title: 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.
authors.affiliation: 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.
authors.forename: Miguel
authors.initials: M
authors.lastname: Moreno-Martet
authors.affiliation: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Feliú
authors.affiliation: 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.
authors.forename: Francisco
authors.initials: F
authors.lastname: Espejo-Porras
authors.affiliation: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Mecha
authors.affiliation: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Carrillo-Salinas
authors.affiliation: 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.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.affiliation: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guaza
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: de Lago
mesh_terms: D000818:Animals; D002185:Cannabidiol; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology*; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010784:Photomicrography; D010880:Piperidines / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C578453:CNR1 protein, mouse; D063385:Cannabinoid Receptor Modulators; D004338:Drug Combinations; D018696:Neuroprotective Agents; D010880:Piperidines; D010936:Plant Extracts; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D002185:Cannabidiol; D013759:Dronabinol; C587251:nabiximols; D000077285:Rimonabant
keywords: CB(1) receptors; EAE mice; Multiple sclerosis; Phytocannabinoid-based medicines; Sativex; Therapeutic effects