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Cannabidiol Recovers Dopaminergic Neuronal Damage Induced by Reserpine or α-synuclein in Caenorhabditis elegans

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Abstract

Progressive neurodegenerative disorders such as Parkinson Disease (PD) lack curative or long-term treatments. At the same time, the increase of the worldwide elderly population and, consequently, the extension in the prevalence of age-related diseases have promoted research interest in neurodegenerative disorders. Caenorhabditis elegans is a free-living nematode widely used as an animal model in studies of human diseases. Here we evaluated cannabidiol (CBD) as a possible neuroprotective compound in PD using the C. elegans models exposed to reserpine. Our results demonstrated that CBD reversed the reserpine-induced locomotor alterations and this response was independent of the NPR-19 receptors, an orthologous receptor for central cannabinoid receptor type 1. Morphological alterations of cephalic sensilla (CEP) dopaminergic neurons indicated that CBD also protects neurons from reserpine-induced degeneration. That is, CBD attenuates the reserpine-induced increase of worms with shrunken soma and dendrites loss, increasing the number of worms with intact CEP neurons. Finally, we found that CBD also reduced ROS formation and α-syn protein accumulation in mutant worms. Our findings collectively provide new evidence that CBD acts as neuroprotector in dopaminergic neurons, reducing neurotoxicity and α-syn accumulation highlighting its potential in the treatment of PD.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Marina Yukari Kubota, Ingrid Kazue Mizuno Watanabe, Vanessa Gusmão, Cícero Ramos dos Santos, Maria de Lourdes Santos, Elizabeth Kanashiro for technical assistance.

Funding

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP: 2017/10863-7; 2019/14722-4 (GJSP); 2019/02821-8 (SSS). Confocal microscope Zeiss LSM 780 and Leica Microsystems TCSSP8 facility from the Instituto de Farmacologia e Biologia Molecular (INFAR) was supported by Financiadora de Estudos e Projetos (FINEP) and FAPESP.Post-doctoral (AHFFL) and Doctoral (ECG) fellowships were supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Post-doctoral (AGE) fellowship was supported by FAPESP: 2020/08840-1.

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ECG, PR, GJSP Conception and design of all experimental protocols. ECG, AGE, AHFFL, CAC, VCA, AWZ, JECH, JAC, CB, SSS, PR, GJSP Development of methodology performed. ECG, AGE, AHFFL, CAC, PR, GJSP Data acquisition, analysis and interpretation of results related to worm behavior on locomotion, defecation, egg production and egg laying parameters, fluorescence microscopy and western blotting. ECG, AGE, AHFFL, CAC, VCA, AWZ, JECH, JAC, CB, SSS, PR, GJSP Writing and/or revision of the manuscript. Study supervision: PR, GJSP All authors approved the final version of the manuscript.

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Correspondence to Gustavo J. S. Pereira.

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Competing Interest

JAC reported receiving grants from the National Institute of Translational Science and Technology in Medicine and personal fees from the National Council for Scientific and Technological Development (CNPq 1A) during the conduct of the study, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs) and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. JAC is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Janssen-Cilag, Torrent, GreenCare, PurMed Global, BioSynthesis Pharma Group (BSPG), and Prati-Donaduzzi. JAC reported receiving grants from FAPESP. The other authors declare no conflicts of interest.

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da Cruz Guedes, E., Erustes, A.G., Leão, A.H.F.F. et al. Cannabidiol Recovers Dopaminergic Neuronal Damage Induced by Reserpine or α-synuclein in Caenorhabditis elegans. Neurochem Res 48, 2390–2405 (2023). https://doi.org/10.1007/s11064-023-03905-z

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