Thomsen_2012_J.Neuroimmunol_251_65

The anti-inflammatory properties of, particularly the alpha7, 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 alpha7 nAChR-mediated modulation of TNF-alpha release. We show that alpha7 nAChR agonists or positive allosteric modulators do not affect LPS-induced release of the pro-inflammatory cytokine TNF-alpha from cultured microglia. This suggests that classical activation of, i.e. ion-flux through, the alpha7 nAChR does not reduce TNF-alpha release from activated microglia. Contrarily, the alpha7 nAChR antagonist methyllycaconitine and the weak (<10%) agonist NS6740 reduced LPS-induced TNF-alpha release, indicating that alpha7 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 alpha7 nAChR, and further suggest that antagonism of alpha7 nAChRs may reduce neuroinflammation.