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Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes.

Abstract

Heavy marijuana use has been linked to white matter histological alterations. However, the impact of cannabis constituents on oligodendroglial pathophysiology remains poorly understood. Here, we investigated the in vitro effects of cannabidiol, the main nonpsychoactive marijuana component, on oligodendrocytes. Exposure to cannabidiol induced an intracellular Ca(2+) rise in optic nerve oligodendrocytes that was not primarily mediated by entry from the extracellular space, nor by interactions with ryanodine or IP(3) receptors. Application of the mitochondrial protonophore carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP; 1 μM) completely prevented subsequent cannabidiol-induced Ca(2+) responses. Conversely, the increase in cytosolic Ca(2+) levels elicited by FCCP was reduced after previous exposure to cannabidiol, further suggesting that the mitochondria acts as the source of cannabidiol-evoked Ca(2+) rise in oligodendrocytes. n addition, brief exposure to cannabidiol (100 nM-10 μM) led to a concentration-dependent decrease of oligodendroglial viability that was not prevented by antagonists of CB(1), CB(2), vanilloid, A(2A) or PPARγ receptors, but was instead reduced in the absence of extracellular Ca(2+). The oligodendrotoxic effect of cannabidiol was partially blocked by inhibitors of caspase-3, -8 and -9, PARP-1 and calpains, suggesting the activation of caspase-dependent and -independent death pathways. Cannabidiol also elicited a concentration-dependent alteration of mitochondrial membrane potential, and an increase in reactive oxygen species (ROS) that was reduced in the absence of extracellular Ca(2+). Finally, cannabidiol-induced cytotoxicity was partially prevented by the ROS scavenger trolox. Together, these results suggest that cannabidiol causes intracellular Ca(2+) dysregulation which can lead to oligodendrocytes demise.

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  • Authors+Show Affiliations

    ,

    Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Spain.

    ,

    Source

    Glia 58:14 2010 Nov 01 pg 1739-47

    MeSH

    Animals
    Calcium
    Calcium Signaling
    Cannabidiol
    Cells, Cultured
    Intracellular Fluid
    Neurotoxins
    Oligodendroglia
    Oxidative Stress
    Rats
    Rats, Sprague-Dawley
    Up-Regulation

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    20645411

    Citation

    Mato, Susana, et al. "Cannabidiol Induces Intracellular Calcium Elevation and Cytotoxicity in Oligodendrocytes." Glia, vol. 58, no. 14, 2010, pp. 1739-47.
    Mato S, Victoria Sánchez-Gómez M, Matute C. Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia. 2010;58(14):1739-47.
    Mato, S., Victoria Sánchez-Gómez, M., & Matute, C. (2010). Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia, 58(14), pp. 1739-47. doi:10.1002/glia.21044.
    Mato S, Victoria Sánchez-Gómez M, Matute C. Cannabidiol Induces Intracellular Calcium Elevation and Cytotoxicity in Oligodendrocytes. Glia. 2010 Nov 1;58(14):1739-47. PubMed PMID: 20645411.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. AU - Mato,Susana, AU - Victoria Sánchez-Gómez,María, AU - Matute,Carlos, PY - 2010/7/21/entrez PY - 2010/7/21/pubmed PY - 2011/6/2/medline SP - 1739 EP - 47 JF - Glia JO - Glia VL - 58 IS - 14 N2 - Heavy marijuana use has been linked to white matter histological alterations. However, the impact of cannabis constituents on oligodendroglial pathophysiology remains poorly understood. Here, we investigated the in vitro effects of cannabidiol, the main nonpsychoactive marijuana component, on oligodendrocytes. Exposure to cannabidiol induced an intracellular Ca(2+) rise in optic nerve oligodendrocytes that was not primarily mediated by entry from the extracellular space, nor by interactions with ryanodine or IP(3) receptors. Application of the mitochondrial protonophore carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP; 1 μM) completely prevented subsequent cannabidiol-induced Ca(2+) responses. Conversely, the increase in cytosolic Ca(2+) levels elicited by FCCP was reduced after previous exposure to cannabidiol, further suggesting that the mitochondria acts as the source of cannabidiol-evoked Ca(2+) rise in oligodendrocytes. n addition, brief exposure to cannabidiol (100 nM-10 μM) led to a concentration-dependent decrease of oligodendroglial viability that was not prevented by antagonists of CB(1), CB(2), vanilloid, A(2A) or PPARγ receptors, but was instead reduced in the absence of extracellular Ca(2+). The oligodendrotoxic effect of cannabidiol was partially blocked by inhibitors of caspase-3, -8 and -9, PARP-1 and calpains, suggesting the activation of caspase-dependent and -independent death pathways. Cannabidiol also elicited a concentration-dependent alteration of mitochondrial membrane potential, and an increase in reactive oxygen species (ROS) that was reduced in the absence of extracellular Ca(2+). Finally, cannabidiol-induced cytotoxicity was partially prevented by the ROS scavenger trolox. Together, these results suggest that cannabidiol causes intracellular Ca(2+) dysregulation which can lead to oligodendrocytes demise. SN - 1098-1136 UR - https://www.unboundmedicine.com/medline/citation/20645411/Cannabidiol_induces_intracellular_calcium_elevation_and_cytotoxicity_in_oligodendrocytes_ L2 - https://doi.org/10.1002/glia.21044 DB - PRIME DP - Unbound Medicine ER -