Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212.
Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.
Croxford
J Ludovic
JL
Department of Microbiology-Immunology, Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
Miller
Stephen D
SD
D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000821:virology; D018188:Cardiovirus Infections / Q000150:complications; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D013759:Dronabinol / Q000378:metabolism; D005260:Female; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D018991:Myelin Proteolipid Protein / Q000276:immunology; D009281:Naphthalenes / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D017945:Theilovirus; D019562:Viral Load
D048588:Benzoxazines; D016207:Cytokines; D009025:Morpholines; D018991:Myelin Proteolipid Protein; D009281:Naphthalenes; D010446:Peptide Fragments; D012333:RNA, Messenger; C435023:myelin proteolipid protein (139-151); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol