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A Comparative In Vitro Study of the Neuroprotective Effect Induced by Cannabidiol, Cannabigerol, and Their Respective Acid Forms: Relevance of the 5-HT1A Receptors

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Abstract

Previous preclinical studies have demonstrated that cannabidiol (CBD) and cannabigerol (CBG), two non-psychotomimetic phytocannabinoids from Cannabis sativa, induce neuroprotective effects on toxic and neurodegenerative processes. However, a comparative study of both compounds has not been reported so far, and the targets involved in this effect remain unknown. The ability of CBD and CBG to attenuate the neurotoxicity induced by two insults involving oxidative stress (hydrogen peroxide, H2O2) and mitochondrial dysfunction (rotenone) was evaluated in neural cell cultures. The involvement of CB-1 and CB-2 or 5-HT1A receptors was investigated. The neuroprotective effect of their respective acids forms, cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), was also analyzed. MTT and immunocytochemistry assays were used to evaluate cell viability. No significant variation on cell viability was per se induced by the lower concentrations tested of CBD and CBG or CBDA and CBGA; however, high concentrations of CBD, CBDA, or CBGA were toxic since a 40–50% reduction of cell viability was observed. CBD and CBG showed neuroprotective effects against H2O2 or rotenone; however, both compounds were more effective in attenuating the rotenone-induced neurotoxicity. A high concentration of CBDA reduced the rotenone-induced neurotoxicity. WAY100635 (5-HT1A receptor antagonist) but not AM251 and AM630 (CB1 or CB2 receptor antagonists, respectively) significantly diminished the neuroprotective effect induced by CBG only against rotenone. Our results contribute to the understanding of the neuroprotective effect of CBD and CBG, showing differences with their acid forms, and also highlight the role of 5-HT1A receptors in the mechanisms of action of CBG.

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Acknowledgments

We are grateful to Dr. Raquel Peyraube for her remarkable help in the Cannabis field, and we thank Analía Richeri PhD for her technical support. This study has a license from IRCCA, Uruguay.

Funding

This study was partially supported by Premio Concursable Junta Nacional de Drogas (Uruguay), PEDECIBA (Uruguay), and FONDECYT-CHILE Grant 1170662.

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Authors and Affiliations

  1. Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Avenida Italia 3318, CP 11600, Montevideo, Uruguay

    Carolina Echeverry, Giselle Prunell & Camila Narbondo

  2. Phytoplant Research S.L., Cordoba, Spain

    Verónica Sánchez de Medina

  3. EthnoPhytoTech Research & Consulting S.L.U., Sant Cugat del Valles, Spain

    Xavier Nadal

  4. Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile

    Miguel Reyes-Parada

  5. Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile

    Miguel Reyes-Parada

  6. Department of Experimental Neuropharmacology, IIBCE, Montevideo, Uruguay

    Cecilia Scorza

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  1. Carolina Echeverry
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Correspondence to Carolina Echeverry.

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Cannabinoids used were donated by Pyhtoplant Research (Spain). Verónica Sánchez de Medina works for Phytoplant Research S.L., and Xavier Nadal is a former employee.

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Echeverry, C., Prunell, G., Narbondo, C. et al. A Comparative In Vitro Study of the Neuroprotective Effect Induced by Cannabidiol, Cannabigerol, and Their Respective Acid Forms: Relevance of the 5-HT1A Receptors. Neurotox Res 39, 335–348 (2021). https://doi.org/10.1007/s12640-020-00277-y

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