Abstract
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.
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We appreciate the excellent technical assistance of Jade Nava-Osorio, Enid Ovalle-Noguez and Marisol Maya-López.
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This work was supported by the CONACYT-TUBITAK collaborative agreement (grant 265991 given to AS) and the National Institute of Environmental Health Sciences (grants R01ES03771 and R01ES10563 given to MA). None of the sponsors were involved in design, collection, analysis, or interpretation of data, neither in writing of the report or decision to submit the article for publication.
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A.L.C.-G. and A.S. designed the whole study. K.J.P.-R., K.C.-R., and S.G.-A. performed all experiments and prepared the figures. S.G.-A., E.R.-L., C.K., I.T., A.V.S., M.A., and M.O.-M. provided critical comments to design, interpretation of results and discussion, as well as reagents. M.A. and A.S. wrote the main manuscript. All authors reviewed the manuscript.
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All experiments were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80–23) revised 1996, and the local Ethical Committees. Formal approval to conduct the experimental procedures was obtained from the animal subjects review board of the Instituto Nacional de Neurología y Neurocirugía (Project numbers 17/20 and 73/20). All efforts were made to minimize animals pain suffering during the experiments.
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Paredes-Ruiz, K.J., Chavira-Ramos, K., Galvan-Arzate, S. et al. Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors. Neurotox Res 41, 514–525 (2023). https://doi.org/10.1007/s12640-023-00661-4
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DOI: https://doi.org/10.1007/s12640-023-00661-4