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Selective α7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis
Author(s) -
Snoek Susanne A,
Verstege Marleen I,
van der Zanden Esmerij P,
Deeks Nigel,
Bulmer David C,
Skynner Michael,
Lee Kevin,
te Velde Anje A,
Boeckxstaens Guy E,
de Jonge Wouter J
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00699.x
Subject(s) - nicotine , colitis , pharmacology , nicotinic agonist , agonist , cytokine , inflammation , chemistry , acetylcholine , acetylcholine receptor , nicotinic acetylcholine receptor , medicine , inflammatory bowel disease , receptor , immunology , disease
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.