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.
Similar content being viewed by others
Data Availability
The data that support the findings of this study are available from the corresponding author, AS, upon reasonable request.
References
Aguilera-Portillo G, Rangel-López E, Villeda-Hernández J, Chavarría A, Castellanos P, Elmazoglu Z, Karasu Ç, Túnez I, Pedraza G, Königsberg M, Santamaría A (2019) The pharmacological inhibition of fatty acid amide hydrolase prevents excitotoxic damage in the rat striatum: possible involvement of CB1 receptors regulation. Mol Neurobiol 56(2):844–856. https://doi.org/10.1007/s12035-018-1129-2
Akanmu MA, Adeosun SO, Ilesanmi OR (2007) Neuropharmacological effects of oleamide in male and female mice. Behav Brain Res 182(1):88–94. https://doi.org/10.1016/j.bbr.2007.05.006
Ano Y, Ozawa M, Kutsukake T, Sugiyama S, Uchida K, Yoshida A, Nakayama H (2015) Preventive effects of a fermented dairy product against Alzheimer’s disease and identification of a novel oleamide with enhanced microglial phagocytosis and anti-inflammatory activity. PLoS ONE 10(3):e0118512. https://doi.org/10.1371/journal.pone.0118512
Aymerich MS, Aso E, Abellanas MA, Tolon RM, Ramos JA, Ferrer I, Romero J, Fernández-Ruiz J (2018) Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system. Biochem Pharmacol 157:67–84. https://doi.org/10.1016/j.bcp.2018.08.016
Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L, Soria-Gómez E, Matias I, Delamarre A, Metna-Laurent M, Cannich A, Hebert-Chatelain E, Mulle C, Ortega-Gutiérrez S, Martín-Fontecha M, Klugmann M, Guggenhuber S, Lutz B, Gertsch J, Chaouloff F, López-Rodríguez ML, Grandes P, Rossignol R, Marsicano G (2012) Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15(4):558–564. https://doi.org/10.1038/nn.3053
Bendiksen Skogvold H, Yazdani M, Sandås EM, Vassli AØ, Kristensen E, Haarr D, Rootwelt H, Prestø Elgstøen KB (2022) A pioneer study on human 3-nitropropionic acid intoxication: contributions from metabolomics. J Appl Toxicol 42(5):818–829. https://doi.org/10.1002/jat.4259
Boger DL, Fecik RA, Patterson JE, Miyauchi H, Patricelli MP, Cravatt BF (2000) Fatty acid amide hydrolase substrate specificity. Bioorg Med Chem Lett 10(23):2613–2616. https://doi.org/10.1016/s0960-894x(00)00528-x
Boger DL, Patterson JE, Guan X, Cravatt BF, Lerner RA, Gilula NB (1998) Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide. Proc Natl Acad Sci USA 95(9):4810–4815. https://doi.org/10.1073/pnas.95.9.4810
Brouillet E, Jacquard C, Bizat N, Blum D (2005) 3-Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington’s disease. J Neurochem 95(6):1521–1540. https://doi.org/10.1111/j.1471-4159.2005.03515.x
Burtscher J, Zangrandi L, Schwarzer C, Gnaiger E (2015) Differences in mitochondrial function in homogenated samples from healthy and epileptic specific brain tissues revealed by high-resolution respirometry. Mitochondrion 25:104–112. https://doi.org/10.1016/j.mito.2015.10.007
Chaturvedi RK, Beal MF (2013) Mitochondrial disease of the brain. Free Radic Biol Med 63:1–29. https://doi.org/10.1016/j.freeradbiomed.2013.03.018
Chavira-Ramos K, Orozco-Morales M, Karasu C, Tinkov AA, Aschner M, Santamaría A, Colín-González AL (2021) URB597 prevents the short-term excitotoxic cell damage in rat cortical slices: role of cannabinoid 1 receptors. Neurotox Res 39(2):146–155. https://doi.org/10.1007/s12640-020-00301-1
Coke CJ, Scarlett KA, Chetram MA, Jones KJ, Sandifer BJ, Davis AS, Marcus AI, Hinton CV (2016) Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and cannabinoid receptor 2 (CB2) reveals a mechanism for regulation of tumor progression. J Biol Chem 291(19):9991–10005. https://doi.org/10.1074/jbc.M115.712661
Colín-González AL, Maya-López M, Pedraza-Chaverrí J, Ali SF, Chavarría A, Santamaría A (2014) The Janus faces of 3-hydroxykynurenine: dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Res 1589:1–14. https://doi.org/10.1016/j.brainres.2014.09.034
Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (1995) Chemical characterization of a family of brain lipids that induce sleep. Science 268(5216):1506–1509. https://doi.org/10.1126/science.7770779
Dionisi M, Alexander SP, Bennett AJ (2012) Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ) in vitro. Lipids Health Dis 11:51. https://doi.org/10.1186/1476-511X-11-51
Du W, Zhang T, Yang F, Gul A, Tang Z, Zhang H, Jiang S, Wang S, Dong J (2022) Endocannabinoid signalling/cannabinoid receptor 2 is involved in icariin-mediated protective effects against bleomycin-induced pulmonary fibrosis. Phytomedicine 103:154187. https://doi.org/10.1016/j.phymed.2022.154187
El-Atawneh S, Goldblum A (2022) Candidate therapeutics by screening for multitargeting ligands: combining the CB2 receptor with CB1, PPARγ and 5-HT4 receptors. Front Pharmacol 13:812745. https://doi.org/10.3389/fphar.2022.812745
Estrada-Valencia R, Hurtado-Díaz ME, Rangel-López E, Retana-Márquez S, Túnez I, Tinkov A, Karasu C, Ferrer B, Pedraza-Chaverri J, Aschner J, Santamaría A (2022) Alpha-mangostin alleviates the short-term 6-hydroxydopamine-induced neurotoxicity and oxidative damage in rat cortical slices and in Caenorhabditis elegans. Neurotox Res 40(2):573–584. https://doi.org/10.1007/s12640-022-00493-8
Fernández-Ruiz J, Gómez-Ruiz M, García C, Hernández M, Ramos JA (2017) Modeling neurodegenerative disorders for developing cannabinoid-based neuroprotective therapies. Methods Enzymol 593:175–198. https://doi.org/10.1016/bs.mie.2017.06.021
Fowler CJ (2004) Oleamide: a member of the endocannabinoid family? Br J Pharmacol 141(2):195–196. https://doi.org/10.1038/sj.bjp.0705608
Gallelli CA, Calcagnini S, Romano A, Koczwara JB, de Ceglia M, Dante D, Villani R, Giudetti AM, Cassano T, Gaetani S (2018) Modulation of the oxidative stress and lipid peroxidation by endocannabinoids and their lipid analogues. Antioxidants 7(7):93. https://doi.org/10.3390/antiox7070093
Galván-Arzate S, Pedraza-Chaverrí J, Medina-Campos ON, Maldonado PD, Vázquez-Román B, Ríos C, Santamaría A (2005) Delayed effects of thallium in the rat brain: regional changes in lipid peroxidation and behavioral markers, but moderate alterations in antioxidants, after a single administration. Food Chem Toxicol 43(7):1037–1045. https://doi.org/10.1016/j.fct.2005.02.006
Gentili M, Ronchetti S, Ricci E, Di Paola R, Gugliandolo E, Cuzzocrea S, Bereshchenko O, Migliorati G, Riccardi C (2019) Selective CB2 inverse agonist JTE907 drives T cell differentiation towards a Treg cell phenotype and ameliorates inflammation in a mouse model of inflammatory bowel disease. Pharmacol Res 141:21–31. https://doi.org/10.1016/j.phrs.2018.12.005
Gifford AN, Tang Y, Gatley SJ, Volkow ND, Lan R, Makriyannis A (1997) Effect of the cannabinoid receptor SPECT agent, AM 281, on hippocampal acetylcholine release from rat brain slices. Neurosci Lett 238(1–2):84–86. https://doi.org/10.1016/s0304-3940(97)00851-3
Hariharan A, Shetty S, Shirole T, Jagtap AG (2014) Potential of protease inhibitor in 3-nitropropionic acid induced Huntington’s disease like symptoms: mitochondrial dysfunction and neurodegeneration. Neurotoxicology 45:139–148. https://doi.org/10.1016/j.neuro.2014.10.004
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza P-V, Benard G, Grandes P, Marsicano G (2014) Cannabinoid control of brain bioenergetics: exploring the subcellular localization of the CB1 receptor. Mol Metab 3(4):495–504. https://doi.org/10.1016/j.molmet.2014.03.007
Hensley K, Mhatre M, Mou S, Pye QN, Stewart C, West M, Williamson KS (2006) On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. Antioxid Redox Signal 8(11–12):2075–2087. https://doi.org/10.1089/ars.2006.8.2075
Hill MN, Gorzalka BB (2005) Pharmacological enhancement of cannabinoid CB1 receptor activity elicits an antidepressant-like response in the rat forced swim test. Eur Neuropsychopharmacol 15(6):593–599. https://doi.org/10.1016/j.euroneuro.2005.03.003
Huitrón-Resendiz S, Gombart L, Cravatt BF, Henriksen SJ (2001) Effect of oleamide on sleep and its relationship to blood pressure, body temperature, and locomotor activity in rats. Exp Neurol 172(1):235–243. https://doi.org/10.1006/exnr.2001.7792
Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, Cass WA, Sullivan PG, Bing G (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100(5):1375–1386. https://doi.org/10.1111/j.1471-4159.2006.04327.x
Kita M, Ano Y, Inoue A, Aoki J (2019) Identification of P2Y receptors involved in oleamide-suppressing inflammatory responses in murine microglia and human dendritic cells. Sci Rep 9(1):3135. https://doi.org/10.1038/s41598-019-40008-8
Kotlar I, Rangel-López E, Colonnello A, Aguilera-Portillo G, Serratos IN, Galván-Arzate S, Pedraza-Chaverri J, Túnez I, Wajner M, Santamaría A (2019) Anandamide reduces the toxic synergism exerted by quinolinic acid and glutaric acid in rat brain neuronal cells. Neuroscience 401:84–95. https://doi.org/10.1016/j.neuroscience.2019.01.014
Lan R, Gatley J, Lu Q, Fan P, Fernando SR, Volkow ND, Pertwee R, Makriyannis A (1999) Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand. AAPS PharmSci 1(2):E4. https://doi.org/10.1208/ps010204
Legare CA, Raup-Konsavage WM, Vrana KE (2022) Therapeutic potential of cannabis, cannabidiol, and cannabinoid-based pharmaceuticals. Pharmacology 107(3–4):131–149. https://doi.org/10.1159/000521683
Leggett JD, Aspley S, Beckett SR, D’Antona AM, Kendall DA, Kendall DA (2004) Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. Br J Pharmacol 141(2):253–262. https://doi.org/10.1038/sj.bjp.0705607
Lowe H, Toyang N, Steele B, Bryant J, Ngwa W (2021) The endocannabinoid system: a potential target for the treatment of various diseases. Int J Mol Sci 22(17):9472. https://doi.org/10.3390/ijms22179472
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275. PMID: 14907713
Maya-López M, Colín-González AL, Aguilera G, de Lima ME, Colpo-Ceolin A, Rangel-López E, Villeda-Hernández J, Rembao-Bojórquez D, Túnez I, Luna-López A, Lazzarini-Lechuga R, González-Puertos VY, Posadas-Rodríguez P, Silva-Palacios A, Königsberg M, Santamaría A (2017) Neuroprotective effect of WIN55,212–2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors. Am J Transl Res 9(2):261–274. PMID: 28337258
Maya-López M, Rubio-López LC, Rodríguez-Alvarez IV, Orduño-Piceno J, Flores-Valdivia Y, Colonnello A, Rangel-López E, Túnez I, Prospéro-García O, Santamaría A (2020) A cannabinoid receptor-mediated mechanism participates in the neuroprotective effects of oleamide against excitotoxic damage in rat brain synaptosomes and cortical slices. Neurotox Res 37(1):126–135. https://doi.org/10.1007/s12640-019-00083-1
Mueller GP, Driscoll WJ (2009) Biosynthesis of oleamide. Vitam Horm 81:55–78. https://doi.org/10.1016/S0083-6729(09)81003-0
Muhl H, Pfeilschifter J (2003) Endothelial nitric oxide synthase: a determinant of TNF-alpha production by human monocytes/macrophages. Biochem Biophys Res Commun 310(3):677–680. https://doi.org/10.1016/j.bbrc.2003.09.039
Murillo-Rodríguez E, Giordano M, Cabeza R, Henriksen SJ, Méndez Díaz M, Navarro L, Prospéro-García O (2001) Oleamide modulates memory in rats. Neurosci Lett 313(1–2):61–64. https://doi.org/10.1016/s0304-3940(01)02256-x
Nam HY, Na EJ, Lee E, Kwon Y, Kim HJ (2017) Antiepileptic and neuroprotective effects of oleamide in rat striatum on kainite induced behavioral seizure and excitotoxic damage via calpain inhibition. Front Pharmacol 8:817. https://doi.org/10.3389/fphar.2017.00817
Nazari M, Komaki A, Karamian R, Shahidi S, Sarihi A, Asadbegi M (2016) The interactive role of CB1 and GABA B receptors in hippocampal synaptic plasticity in rats. Brain Res Bull 120:123–130. https://doi.org/10.1016/j.brainresbull.2015.11.013
O’Sullivan S (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152(5):576–582. https://doi.org/10.1038/sj.bjp.0707423
O’Sullivan S (2016) An update on PPAR activation by cannabinoids. Br J Pharmacol 173(12):1899–1910. https://doi.org/10.1111/bph.13497
Oh YT, Lee JY, Lee J, Lee JH, Kim J-E, Ha J, Kang I (2010) Oleamide suppresses lipopolysaccharide-induced expression of iNOS and COX-2 through inhibition of NF-κB activation in BV2 murine microglial cells. Neurosci Lett 474(3):148–153. https://doi.org/10.1016/j.neulet.2010.03.026
Pascual AC, Gaveglio VL, Giusto NM, Pasquaré SJ (2014) Cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging. Exp Gerontol 55:134–142. https://doi.org/10.1016/j.exger.2014.04.008
Piomelli D (2003) The molecular logic of endocannabinoid signaling. Nat Rev Neurosci 4(11):873–884. https://doi.org/10.1038/nrn1247
Rangel-López E, Colín-González AL, Paz-Loyola AL, Pinzón E, Torres I, Serratos IN, Castellanos P, Wajner M, Souza DO, Santamaría A (2015) Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain. Neuroscience 285:97–106. https://doi.org/10.1016/j.neuroscience.2014.11.016
Rea K, McGowan F, Corcoran L, Roche M, Finn DP (2019) The prefrontal cortical endocannabinoid system modulates fear-pain interactions in a subregion-specific manner. Br J Pharmacol 176(10):1492–1505. https://doi.org/10.1111/bph.14376
Reyes-Soto CY, Rangel-López E, Galván-Arzate S, Colín-González AL, Silva-Palacios A, Zazueta C, Pedraza-Chaverri J, Ramírez J, Chavarria A, Túnez I, Ke T, Aschner M, Santamaría A (2020) S-Allylcysteine protects against excitotoxic damage in rat cortical slices via reduction of oxidative damage, activation of Nrf2/ARE binding, and BDNF preservation. Neurotox Res 38(4):929–940. https://doi.org/10.1007/s12640-020-00260-7
Robson PJ (2014) Therapeutic potential of cannabinoid medicines. Drug Test Analysis 6(1–2):24–30. https://doi.org/10.1002/dta.1529
Rodríguez-Muñoz M, Sánchez-Blázquez P, Merlos M, Garzón Niño J (2016) Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction. Oncotarget 7(34):55840–55862. https://doi.org/10.18632/oncotarget.10095
Sánchez-Blázquez P, Rodríguez-Muñoz M, Garzón J (2014) The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front Pharmacol 4:169. https://doi.org/10.3389/fphar.2013.00169
Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J (2013) Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate. Antioxid Redox Signal 19(15):1766–1782. https://doi.org/10.1089/ars.2012.5100
Schinder AF, Olson EC, Spitzer NC, Montal M (1996) Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci 16(19):6125–6133. https://doi.org/10.1523/JNEUROSCI.16-19-06125.1996
Sgambato-Faure V, Cenci MA (2012) Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson’s disease. Prog Neurobiol 96(1):69–86. https://doi.org/10.1016/j.pneurobio.2011.10.005
Strack A, Duffy CF, Malvey M, Arriaga EA (2001) Individual mitochondrion characterization: a comparison of classical assays to capillary electrophoresis with laser-induced fluorescence detection. Anal Biochem 294(2):141–147. https://doi.org/10.1006/abio.2001.5148
Tilleux S, Hermans E (2007) Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res 85(10):2059–2070. https://doi.org/10.1002/jnr.21325
Ting JT, Lee BR, Chong P, Soler-Llavina G, Cobbs C, Koch C, Zeng H, Lein E (2018) Preparation of acute brain slices using an optimized N-methyl-D-glucamine protective recovery method. J vis Exp 132:e53825. https://doi.org/10.3791/53825
Túnez I, Montilla P, Muñoz MC, Drucker-Colín R (2004) Effect of nicotine on 3-nitropropionic acid-induced oxidative stress in synaptosomes. Eur J Pharmacol 504(3):169–175. https://doi.org/10.1016/j.ejphar.2004.09.061
Túnez I, Tasset I, Pérez-De La Cruz V, Santamaria A (2010) 3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington’s disease: past, present and future. Molecules 15(2):878–916. https://doi.org/10.3390/molecules15020878
van der Meer P, Ulrich AM, González-Scarano F, Lavi E (2000) Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp Mol Pathol 69(3):192–201. https://doi.org/10.1006/exmp.2000.2336
Verdon B, Zheng J, Nicholson RA, Ganellin CR, Lees G (2000) Stereoselective modulatory actions of oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNS. Br J Pharmacol 129(2):283–290. https://doi.org/10.1038/sj.bjp.0703051
Viscomi MT, Oddi S, Latini L, Bisicchia E, Maccarrone M, Molinari M (2010) The endocannabinoid system: a new entry in remote cell death mechanisms. Exp Neurol 224(1):56–65. https://doi.org/10.1016/j.expneurol.2010.03.023
Yang JY, Abe K, Xu NJ, Matsuki N, Wu CF (2002) Oleamide attenuates apoptotic death in cultured rat cerebellar granule neurons. Neurosci Lett 328(2):165–169. https://doi.org/10.1016/s0304-3940(02)00460-3
Yang L, Li Z, Xu Z, Zhang B, Liu A, He Q, Zheng F, Zhan J (2022) Protective effects of cannabinoid type 2 receptor activation against microglia overactivation and neuronal pyroptosis in sepsis-associated encephalopathy. Neuroscience 493:99–108. https://doi.org/10.1016/j.neuroscience.2022.04.011
Young AP, Denovan-Wright EM (2022) Synthetic cannabinoids reduce the inflammatory activity of microglia and subsequently improve neuronal survival in vitro. Brain Behav Immun 105:29–43. https://doi.org/10.1016/j.bbi.2022.06.011
Funding
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Ethics Approval
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.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-022-00575-7