| Title : Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates - Shifrin_2017_J.Neuroimmune.Pharmacol_12_484 |
| Author(s) : Shifrin H , Mouhadeb O , Gluck N , Varol C , Weinstock M |
| Ref : J Neuroimmune Pharmacol , 12 :484 , 2017 |
| Abstract : Indoline carbamates, AN680 and AN917 decrease cytokines, TNF-alpha and IL-6 in peritoneal macrophages activated by lipopolysaccharide (LPS) and in mouse tissues after LPS injection. They prevent nuclear translocation of nuclear factor kappaB (NF-kappaB) and activator protein 1. Only AN917 inhibits cholinesterase (ChE) at relevant concentrations. ChE inhibitors decrease NF-kappaB by activating alpha7 nicotinic acetylcholine receptors (alpha7nAChR). 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-alpha, IL-6, IL-1beta and myeloid peroxidase (MPO) activity. AN680 (5 mg/kg) reduced DAI, colon shrinkage, weight loss, histopathological signs of colon damage, MPO activity, TNF-alpha, IL-1beta 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-alpha or IL-1beta. 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 alpha7nAChR. CONCLUSIONS: 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 alpha7nAChR lessens the efficacy of AN917 in this model. |
| ESTHER : Shifrin_2017_J.Neuroimmune.Pharmacol_12_484 |
| PubMedSearch : Shifrin_2017_J.Neuroimmune.Pharmacol_12_484 |
| PubMedID: 28271317 |
Shifrin H, Mouhadeb O, Gluck N, Varol C, Weinstock M (2017)
Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates
J Neuroimmune Pharmacol
12 :484
Shifrin H, Mouhadeb O, Gluck N, Varol C, Weinstock M (2017)
J Neuroimmune Pharmacol
12 :484