agonists have been involved in the modulation of the N-methyl-D-aspartate receptor (NMDAr) activation. Glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids are endogenous metabolites produced and accumulated in the brain of children affected by severe organic acidemias (OAs) with neurodegeneration. Oxidative stress and excitotoxicity have been involved in the toxic pattern exerted by these organic acids. Studying the early pattern of toxicity exerted by these metabolites is crucial to explain the extent of damage that they can produce in the brain. Herein, we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) on early markers of GA-, 3-OHGA-, MMA- and PA-induced toxicity in brain synaptosomes from adult (90-day-old) and adolescent (30-day-old) rats. As pre-treatment, WIN exerted protective effects on the GA- and MMA-induced mitochondrial dysfunction, and prevented the reactive oxygen species (ROS) formation and lipid peroxidation induced by all metabolites. Our findings support a protective and modulatory role of cannabinoids in the early toxic events elicited by toxic metabolites involved in OAs.
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
authors.forename: A L
authors.initials: AL
authors.lastname: Colín-González
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
authors.forename: A L
authors.initials: AL
authors.lastname: Paz-Loyola
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico; Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico.
authors.forename: I N
authors.initials: IN
authors.lastname: Serratos
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: C A J
authors.initials: CA
authors.lastname: Ribeiro
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Sáude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: D O
authors.initials: DO
authors.lastname: Souza
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Wajner
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico. Electronic address: absada@yahoo.com.
authors.forename: A
authors.initials: A
authors.lastname: Santamaría
mesh_terms: D000144:Acids, Acyclic / Q000378:metabolism* / Q000633:toxicity*; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000378:metabolism*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; 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; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011422:Propionates / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: C108959:3-hydroxyglutaric acid; D000144:Acids, Acyclic; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D005977:Glutarates; D009025:Morpholines; D009281:Naphthalenes; D011422:Propionates; D017382:Reactive Oxygen Species; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D008764:Methylmalonic Acid; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid; C029658:propionic acid
keywords: endocannabinoid system; mitochondrial dysfunction; neuroprotection; organic acids; oxidative stress; synaptosomes