title: Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates.
abstract: Indoline carbamates, AN680 and AN917 decrease cytokines, TNF-α and IL-6 in peritoneal macrophages activated by lipopolysaccharide (LPS) and in mouse tissues after LPS injection. They prevent nuclear translocation of nuclear factor κB (NF-κB) and activator protein 1. Only AN917 inhibits cholinesterase (ChE) at relevant concentrations. ChE inhibitors decrease NF-κB by activating α7 nicotinic acetylcholine receptors (α7nAChR). The current study compared the effect of rivastigmine, a ChE inhibitor, AN680 and AN917 on ulcerative colitis induced in mice by ingestion of dextran sodium sulfate (4.5%) solution. Rivastigmine (1 mg/kg), AN680 (2.5-10 mg/kg) and AN917 (2-5 mg/kg) were injected subcutaneously once daily for 8 days. Disease severity was assessed by disease activity index (DAI), colonoscopy, colon length and body weight loss, colonic levels of TNF-α, IL-6, IL-1β and myeloid peroxidase (MPO) activity. AN680 (5 mg/kg) reduced DAI, colon shrinkage, weight loss, histopathological signs of colon damage, MPO activity, TNF-α, IL-1β and IL-6 levels without inhibiting ChE. AN917 (5 mg/kg) and rivastigmine (1 mg/kg) inhibited ChE in plasma and colon by 65%, reduced DAI, MPO activity and IL-6, but not TNF-α or IL-1β. AN917 did not prevent weight loss or colon shrinkage. Mecamylamine abolished the reduction of DAI, MPO activity and IL-6 by AN917 and rivastigmine, indicating they were mediated by α7nAChR.
  
  
  
  AN680 is very effective in preventing DSS-induced UC in mice and may therefore have potential therapeutic application in humans. Addition of ChE inhibition and indirect activation of α7nAChR lessens the efficacy of AN917 in this model.
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Helena
authors.initials: H
authors.lastname: Shifrin
authors.affiliation: Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Odelia
authors.initials: O
authors.lastname: Mouhadeb
authors.affiliation: Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Nathan
authors.initials: N
authors.lastname: Gluck
authors.affiliation: Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Varol
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel. martar@ekmd.huji.ac.il.
authors.forename: Marta
authors.initials: M
authors.lastname: Weinstock
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000473:pathology*; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D000068836:Rivastigmine / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007211:Indoles; D064569:alpha7 Nicotinic Acetylcholine Receptor; C057812:indoline; D000068836:Rivastigmine
keywords: Cholinesterase inhibition; Colonoscopy; Cytokines; Dextran sodium sulfate; Mice; Myeloid peroxidase activity