Abstract
The potential treatment of neurodegenerative disorders requires the development of novel pharmacological strategies at the experimental level, such as the endocannabinoid-based therapies. The effects of oleamide (OEA), a fatty acid primary amide with activity on cannabinoid receptors, was tested against mitochondrial toxicity induced by the electron transport chain complex II inhibitor, 3-nitropropionic acid (3-NP), in rat cortical slices. OEA prevented the 3-NP-induced loss of mitochondrial function/cell viability at a concentration range of 5 nM–25 µM, and this protective effect was observed only when the amide was administered as pretreatment, but not as post-treatment. The preservation of mitochondrial function/cell viability induced by OEA in the toxic model induced by 3-NP was lost when the slices were pre-incubated with the cannabinoid receptor 1 (CB1R) selective inhibitor, AM281, or the cannabinoid receptor 2 (CB2R) selective inhibitor, JTE-907. The 3-NP-induced inhibition of succinate dehydrogenase (mitochondrial Complex II) activity was recovered by 25 nM OEA. The amide also prevented the increased lipid peroxidation and the changes in reduced/oxidized glutathione (GSH/GSSG) ratio induced by 3-NP. The cell damage induced by 3-NP, assessed as incorporation of cellular propidium iodide, was mitigated by OEA. Our novel findings suggest that the neuroprotective properties displayed by OEA during the early stages of damage to cortical cells involve the converging activation of CB1R and CB2R and the increase in antioxidant activity, which combined may emerge from the preservation of the functional integrity of mitochondria.
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Data Availability
The data that support the findings of this study are available from the corresponding author, AS, upon reasonable request.
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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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M.A. and A.S. designed the whole study. C.Y.R.-S., M.V.-F., E.A.O.-N., J.N.-O., S.G.-A., E.R.-L., M.M.-L., and T.K. performed all experiments and prepared Figs. 1, 2, 3, and 4. S.R.-M., I.T., and A.A.T. provided critical comments to design, interpretation of results and discussion. S.R.-M., I.T., and A.A.T. also provided 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 Publications 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 number 126/17). All efforts were made to minimize animals pain suffering during the experiments.
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Reyes-Soto, C.Y., Villaseca-Flores, M., Ovalle-Noguez, E.A. et al. Oleamide Reduces Mitochondrial Dysfunction and Toxicity in Rat Cortical Slices Through the Combined Action of Cannabinoid Receptors Activation and Induction of Antioxidant Activity. Neurotox Res 40, 2167–2178 (2022). https://doi.org/10.1007/s12640-022-00575-7
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DOI: https://doi.org/10.1007/s12640-022-00575-7