Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.

Autor: Paredes-Ruiz KJ; Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, S.S.A, 14269, Mexico City, Mexico.; Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico., Chavira-Ramos K; Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, S.S.A, 14269, Mexico City, Mexico.; Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico., Galvan-Arzate S; Departamento de Neuroquímica, Instituto Nacional de Neurología Y Neurocirugía, S.S.A, 14269, Mexico City, Mexico., Rangel-López E; Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, S.S.A, 14269, Mexico City, Mexico., Karasu Ç; Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, 06500, Beşevler, Ankara, Turkey., Túnez I; Instituto de Investigaciones Biomédicas Maimonides de Córdoba (IMIBIC); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Universidad de Córdoba Red Española de Excelencia en Estimulación Cerebral (REDESTIM), Córdoba, Spain., Skalny AV; IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.; Peoples' Friendship, University of Russia (RUDN University), Moscow, Russia., Ke T; Department of Molecular Pharmacology, Albert Einstein College of Medicine, 11354, Bronx, NY, USA., Aschner M; Department of Molecular Pharmacology, Albert Einstein College of Medicine, 11354, Bronx, NY, USA., Orozco-Morales M; Laboratorio de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, S.S.A, 14269, Mexico City, Mexico., Colín-González AL; Banco de Tumores, Instituto Nacional de Cancerología, S.S.A., 14080, Mexico City, Mexico. coling.laura@gmail.com., Santamaría A; Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, S.S.A, 14269, Mexico City, Mexico. absada@yahoo.com.; Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico. absada@yahoo.com.
Jazyk: angličtina
Zdroj: Neurotoxicity research [Neurotox Res] 2023 Dec; Vol. 41 (6), pp. 514-525. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1007/s12640-023-00661-4
Abstrakt: Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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