title: Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK.
abstract: OBJECTIVE
  To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future.
  
  
  METHODS
  We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium (DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the myeloperoxidase (MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase (p38MAPK) and its phosphorylated form (p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580 (SB), an inhibitor of p38, was investigated in parallel experiments, and the data were compared with those from intervention groups of WIN55 and SB alone or used together.
  
  
  RESULTS
  The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38MAPK was inhibited.
  
  
  CONCLUSIONS
  These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.
authors.affiliation: Ya-Jing Feng, Yong-Yu Li, Xu-Hong Lin, Kun Li, Ming-Hua Cao, Department of Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Feng
authors.affiliation: Ya-Jing Feng, Yong-Yu Li, Xu-Hong Lin, Kun Li, Ming-Hua Cao, Department of Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Yong-Yu
authors.initials: YY
authors.lastname: Li
authors.affiliation: Ya-Jing Feng, Yong-Yu Li, Xu-Hong Lin, Kun Li, Ming-Hua Cao, Department of Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Xu-Hong
authors.initials: XH
authors.lastname: Lin
authors.affiliation: Ya-Jing Feng, Yong-Yu Li, Xu-Hong Lin, Kun Li, Ming-Hua Cao, Department of Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.affiliation: Ya-Jing Feng, Yong-Yu Li, Xu-Hong Lin, Kun Li, Ming-Hua Cao, Department of Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Cao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; C578453:CNR1 protein, mouse; D063386:Cannabinoid Receptor Agonists; C571431:Cnr2 protein, mouse; D007093:Imidazoles; D015850:Interleukin-6; D009025:Morpholines; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D016264:Dextran Sulfate; D009195:Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Claudin-1; Endogenous cannabinoid system; Experimental colitis; Inflammatory bowel disease; p38MAPK