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 alpha 7 nAChR has been put forward to mediate this effect, we studied the effect of nicotine and two selective alpha 7 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 mu mol center dot kg-1), AR-R17779 (0.6-30 mu mol center dot kg-1) or GSK1345038A (6-120 mu mol center dot 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 alpha 7 nAChR agonists reduced the activation of NF-kappa B 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 mu mol center dot kg-1) and AR-R17779 (30 mu mol center dot 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 alpha 7 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 alpha 7 nAChR as a drug target in colitis.