The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation

Abstract

The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system. Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders. In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats. URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 μL intrastriatal, 240 nmol/μL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1). Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.

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Acknowledgements

Gabriela Aguilera-Portillo presents this article as the first author as it encompasses her work and efforts to obtain a Ph.D. degree at the Universidad Autónoma Metropolitana-Iztapalapa (Mexico). Authors express sincere gratitude to the Programa de Posgrado en Biología Experimental from the Universidad Autónoma Metropolitana-Iztapalapa for all the support provided throughout this study. We gratefully acknowledge the technical assistance of Dr. Ana Laura Colín-González. We also thank to the TUBITAK-SBAG (Project No.: 315S088).

Funding

This work was supported by CONACyT-TUBITAK Grant 265991 (A.S.). Gabriela Aguilera-Portillo received a scholarship from CONACyT (CVU486539).

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Authors

Contributions

GAP, AC, CK, IT, MK, and AS conceived and designed the experiments. GAP, ERL, JVH, GP, and AS performed the experiments and analyzed the data. GAP and AS wrote the paper. ÇK, ZE, AC, MK, GAP, and AS developed the theory and contributed to the final version of the manuscript.

Corresponding author

Correspondence to Abel Santamaría.

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The authors declare that they have no competing interests.

Research Involving Animals

Procedures carried out with animals were strictly developed to comply with the local guidelines for the use and care of laboratory animals (Norma Oficial Mexicana NOM-062-ZOO-2001), and the “Guidelines for the Use of Animals in Neuroscience Research” from the Society of Neuroscience. All experiments performed were timely approved by the Ethics Committee of the Instituto Nacional de Neurología y Neurocirugía. All efforts were made to minimize animal suffering during the experiments.

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Aguilera-Portillo, G., Rangel-López, E., Villeda-Hernández, J. et al. The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation. Mol Neurobiol 56, 844–856 (2019). https://doi.org/10.1007/s12035-018-1129-2

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Keywords

  • Endocannabinoid system
  • Fatty acid amide hydrolase
  • Cannabinoid receptor agonists
  • Neuroprotection
  • Excitotoxicity
  • Oxidative stress