Selective alpha7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis.
OBJECTIVE
In various models vagus nerve activation has been shown to ameliorate intestinal inflammation, via nicotinic acetylcholine receptors (nAChRs) expressed on immune cells. As the alpha7 nAChR has been put forward to mediate this effect, we studied the effect of nicotine and two selective alpha7 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.


METHODS
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 micromol.kg(-1)), AR-R17779 (0.6-30 micromol.kg(-1)) or GSK1345038A (6-120 micromol.kg(-1)) was administered daily by i.p. injection. After 7 (DSS) or 5 (TNBS) days clinical parameters and colonic inflammation were scored.


RESULTS
Nicotine and both alpha7 nAChR agonists reduced the activation of NF-kappaB 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 micromol.kg(-1)) and AR-R17779 (30 micromol.kg(-1)) ameliorated clinical parameters, without affecting colonic inflammation. Neither agonist ameliorated TNBS-induced colitis.


CONCLUSIONS
Although nicotine reduced cytokine responses in vitro, both selective alpha7 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 alpha7 nAChR as a drug target in colitis.
Snoek
Susanne A
SA
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands.
Verstege
Marleen I
MI
van der Zanden
Esmerij P
EP
Deeks
Nigel
N
Bulmer
David C
DC
Skynner
Michael
M
Lee
Kevin
K
Te Velde
Anje A
AA
Boeckxstaens
Guy E
GE
de Jonge
Wouter J
WJ
D000818:Animals; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012720:Severity of Illness Index; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D064569:alpha7 Nicotinic Acetylcholine Receptor
C408128:AR-R 17779; D001952:Bridged-Ring Compounds; C579166:Chrna7 protein, mouse; D016207:Cytokines; D016328:NF-kappa B; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine