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

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 therefore have potential therapeutic application in humans. addition of che inhibition and indirect activation of α7nachr lessens the efficacy of an917 in this model.