The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation
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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.
KeywordsEndocannabinoid system Fatty acid amide hydrolase Cannabinoid receptor agonists Neuroprotection Excitotoxicity Oxidative stress
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).
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.
This work was supported by CONACyT-TUBITAK Grant 265991 (A.S.). Gabriela Aguilera-Portillo received a scholarship from CONACyT (CVU486539).
Compliance with Ethical Standards
Conflicts of Interest
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.
- 12.Pérez-De La Cruz V, Elinos-Calderón D, Carrillo-Mora P, Silvia-Adaya D, Konigsberg M, Morán J, Ali S, Chánez-Cárdenas M et al (2010) Time-course correlation of early toxic events in three models of striatal damage: modulation by proteases inhibition. Neurochem Int 56:834–842CrossRefPubMedGoogle Scholar
- 15.Ashton J, Friberg D, Darlington C, Smith P (2006) Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neuroscience 396:113–116Google Scholar
- 22.Maya-López M, Ruiz-Contreras H, de Jesús Negrete-Ruiz M, Martínez-Sánchez J, Benítez-Valenzuela J, Colín-González A, Villeda-Hernández J et al (2017) URB597 reduces biochemical, behavioral and morphological alterations in two neurotoxic models in rats. Biomed Pharmacother 88:745–753CrossRefPubMedGoogle Scholar
- 27.Rodríguez-Muños 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
- 30.Escamilla-Ramírez A, García E, Palencia-Hernández G, Colín-González A, Galván-Arzate S, Túnez I, Sotelo J, Santamaría A (2017) URB597 and the cannabinoid WIN55,212-2 reduce behavioral and neurochemical deficits induced by MPTP in mice: possible role of redox modulation and NMDA receptors. Neurotox Res 34:532–544CrossRefGoogle Scholar
- 31.Colín-González A, Orozco-Ibarra M, Chánez-Cárdenas M, Rangel-López E, Santamaría A, Pedraza-Chaverri J, Barrera-Oviedo D, Maldonado P (2013) Heme oxygenase-1 (HO-1) upregulation delays morphological and oxidative damage induced in an excitotoxic/pro-oxidabt model in the rat striatum. Neuroscience 12:91–101CrossRefGoogle Scholar
- 32.Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th ed. Academic PressGoogle Scholar
- 34.González R, Woods R (2008) Digital image processing, 3rd edn. Pearson Prentice Hall, USAGoogle Scholar
- 35.Rangel-López E, Colín-González A, Paz-Loyola A, Pinzón E, Torres I, Serratos I, Castellanos P, Wajner M et al (2015) Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain. Neuroscience 285:97–106CrossRefPubMedGoogle Scholar
- 36.Dunbar J, Hitchcock K, Latimer M, Rugg E, Ward N, Winn P (1992) Exctitotoxic lesions of the pedunculopontine tegmental nucleus of the rat. II. Examination of eating and drinking, rotation, and reaching and grasping following unilateral ibotenate of quinolinate lesions. Brain Res 589:194–206CrossRefPubMedGoogle Scholar
- 38.Santamaría A, Salvatierra-Sánchez R, Vázquez-Román B, Santiago-López D, Villeda-Hernández J, Galván-Arzate S, Jiménez-Capdeville M et al (2003) Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: In vitro and in vivo studies. J Neurochem 86:479–488CrossRefPubMedGoogle Scholar
- 42.Santana-Martínez R, Galván-Arzáte S, Hernández-Pando R, Chánez-Cárdenaz M, Avila-Chávez E, López-Acosta G, Pedraza-Chaverrí J, Santamaría A et al (2014) Sulphoraphane reduces the alterations induced by quinolinic acid: Modulation of glutathione levels. Neuroscience 272:188–198CrossRefPubMedGoogle Scholar
- 47.Casteels C, Martinez E, Bormans G, Camon L, de Vera N, Baekelandt V, Planas A, Laere K (2010) Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism. Eur J Nucl Med Mol Imaging 37:2354–2363CrossRefPubMedGoogle Scholar
- 52.Diaz-Alonso J, Paraíso-Luna J, Navarrete C, del Rïo C, Cantarero I, Palomares B, Aguareles J, Fernández-Ruiz J et al (2016) VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease. Sci Rep 6:29789CrossRefPubMedPubMedCentralGoogle Scholar