title: Role of α7 nicotinic acetylcholine receptors in regulating tumor necrosis factor-α (TNF-α) as revealed by subtype selective agonists.
abstract: Immunological responses to protect against excessive inflammation can be regulated by the central nervous system through the cholinergic anti-inflammatory pathway wherein acetylcholine released from vagus nerves can inhibit inflammatory cytokines. Although a role for the α7 nicotinic acetylcholine receptor (α7 nAChR) in mediating this pathway has been suggested, pharmacological modulation of the pathway by selective agonists remains to be further elucidated. In this study, the role of α7 nAChRs in the regulation of TNF-α release was investigated using high affinity and selective α7 nAChR agonists in mouse peritoneal macrophage and human whole blood in vitro, and in mouse serum in vivo. In mouse peritoneal macrophages, LPS-induced TNF-α release in vitro was inhibited by a selective α7 nAChR agonist, A-833834 (5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole), and that effect was attenuated by α7 nAChR antagonist methyllycaconitine. The inhibitory effect of A-833834 on LPS-induced TNF-α release was also observed in human whole blood in vitro. I.v. LPS-induced TNF-α release in mouse serum was attenuated following i.p. administration of A-833834. Similarly, i.v. LPS-induced TNF-α release in mouse serum was also attenuated following i.p. administration of A-585539, another α7 nAChR agonist with limited brain penetration, suggesting that these effects are mediated by peripheral α7 nAChRs. A-833834 was also efficacious in suppressing TNF-α release in mouse serum following oral administration in zymosan-induced peritonitis. These studies collectively demonstrate that selectively targeting α7 nAChRs could offer a novel therapeutic modality to treat acute and chronic inflammatory disease states.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, United States.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Li
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Mathieu
authors.forename: Richard
authors.initials: R
authors.lastname: Harris
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: John
authors.initials: J
authors.lastname: Malysz
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Anwar
authors.initials: A
authors.lastname: Murtaza
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Olson
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000097:blood; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018722:Nicotinic Agonists / Q000097:blood* / Q000494:pharmacology*; D009865:Oocytes; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D011978:Receptors, Nicotinic / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor