Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model.
Multiple sclerosis (MS) is the most common of the immune demyelinating disorders of the central nervous system (CNS). Leukocyte/endothelial interactions are important steps in the progression of the disease and substances that interfere with these activities have been evaluated as potential therapeutic agents. Cannabinoid receptor agonists have been shown to downregulate immune responses and there is preliminary evidence that they may slow the progress of MS. The purpose of this investigation was to determine how cannabinoid receptor agonists interfere with leukocyte rolling and adhesion. This was investigated in an experimental autoimmune encephalomyelitis (EAE) model using six to eight week old C57BL/6 mice. Mouse myelin oligodendrocyte protein and pertussis toxin were used to induce EAE. WIN 55212-2, CB1 and CB2 antagonist were given. By use of in vivo intravital microscopy, leukocyte/endothelial interactions were evaluated via a cranial window implanted two days before. The results demonstrated that EAE increases leukocyte rolling and firm adhesion in the brain, and that this increased leukocyte/endothelial interaction can be attenuated by administration of WIN 55212-2. Furthermore, use of the selective antagonists for the CB1 receptor (SR 141716A) and the CB2 receptor (SR144528) in this study demonstrated that the cannabinoid's inhibitory effects on leukocyte/endothelial interactions can be mediated by activating CB2 receptor.
Ni
Xiang
X
Department of Physiology, Temple University, 3420 N. Broad Street, Philadelphia, PA 19140, USA.
Geller
Ellen B
EB
Eppihimer
Michael J
MJ
Eisenstein
Toby K
TK
Adler
Martin W
MW
Tuma
Ronald F
RF
D000818:Animals; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology*; D005260:Female; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D009281:Naphthalenes / Q000494:pharmacology*; D010243:Paralysis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone