Selective α7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis

Background and purpose: In various models vagus nerve activation has been shown to ameliorate intestinal inflammation, via nicotinic acetylcholine receptors (nAChRs) expressed on immune cells. As the α7 nAChR has been put forward to mediate this effect, we studied the effect of nicotine and two selective α7 nAChR agonists (AR‐R17779, (‐)‐spiro[1‐azabicyclo[2.2.2] octane‐3,5′‐oxazolidin‐2′‐one and GSK1345038A) on disease severity in two mouse models of experimental colitis. Experimental approach: Colitis was induced by administration of 1.5% dextran sodium sulphate (DSS) in drinking water or 2 mg 2,4,6‐trinitrobenzene sulphonic acid (TNBS) intrarectally. Nicotine (0.25 and 2.50 µmol·kg−1), AR‐R17779 (0.6–30 µmol·kg−1) or GSK1345038A (6–120 µmol·kg−1) was administered daily by i.p. injection. After 7 (DSS) or 5 (TNBS) days clinical parameters and colonic inflammation were scored. Key results: Nicotine and both α7 nAChR agonists reduced the activation of NF‐κB and pro‐inflammatory cytokines in whole blood and macrophage cultures. In DSS colitis, nicotine treatment reduced colonic cytokine production, but failed to reduce disease parameters. Reciprocally, treatment with AR‐R17779 or GSK1345038A worsened disease and led to increased colonic pro‐inflammatory cytokine levels in DSS colitis. The highest doses of GSK1345038A (120 µmol·kg−1) and AR‐R17779 (30 µmol·kg−1) ameliorated clinical parameters, without affecting colonic inflammation. Neither agonist ameliorated TNBS‐induced colitis. Conclusions and implications: Although nicotine reduced cytokine responses in vitro, both selective α7 nAChR agonists worsened the effects of DSS‐induced colitis or were ineffective in those of TNBS‐induced colitis. Our data indicate the need for caution in evaluating α7 nAChR as a drug target in colitis.