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URB597 Prevents the Short-Term Excitotoxic Cell Damage in Rat Cortical Slices: Role of Cannabinoid 1 Receptors

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Abstract

Endocannabinoid-based therapies constitute an emerging tool for the potential treatment of neurodegenerative disorders, requiring characterization at the experimental level. The effects of URB597, an inhibitor of the fatty acid amide hydrolase (FAAH), were tested against the quinolinic acid (QUIN)-induced early toxic effects in rat cortical slices, and compared with those effects exerted by the endocannabinoid anandamide (AEA). URB597 prevented the QUIN-induced loss of mitochondrial function/cell viability and lipid peroxidation, while reduced necrosis, and to a lesser extent, apoptosis. The protective effects of URB597 were mediated by activation of cannabinoid receptor 1 (CB1r), as evidenced by their inhibition by the selective CB1r antagonist AM281. Similar effects were observed when testing AEA against QUIN toxicity. Our findings demonstrate the neuroprotective properties of URB597 during the early stages of excitotoxic damage to cortical tissue, suggesting that these properties are mediated by FAAH inhibition, and might be linked to the protective effects of AEA, or the combination of endocannabinoids.

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Funding

This work was supported by the CONACYT-TUBITAK collaborative agreement (grant 265991 given to AS) and the National Institute of Environmental Health Sciences (grants R01ES03771, R01ES10563, and R01ES020852 given to MA). None of the sponsors were involved in design, collection, analysis, or interpretation of data, neither in writing of the report or decision to submit the article for publication.

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Authors and Affiliations

  1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., 14269, Mexico City, Mexico

    Karla Chavira-Ramos, Abel Santamaría & Ana Laura Colín-González

  2. Laboratorio de Medicina Personalizada, Instituto Nacional de Cancerología, S.S.A., 14080, Mexico City, Mexico

    Mario Orozco-Morales

  3. Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Beşevler, 06500, Ankara, Turkey

    Çimen Karasu

  4. IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

    Alexey A. Tinkov

  5. Yaroslavl State University, Yaroslavl, Russia

    Alexey A. Tinkov

  6. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 11354, USA

    Michael Aschner

  7. Banco de Tumores, Instituto Nacional de Cancerología, S.S.A., 14080, Mexico City, Mexico

    Ana Laura Colín-González

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  1. Karla Chavira-Ramos
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  2. Mario Orozco-Morales
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  3. Çimen Karasu
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  4. Alexey A. Tinkov
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  6. Abel Santamaría
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  7. Ana Laura Colín-González
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Correspondence to Abel Santamaría.

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Chavira-Ramos, K., Orozco-Morales, M., Karasu, Ç. et al. URB597 Prevents the Short-Term Excitotoxic Cell Damage in Rat Cortical Slices: Role of Cannabinoid 1 Receptors. Neurotox Res 39, 146–155 (2021). https://doi.org/10.1007/s12640-020-00301-1

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