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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.

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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).

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Correspondence to Abel Santamaría.

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The experimental protocols were approved by the Ethics Committee for Animal Research of the Instituto Nacional de Neurología y Neurocirugía (Project No. 126/17).

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The authors declare that they have no competing interests.

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Maya-López, M., Rubio-López, L.C., Rodríguez-Alvarez, I.V. et al. 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, 126–135 (2020).

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  • Excitotoxicity
  • Endocannabinoid system
  • Neuroprotection
  • Oleamide
  • Quinolinic acid
  • Cannabinoid receptors