title: The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia.
abstract: The anti-inflammatory properties of, particularly the α7, nicotinic acetylcholine receptors (nAChRs) in the peripheral immune system are well documented. There are also reports of anti-inflammatory actions of nicotine in the CNS, but it is unclear, whether this is due to activation or inhibition of nAChRs. Here we investigate the mechanisms behind α7 nAChR-mediated modulation of TNF-α release. We show that α7 nAChR agonists or positive allosteric modulators do not affect LPS-induced release of the pro-inflammatory cytokine TNF-α from cultured microglia. This suggests that classical activation of, i.e. ion-flux through, the α7 nAChR does not reduce TNF-α release from activated microglia. Contrarily, the α7 nAChR antagonist methyllycaconitine and the weak (<10%) agonist NS6740 reduced LPS-induced TNF-α release, indicating that α7 nAChR antagonism conveys anti-inflammatory properties on microglia. The effect of methyllycaconitine or NS6740 was not due to changes in MAPK signaling. These results suggest that the anti-inflammatory effects of nicotine seen in vivo are not due to classical activation of the α7 nAChR, and further suggest that antagonism of α7 nAChRs may reduce neuroinflammation.
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark. morten.s.thomsen@nru.dk
authors.forename: Morten S
authors.initials: MS
authors.lastname: Thomsen
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C547286:1,4-diazabicyclo(3.2.2)nonan-4-yl(5-(3-(trifluoromethyl)phenyl)furan-2-yl)methanone; D000893:Anti-Inflammatory Agents; D053961:Azabicyclo Compounds; D001597:Benzylidene Compounds; C579165:Chrna7 protein, rat; D005663:Furans; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D000157:Aconitine