title: A Sativex(®) -like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.
abstract: OBJECTIVE
  Sativex(®) is an oromucosal spray, containing equivalent amounts of Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler's murine encephalomyelitis virus-induced demyelinating disease model of MS.
  
  
  METHODS
  A Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures.
  
  
  RESULTS
  Sativex improved motor activity - reduced CNS infiltrates, microglial activity, axonal damage - and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1β gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ(9) -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors.
  
  
  CONCLUSIONS
  The data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair.
authors: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors: A
authors: A
authors: Feliú
authors: Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.
authors: M
authors: M
authors: Moreno-Martet
authors: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors: M
authors: M
authors: Mecha
authors: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors: F J
authors: FJ
authors: Carrillo-Salinas
authors: Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.
authors: E
authors: E
authors: de Lago
authors: Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.
authors: J
authors: J
authors: Fernández-Ruiz
authors: Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors: C
authors: C
authors: Guaza
mesh_terms: D000818:Animals; D002185:Cannabidiol / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology*; D010936:Plant Extracts / Q000008:administration & dosage / Q000627:therapeutic use*; D017945:Theilovirus / Q000472:pathogenicity*
chemical_list: D004338:Drug Combinations; D010936:Plant Extracts; D002185:Cannabidiol; D013759:Dronabinol; C587251:nabiximols