Tags

Type your tag names separated by a space and hit enter

The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors.

Abstract

Sativex(®), an equimolecular combination of Δ(9)-tetrahydrocannabinol-botanical drug substance (Δ(9)-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain. However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components. In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice. We compared the effect of a Sativex-like combination of Δ(9)-THC-BDS (10 mg/kg) and CBD-BDS (10 mg/kg) with Δ(9)-THC-BDS (20 mg/kg) or CBD-BDS (20 mg/kg) administered separately by intraperitoneal administration to EAE mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease. The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS. These effects were completely reproduced by the treatment with Δ(9)-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord. Next, we investigated the potential targets involved in the effects of Δ(9)-THC-BDS by selectively blocking CB(1) or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB(1) receptor antagonist. Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ(9)-THC-BDS acting through CB(1) receptors.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Ciudad Universitaria s/n, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.

    ,

    Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.

    ,

    Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Ciudad Universitaria s/n, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.

    ,

    Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.

    ,

    Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.

    ,

    Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Ciudad Universitaria s/n, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. Electronic address: jjfr@med.ucm.es.

    ,

    Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.

    Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Ciudad Universitaria s/n, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.

    Source

    MeSH

    Animals
    Cannabidiol
    Cannabinoid Receptor Modulators
    Dronabinol
    Drug Combinations
    Drug Evaluation, Preclinical
    Encephalomyelitis, Autoimmune, Experimental
    Female
    Mice, Inbred C57BL
    Neuroprotective Agents
    Photomicrography
    Piperidines
    Plant Extracts
    Pyrazoles
    Receptor, Cannabinoid, CB1
    Rimonabant
    Spinal Cord

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    26590655

    Citation

    Moreno-Martet, Miguel, et al. "The Disease-modifying Effects of a Sativex-like Combination of Phytocannabinoids in Mice With Experimental Autoimmune Encephalomyelitis Are Preferentially Due to Δ9-tetrahydrocannabinol Acting Through CB1 Receptors." Multiple Sclerosis and Related Disorders, vol. 4, no. 6, 2015, pp. 505-11.
    Moreno-Martet M, Feliú A, Espejo-Porras F, et al. The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors. Mult Scler Relat Disord. 2015;4(6):505-11.
    Moreno-Martet, M., Feliú, A., Espejo-Porras, F., Mecha, M., Carrillo-Salinas, F. J., Fernández-Ruiz, J., ... de Lago, E. (2015). The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors. Multiple Sclerosis and Related Disorders, 4(6), pp. 505-11. doi:10.1016/j.msard.2015.08.001.
    Moreno-Martet M, et al. The Disease-modifying Effects of a Sativex-like Combination of Phytocannabinoids in Mice With Experimental Autoimmune Encephalomyelitis Are Preferentially Due to Δ9-tetrahydrocannabinol Acting Through CB1 Receptors. Mult Scler Relat Disord. 2015;4(6):505-11. PubMed PMID: 26590655.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors. AU - Moreno-Martet,Miguel, AU - Feliú,Ana, AU - Espejo-Porras,Francisco, AU - Mecha,Miriam, AU - Carrillo-Salinas,Francisco J, AU - Fernández-Ruiz,Javier, AU - Guaza,Carmen, AU - de Lago,Eva, Y1 - 2015/08/05/ PY - 2015/04/01/received PY - 2015/07/22/revised PY - 2015/08/04/accepted PY - 2015/11/23/entrez PY - 2015/11/23/pubmed PY - 2016/8/27/medline KW - CB(1) receptors KW - EAE mice KW - Multiple sclerosis KW - Phytocannabinoid-based medicines KW - Sativex KW - Therapeutic effects SP - 505 EP - 11 JF - Multiple sclerosis and related disorders JO - Mult Scler Relat Disord VL - 4 IS - 6 N2 - Sativex(®), an equimolecular combination of Δ(9)-tetrahydrocannabinol-botanical drug substance (Δ(9)-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain. However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components. In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice. We compared the effect of a Sativex-like combination of Δ(9)-THC-BDS (10 mg/kg) and CBD-BDS (10 mg/kg) with Δ(9)-THC-BDS (20 mg/kg) or CBD-BDS (20 mg/kg) administered separately by intraperitoneal administration to EAE mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease. The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS. These effects were completely reproduced by the treatment with Δ(9)-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord. Next, we investigated the potential targets involved in the effects of Δ(9)-THC-BDS by selectively blocking CB(1) or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB(1) receptor antagonist. Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ(9)-THC-BDS acting through CB(1) receptors. SN - 2211-0356 UR - https://www.unboundmedicine.com/medline/citation/26590655/The_disease_modifying_effects_of_a_Sativex_like_combination_of_phytocannabinoids_in_mice_with_experimental_autoimmune_encephalomyelitis_are_preferentially_due_to_Δ9_tetrahydrocannabinol_acting_through_CB1_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-0348(15)00118-2 DB - PRIME DP - Unbound Medicine ER -