The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia

• Published in: Journal of neuroimmunology 2012-10, Vol.251 (1), p.65-72
• Main Authors: Thomsen, Morten S, Mikkelsen, Jens D
• Format: Article
• Language: English
• Subjects: Aconitine - analogs & derivatives; Aconitine - pharmacology; Allergy and Immunology; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents - pharmacology; Azabicyclo Compounds - pharmacology; Aβ1–42; Benzylidene Compounds - pharmacology; Furans - pharmacology; GTS-21; Inflammation; Lipopolysaccharides - pharmacology; Male; MAP Kinase Signaling System - drug effects; Microglia - drug effects; Mitogen-activated protein kinase; Neuroinflammation; Neurology; Nicotinic acetylcholine receptor; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - pharmacology; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - drug effects; Tumor Necrosis Factor-alpha - secretion
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2012.07.006

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.