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

  • Gabriela Aguilera-Portillo
  • Edgar Rangel-López
  • Juana Villeda-Hernández
  • Anahí Chavarría
  • Pilar Castellanos
  • Zubeyir Elmazoglu
  • Çimen Karasu
  • Isaac Túnez
  • Gibrán Pedraza
  • Mina Königsberg
  • Abel Santamaría
Article
  • 125 Downloads

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.

Keywords

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

Notes

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).

Author 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.

Funding

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.

References

  1. 1.
    Zádori D, Klivényi P, Szalárdy L, Fülöp F, Toldi J, Vécsei L (2012) Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: novel therapeutic strategies for neurodegenerative disorders. J Neurol Sci 322:187–191CrossRefPubMedGoogle Scholar
  2. 2.
    Essa M, Braidy N, Vijayan K, Subash S, Guillemin G (2013) Excitotoxicity in the pathogenesis of autism. Neurotox Res J 23:393–400CrossRefGoogle Scholar
  3. 3.
    Iacobucci G, Popescu G (2017) NMDA receptors: linking physiological output to biophysical operation. Nat Rev Neurosci 18:236–249CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rami A, Ferger D, Krieglstein J (1997) Blockade of calpain proteolytic activity rescues neurons from glutamate excitotoxicity. Neurosci Res 27:93–97CrossRefPubMedGoogle Scholar
  5. 5.
    Majewski M, Kozlowska A, Thoene M, Lepiarczyk E, Grzegorzewski W (2016) Overview of the role of vitamins and minerals on the kynurenine pathway in health and disease. J Physiol Pharmacol 67:3–19PubMedGoogle Scholar
  6. 6.
    Pérez-De La Cruz V, Konigsberg M, Santamaría A (2007) Kynurenine pathway and disease: an overview. CNS Neurol Disord Drug Targets 6:398–410CrossRefPubMedGoogle Scholar
  7. 7.
    Ghorayeb I, Bezard E, Fernagut P, Bioulac B, Tison F (2005) Animal models of parkinsonism. Rev Neurol (Paris) 161:907–915CrossRefGoogle Scholar
  8. 8.
    Ramaswamy S, McBride J, Kordower J (2007) Animal models of Huntington’s disease. ILAR J 48:356–373CrossRefPubMedGoogle Scholar
  9. 9.
    More S, Kumar H, Cho D, Yun Y, Choi D (2016) Toxin-induced experimental models of learning and memory impairment. Int J Mol Sci 17:E1447CrossRefPubMedGoogle Scholar
  10. 10.
    Stone T, Mackay G, Forrest C, Clark C, Darlington L (2003) Tryptophan metabolites and brain disorders. Clin Chem Lab Med 41:852–859CrossRefPubMedGoogle Scholar
  11. 11.
    Braidy N, Grant R, Adams S, Brew B, Guillemin G (2009) Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res J 16:77–86CrossRefGoogle Scholar
  12. 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
  13. 13.
    Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M et al (2002) International Union of Pharmacology. XXVII . Classification of cannabinoid receptors. Pharmacol Rev 54:161–202CrossRefPubMedGoogle Scholar
  14. 14.
    Kendall D, Yudowski G (2016) Cannabinoid receptors in the central nervous system: their signaling and roles in disease. Front Cell Neurosci 10:294PubMedGoogle Scholar
  15. 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
  16. 16.
    Lauckner J, Hille B, Mackie K (2005) The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci 102:19144–19149CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Basavarajappa B, Shivakumar M, Joshi V, Subbanna S (2017) Endocannabinoid system in neurodegenerative disorders. J Neurochem 142:624–648CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    De Petrocellis L, Cascio M, Di Marzo V (2004) The endocannabionid system: a general view and latest additions. Br J Pharmacol 141:765–774CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Palazuelos J, Aguado T, Pazos M, Julien B, Carrasco C, Resel E, Sagredo O, Benito C et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132:3152–3164CrossRefPubMedGoogle Scholar
  20. 20.
    Fowler C (2006) The cannabinoid system and its pharmacological manipulation—a review, with emphasis upon the uptake and hydrolysis of anandamide. Fundam Clin Pharmacol 20(6):549–562CrossRefPubMedGoogle Scholar
  21. 21.
    Hillard C, Jarrahian A (2003) Cellular accumulation of anandamide: consensus and controversy. Brain J Pharmacol 140:802–808CrossRefGoogle Scholar
  22. 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
  23. 23.
    Pelicao R, Santos M, Freitas-Lima L, Meyrelles S, Vasquez E, Nakamura-Palacios E, Rodrigues L (2016) URB597 inhibits oxidative stress induced by alcohol binging in the prefrontal cortex of adolescent rats. Neurosci Lett 15:17–22CrossRefGoogle Scholar
  24. 24.
    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 120:123–130CrossRefPubMedGoogle Scholar
  25. 25.
    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):1766–1782CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sánchez-Blázquez P, Rodríguez-Muñóz M, Garzón J (2014) The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front Pharmacol 4:169CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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
  28. 28.
    O’Sullivan S (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    O’Sullivan S (2016) An update on PPAR activation by cannabinoids. Br J Pharmacol 12:1899–1910CrossRefGoogle Scholar
  30. 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. 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. 32.
    Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th ed. Academic PressGoogle Scholar
  33. 33.
    Borlongan C, Randall T, Cahill D, Sanberg P (1995) Asymmetrical motor behavior in rats with unilateral striatal excitotoxic lesions as revealed by the elevated body swing test. Brain Res 676:231–234CrossRefPubMedGoogle Scholar
  34. 34.
    González R, Woods R (2008) Digital image processing, 3rd edn. Pearson Prentice Hall, USAGoogle Scholar
  35. 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. 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
  37. 37.
    Trigo-Damas I, Del Rey N, Blesa J (2018) Novel models for Parkinson’s disease and their impact on future drug discovery. Expert Opin Drug Discovery 13:229–239CrossRefGoogle Scholar
  38. 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
  39. 39.
    Holley S, Joshi P, Parievsky A, Galvan L, Chen J, Fisher Y, Huynh M, Cepeda C et al (2015) Enhanced GABAergic inputs contribute to functional alterations of cholinergic interneurons in the R6/2 mouse model of Huntington’s disease. eNeuro 2:e0008CrossRefPubMedGoogle Scholar
  40. 40.
    Kerr S, Armati P, Guillemin G, Brew B (1998) Chronic exposure of human neurons to quinolonic acid results in neuronal changes consistent with AIDS dementia complex. AIDS 5:355–363CrossRefGoogle Scholar
  41. 41.
    Qin Y, Soghomonian J, Chesselet M (1992) Effects of quinolinic acid on messenger RNAs encoding somatostatin and glutamic acid decarboxylases in the striatum of adult rats. Exp Neurol 115:200–211CrossRefPubMedGoogle Scholar
  42. 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
  43. 43.
    Rios C, Santamaría A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 16:1139–1143CrossRefPubMedGoogle Scholar
  44. 44.
    Santamaría A, Galván-Arzate S, Lisý V, Ali S, Duhart H, Osorio-Rico L, Ríos C, St’astný F (2001) Quinolinic acid induces oxidative stress in rat brain synaptosomes. Neuroreport 12:871–874CrossRefPubMedGoogle Scholar
  45. 45.
    Rodríguez-Martínez E, Camacho A, Maldonado P, Pedraza-Chaverrí J, Santamaría D, Galván-Arzate S, Santamaría A (2000) Effect of quinolinic acid on endogenous antioxidants in rat corpus striatum. Brain Res 858:436–439CrossRefPubMedGoogle Scholar
  46. 46.
    Howlett A, Abood M (2017) CB1 and CB2 receptor pharmacology. Adv Pharmacol 80:169–206CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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
  48. 48.
    Dowie M, Howard M, Nicholson L, Faull R, Hannan A, Glass M (2010) Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington’s disease transgenic mice. Neuroscience 170:324–336CrossRefPubMedGoogle Scholar
  49. 49.
    Sagredo O, Pazos M, Valdeolivas S, Fernández-Ruiz J (2012) Cannabinoids: novel medicines for the treatment of Huntington’s disease. Recent Patents CNS Drug Discov 7:41–48CrossRefGoogle Scholar
  50. 50.
    Pintor A, Tebano M, Martire A, Grieco R, Galluzzo M, Scattoni M, Pézzola A, Cocurello R et al (2006) The cannabinoid receptor agonists WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum. Neuropharmacology 51:1004–1012CrossRefPubMedGoogle Scholar
  51. 51.
    Chiarlone A, Bellocchio L, Blázquez C, Resel E, Soria-Gómez E, Cannich A, Ferrero J, Sagredo O et al (2014) A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci Press 111:8257–8262CrossRefGoogle Scholar
  52. 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
  53. 53.
    Rodríguez-Muñoz M, Cortés-Montero E, Pozo-Rodrigálvarez A, Sánchez-Blázquez P, Garzón-Niño J (2015) The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: Implications in neurological disorders. Oncotarget 6:35458–35477CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Panlilio LV, Justinova Z, Goldberg SR (2010) Animal models of cannabinoid reward. Br J Pharmacol 160:499–510CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Gabriela Aguilera-Portillo
    • 1
    • 2
  • Edgar Rangel-López
    • 1
  • Juana Villeda-Hernández
    • 3
  • Anahí Chavarría
    • 4
  • Pilar Castellanos
    • 5
  • Zubeyir Elmazoglu
    • 6
  • Çimen Karasu
    • 6
  • Isaac Túnez
    • 7
  • Gibrán Pedraza
    • 8
  • Mina Königsberg
    • 8
  • Abel Santamaría
    • 1
  1. 1.Laboratorio de Aminoácidos ExcitadoresInstituto Nacional de Neurología y Neurocirugía Manuel Velasco SuárezMexicoMexico
  2. 2.Posgrado en Biología Experimental, DCBSUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico
  3. 3.Laboratorio de Patología ExperimentalInstituto Nacional de Neurología y NeurocirugíaMexicoMexico
  4. 4.Unidad de Investigación en Medicina Experimental, Facultad de MedicinaUniversidad Nacional Autónoma de MéxicoMexicoMexico
  5. 5.Departamento de Ingeniería Eléctrica, División de Ciencias Biológicas y de la SaludUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico
  6. 6.Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical PharmacologyGazi UniversityAnkaraTurkey
  7. 7.Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) & Departmento de Bioquímica y Biología Molecular, Facultad de Medicina y EnfermeríaUniversidad de CórdobaCordobaSpain
  8. 8.Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la SaludUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico

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