A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules.
Adhesion molecules are critical players in the regulation of transmigration of blood leukocytes across the blood-brain barrier in multiple sclerosis (MS). Cannabinoids (CBs) are potential therapeutic agents in the treatment of MS, but the mechanisms involved are only partially known. Using a viral model of MS we observed that the cannabinoid agonist WIN55,212-2 administered at the time of virus infection suppresses intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in brain endothelium, together with a reduction in perivascular CD4+ T lymphocytes infiltrates and microglial responses. WIN55,212-2 also interferes with later progression of the disease by reducing symptomatology and neuroinflammation. In vitro data from brain endothelial cell cultures, provide the first evidence of a role of peroxisome proliferator-activated receptors gamma (PPARgamma) in WIN55,212-2-induced downregulation of VCAM-1. This study highlights that inhibition of brain adhesion molecules by WIN55,212-2 might underline its therapeutic effects in MS models by targeting PPAR-gamma receptors.
Mestre
L
L
Neuroimmunology Group, Functional and Systems Neurobiology Department, Cajal Institute (CSIC), Av. Doctor Arce 37, 28002 Madrid, Spain.
Docagne
F
F
Correa
F
F
Loría
F
F
Hernangómez
M
M
Borrell
J
J
Guaza
C
C
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D048588:Benzoxazines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002186:Cannabinoids / Q000819:agonists* / Q000494:pharmacology* / Q000627:therapeutic use; D018188:Cardiovirus Infections / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000502:physiology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D009281:Naphthalenes / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D017945:Theilovirus / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D047495:PPAR gamma; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone