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.