PMID- 26431622 OWN - NLM STAT- MEDLINE DCOM- 20160815 LR - 20210223 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 310 DP - 2015 Dec 3 TI - 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. PG - 578-88 LID - S0306-4522(15)00862-3 [pii] LID - 10.1016/j.neuroscience.2015.09.043 [doi] AB - 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. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Colin-Gonzalez, A L AU - Colin-Gonzalez AL AD - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y Neurocirugia, S.S.A., Mexico City, Mexico. FAU - Paz-Loyola, A L AU - Paz-Loyola AL AD - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y Neurocirugia, S.S.A., Mexico City, Mexico. FAU - Serratos, I N AU - Serratos IN AD - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y Neurocirugia, S.S.A., Mexico City, Mexico; Departamento de Quimica, Universidad Autonoma Metropolitana-Iztapalapa, Mexico. FAU - Seminotti, B AU - Seminotti B AD - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Ribeiro, C A J AU - Ribeiro CA AD - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Leipnitz, G AU - Leipnitz G AD - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Souza, D O AU - Souza DO AD - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Wajner, M AU - Wajner M AD - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Servico de Genetica Medica, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br. FAU - Santamaria, A AU - Santamaria A AD - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y Neurocirugia, S.S.A., Mexico City, Mexico. Electronic address: absada@yahoo.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150930 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (3-hydroxyglutaric acid) RN - 0 (Acids, Acyclic) RN - 0 (Benzoxazines) RN - 0 (Cannabinoid Receptor Agonists) RN - 0 (Glutarates) RN - 0 (Morpholines) RN - 0 (Naphthalenes) RN - 0 (Propionates) RN - 0 (Reactive Oxygen Species) RN - 5H31GI9502 ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone) RN - 8LL8S712J7 (Methylmalonic Acid) RN - EC 1.3.8.6 (Glutaryl-CoA Dehydrogenase) RN - H849F7N00B (glutaric acid) RN - JHU490RVYR (propionic acid) RN - Glutaric Acidemia I SB - IM MH - Acids, Acyclic/*metabolism/*toxicity MH - Amino Acid Metabolism, Inborn Errors/*metabolism MH - Animals MH - Benzoxazines/*pharmacology MH - Brain/drug effects/*metabolism MH - Brain Diseases, Metabolic/*metabolism MH - Cannabinoid Receptor Agonists/*pharmacology MH - Glutarates/metabolism/toxicity MH - Glutaryl-CoA Dehydrogenase/*deficiency/metabolism MH - Lipid Peroxidation/drug effects MH - Male MH - Methylmalonic Acid/metabolism/toxicity MH - Mitochondria/drug effects/metabolism MH - Morpholines/*pharmacology MH - Naphthalenes/*pharmacology MH - Oxidative Stress/*drug effects MH - Propionates/metabolism/toxicity MH - Rats MH - Rats, Wistar MH - Reactive Oxygen Species/metabolism MH - Synaptosomes/drug effects/metabolism OTO - NOTNLM OT - endocannabinoid system OT - mitochondrial dysfunction OT - neuroprotection OT - organic acids OT - oxidative stress OT - synaptosomes EDAT- 2015/10/04 06:00 MHDA- 2016/08/16 06:00 CRDT- 2015/10/04 06:00 PHST- 2015/04/22 00:00 [received] PHST- 2015/09/03 00:00 [revised] PHST- 2015/09/18 00:00 [accepted] PHST- 2015/10/04 06:00 [entrez] PHST- 2015/10/04 06:00 [pubmed] PHST- 2016/08/16 06:00 [medline] AID - S0306-4522(15)00862-3 [pii] AID - 10.1016/j.neuroscience.2015.09.043 [doi] PST - ppublish SO - Neuroscience. 2015 Dec 3;310:578-88. doi: 10.1016/j.neuroscience.2015.09.043. Epub 2015 Sep 30.