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Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity.

Abstract

Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.

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  • Authors+Show Affiliations

    ,

    Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifique, 06560 Valbonne, France.

    , , ,

    Source

    MeSH

    Animals
    Cannabidiol
    Cannabinoids
    Cell Movement
    Cells, Cultured
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Mice
    Mice, Inbred C57BL
    Mice, Neurologic Mutants
    Microglia
    Nerve Degeneration
    Neurons
    Neuroprotective Agents
    Prions
    Scrapie
    Sheep
    Survival Rate
    Treatment Outcome

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17804615

    Citation

    Dirikoc, Sevda, et al. "Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons Against Prion Toxicity." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 27, no. 36, 2007, pp. 9537-44.
    Dirikoc S, Priola SA, Marella M, et al. Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. J Neurosci. 2007;27(36):9537-44.
    Dirikoc, S., Priola, S. A., Marella, M., Zsürger, N., & Chabry, J. (2007). Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 27(36), pp. 9537-44.
    Dirikoc S, et al. Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons Against Prion Toxicity. J Neurosci. 2007 Sep 5;27(36):9537-44. PubMed PMID: 17804615.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. AU - Dirikoc,Sevda, AU - Priola,Suzette A, AU - Marella,Mathieu, AU - Zsürger,Nicole, AU - Chabry,Joëlle, PY - 2007/9/7/pubmed PY - 2007/10/3/medline PY - 2007/9/7/entrez SP - 9537 EP - 44 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 27 IS - 36 N2 - Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/17804615/Nonpsychoactive_cannabidiol_prevents_prion_accumulation_and_protects_neurons_against_prion_toxicity_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17804615 DB - PRIME DP - Unbound Medicine ER -