title: Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain.
abstract: The endocannabinoid system (ECS) is involved in a considerable number of physiological processes in the Central Nervous System. Recently, a modulatory role of cannabinoid receptors (CBr) and CBr agonists on the reduction of the N-methyl-d-aspartate receptor (NMDAr) activation has been demonstrated. Quinolinic acid (QUIN), an endogenous analog of glutamate and excitotoxic metabolite produced in the kynurenine pathway (KP), selectively activates NMDAr and has been shown to participate in different neurodegenerative disorders. Since the early pattern of toxicity exerted by this metabolite is relevant to explain the extent of damage that it can produce in the brain, in this work we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) and other agonists (anandamide or AEA, and CP 55,940 or CP) on early markers of QUIN-induced toxicity in rat striatal cultured cells and rat brain synaptosomes. WIN, AEA and CP exerted protective effects on the QUIN-induced loss of cell viability. WIN also preserved the immunofluorescent signals for neurons and CBr labeling that were decreased by QUIN. The QUIN-induced early mitochondrial dysfunction, lipid peroxidation and reactive oxygen species (ROS) formation were also partially or completely prevented by WIN pretreatment, but not when this CBr agonist was added simultaneously with QUIN to brain synaptosomes. These findings support a neuroprotective and modulatory role of cannabinoids in the early toxic events elicited by agents inducing excitotoxic processes.
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City, Mexico.
authors.forename: E
authors.initials: E
authors.lastname: Rangel-López
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, 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, SSA, Mexico City, Mexico.
authors.forename: A L
authors.initials: AL
authors.lastname: Paz-Loyola
authors.affiliation: Unidad de Bioterio, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: E
authors.initials: E
authors.lastname: Pinzón
authors.affiliation: Unidad de Bioterio, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: I
authors.initials: I
authors.lastname: Torres
authors.affiliation: Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.
authors.forename: I N
authors.initials: IN
authors.lastname: Serratos
authors.affiliation: Departamento de Ingenieria Eléctrica, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.
authors.forename: P
authors.initials: P
authors.lastname: Castellanos
authors.affiliation: Departamento de Bioquímica, PPG en Bioquímica, PPG en Educación en Ciencia, Instituto de Ciencias Básicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Wajner
authors.affiliation: Departamento de Bioquímica, PPG en Bioquímica, PPG en Educación en Ciencia, Instituto de Ciencias Básicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: D O
authors.initials: DO
authors.lastname: Souza
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City, Mexico. Electronic address: absada@yahoo.com.
authors.forename: A
authors.initials: A
authors.lastname: Santamaría
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003511:Cyclohexanols / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D017378:Quinolinic Acid / Q000633:toxicity*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; D063388:Endocannabinoids; D018683:Excitatory Amino Acid Agents; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D017382:Reactive Oxygen Species; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D017378:Quinolinic Acid; C078814:anandamide
keywords: cannabinoid receptor agonists; endocannabinoid system; excitotoxicity; mitochondrial dysfunction; neuroprotection; oxidative stress