title: URB597 and the Cannabinoid WIN55,212-2 Reduce Behavioral and Neurochemical Deficits Induced by MPTP in Mice: Possible Role of Redox Modulation and NMDA Receptors.
abstract: Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more "physiological" activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. MPTP (40 mg/kg, s.c., single injection) decreased locomotor activity, depleted the striatal and nigral levels of dopamine (DA), augmented the levels of lipid peroxidation and protein carbonylation in both regions, decreased the striatal protein levels of tyrosine hydroxylase, and increased the striatal protein content of the subunit 1 (NR1) of the N-methyl-D-aspartate receptor (NMDAr). Both URB597 (0.3 mg/kg, i.p., once a day) and WIN55,212-2 (10 μg/kg, i.p., twice a day), administered for five consecutive days, either before or after the MPTP injection, prevented the alterations elicited by MPTP and downregulated NMDAr. Our results support a modulatory role of the ECS on the toxic profile exerted by MPTP in mice via the stimulation of antioxidant activity and the induction of NMDAr downregulation and hypofunction, and favor the stimulation of CBr as an effective experimental therapeutic strategy.
authors.affiliation: Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, 14269, México D.F, Mexico.
authors.forename: Angel
authors.initials: A
authors.lastname: Escamilla-Ramírez
authors.affiliation: Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, 14269, México D.F, Mexico. egarciainnn@gmail.com.
authors.forename: Esperanza
authors.initials: E
authors.lastname: García
authors.affiliation: Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, 14269, México D.F, Mexico.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Palencia-Hernández
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, 14269, Mexico City, Mexico.
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: Colín-González
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, 14269, México D.F, Mexico.
authors.forename: Sonia
authors.initials: S
authors.lastname: Galván-Arzate
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Cordoba, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Túnez
authors.affiliation: Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, 14269, México D.F, Mexico.
authors.forename: Julio
authors.initials: J
authors.lastname: Sotelo
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, 14269, Mexico City, Mexico. absada@yahoo.com.
authors.forename: Abel
authors.initials: A
authors.lastname: Santamaría
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects*; D020267:MPTP Poisoning / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001549:Benzamides; D048588:Benzoxazines; D002219:Carbamates; D009025:Morpholines; C409466:NR1 NMDA receptor; D009281:Naphthalenes; D016194:Receptors, N-Methyl-D-Aspartate; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Cannabinoid receptor agonists; Endocannabinoid system; MPTP toxic model; NMDAr hypofunction; Neurochemical deficits; Oxidative stress