title: Sex Differences and Drug Dose Influence the Role of the α7 Nicotinic Acetylcholine Receptor in the Mouse Dextran Sodium Sulfate-Induced Colitis Model.
abstract: BACKGROUND
  α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis.
  
  
  METHODS
  Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels.
  
  
  RESULTS
  Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses.
  
  
  CONCLUSIONS
  Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse.
  
  
  CONCLUSIONS
  Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.
authors.affiliation: Department of Pharmacology and Toxicology, King Saud University, Riyadh, Saudi Arabia.|Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Shakir D
authors.initials: SD
authors.lastname: AlSharari
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA.|Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Bagdas
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Patraic A
authors.initials: PA
authors.lastname: Lichtman
authors.affiliation: Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Erinn S
authors.initials: ES
authors.lastname: Raborn
authors.affiliation: Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Cabral
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont, Burlington, VT.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McGee
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000235:genetics; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D000893:Anti-Inflammatory Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007555:Isoxazoles; C513163:N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide; D010671:Phenylurea Compounds; D011812:Quinuclidines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016264:Dextran Sulfate