Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal / physiology
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Benzoxazines / pharmacology
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Calcium Channel Blockers / pharmacology
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Cannabinoids / agonists*
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Cannabinoids / pharmacology*
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Cannabinoids / therapeutic use
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Cardiovirus Infections / physiopathology
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Disease Models, Animal
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Disease Progression
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Endothelium / cytology
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Endothelium / drug effects*
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Endothelium / metabolism
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Female
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Humans
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism*
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Mice
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Morpholines / pharmacology
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Motor Activity / physiology
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Multiple Sclerosis / drug therapy*
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Multiple Sclerosis / pathology*
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Multiple Sclerosis / physiopathology
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Naphthalenes / pharmacology
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PPAR gamma / metabolism
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / metabolism
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Theilovirus / metabolism
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Vascular Cell Adhesion Molecule-1 / genetics
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Vascular Cell Adhesion Molecule-1 / metabolism*
Substances
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Benzoxazines
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Calcium Channel Blockers
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Cannabinoids
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Morpholines
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Naphthalenes
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PPAR gamma
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone