A Cannabinoid Receptor-Mediated Mechanism Participates in the Neuroprotective Effects of Oleamide Against Excitotoxic Damage in Rat Brain Synaptosomes and Cortical Slices
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A number of physiological responses in the central nervous system (CNS) are regulated by the endocannabinoid system (ECS). Inhibition of neuronal excitability via activation of cannabinoid receptors (CBr) constitutes a potential protective response against neurotoxic insults. Oleamide (ODA) is a fatty acid amide with endocannabinoid profile exerting several effects in the CNS, though its neuroprotective properties remain unknown. The tryptophan metabolite quinolinic acid (QUIN) elicits toxic effects via overactivation of N-methyl-d-aspartate receptors (NMDAr) after its accumulation in the CNS under pathological conditions. Here, we investigated the protective properties of ODA against the excitotoxic damage induced by QUIN in rat brain synaptosomes and cortical slices, and whether these effects are linked to the stimulation of the endocannabinoid system via CB1 and/or CB2 receptor activation. ODA (1–50 μM) prevented the QUIN (100 μM)-induced loss of mitochondrial reductive capacity in synaptosomes in a mechanism partially mediated by CB1 receptor, as evidenced by the recovery of mitochondrial dysfunction induced by co-incubation with the CB1 receptor antagonist/inverse agonist AM281 (1 μM). In cortical slices, ODA prevented the short-term QUIN-induced loss of cell viability and the cell damage in a partial CB1 and CB2 receptor-dependent manner. Altogether, these findings demonstrate the neuroprotective and modulatory properties of ODA in biological brain preparations exposed to excitotoxic insults and the partial role that the stimulation of CB1 and CB2 receptors exerts in these effects.
KeywordsExcitotoxicity Endocannabinoid system Neuroprotection Oleamide Quinolinic acid Cannabinoid receptors
The authors wish to express gratitude to Dr. Edith Monroy for her assistance for language improvement.
This work was supported by CONACYT-TUBITAK grants 265991 (CONACYT/SRE given to AS) and IN215218 (DGAPA-PAPIIT-UNAM given to OPG).
Compliance with Ethical Standards
The experimental protocols were approved by the Ethics Committee for Animal Research of the Instituto Nacional de Neurología y Neurocirugía (Project No. 126/17).
Conflict of Interest
The authors declare that they have no competing interests.
- 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 56:844–856CrossRefGoogle Scholar
- 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:e0118512CrossRefGoogle Scholar
- 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 15:558–566CrossRefGoogle Scholar
- Chiarlone A, Bellocchio L, Blázquez C, Resel E, Soria-Gómez E, Cannich A, Ferrero JJ, Sagredo O, Benito C, Romero J, Sánchez-Prieto J, Lutz B, Fernández-Ruiz J, Galve-Roperh I, Guzmán M (2014) A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci U S A 111:8257–8262CrossRefGoogle Scholar
- 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 291:9991–10005CrossRefGoogle Scholar
- Colín-González AL, Paz-Loyola AL, Serratos I, Seminotti B, Ribeiro CA, Leipnitz G, Souza DO, Wajner M, Santamaria A (2015) Toxic synergism between quinolinic acid and organic acids accumulating in glutaric acidemia type I and in disorders of propionate metabolism in rat brain synaptosomes: relevance for metabolic acidemias. Neuroscience 308:64–74CrossRefGoogle Scholar
- Iwamura H, Suzuki H, Ueda Y, Kaya T, Inaba T (2001) In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J Pharmacol Exp Ther 296:420–425Google Scholar
- 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 401:84–95CrossRefGoogle Scholar
- Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- Ortega A, Rangel-López E, Hidalgo-Miranda A, Morales A, Ruiz-García E, Meneses-García A, Herrera-Gómez A, Aguilar-Ponce JL, González-Herrera IG, Guevara-Salazar P, Prospero-García O, Del Angel SA (2015) On the effects of CP 55-940 and other cannabinoid receptor agonists in C6 and U373 cell lines. Toxicol in Vitro 29:1941–1951CrossRefGoogle Scholar
- Pérez-De La Cruz V, Carrillo-Mora P, Santamaría A (2012) Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms. Int J Tryptophan Res 5:1–8Google Scholar
- 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 285:97–106CrossRefGoogle Scholar
- 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 34:55840–55862Google Scholar