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Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates

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Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

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. 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 α7nAChR lessens the efficacy of AN917 in this model.

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Acknowledgements

We thank Corina Bejar for her technical assistance and Dr. Eli Brazowski for analyzing the H&E colon sections.

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Authors and Affiliations

  1. Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel

    Helena Shifrin & Marta Weinstock

  2. Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Odelia Mouhadeb, Nathan Gluck & Chen Varol

Authors
  1. Helena Shifrin
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  2. Odelia Mouhadeb
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  3. Nathan Gluck
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  4. Chen Varol
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  5. Marta Weinstock
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Correspondence to Marta Weinstock.

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Shifrin, H., Mouhadeb, O., Gluck, N. et al. Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates. J Neuroimmune Pharmacol 12, 484–491 (2017). https://doi.org/10.1007/s11481-017-9735-8

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  • DOI: https://doi.org/10.1007/s11481-017-9735-8

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