Li_2011_J.Neuroimmunol_239_37

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 alpha7 nicotinic acetylcholine receptor (alpha7 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 alpha7 nAChRs in the regulation of TNF-alpha release was investigated using high affinity and selective alpha7 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-alpha release in vitro was inhibited by a selective alpha7 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 alpha7 nAChR antagonist methyllycaconitine. The inhibitory effect of A-833834 on LPS-induced TNF-alpha release was also observed in human whole blood in vitro. I.v. LPS-induced TNF-alpha release in mouse serum was attenuated following i.p. administration of A-833834. Similarly, i.v. LPS-induced TNF-alpha release in mouse serum was also attenuated following i.p. administration of A-585539, another alpha7 nAChR agonist with limited brain penetration, suggesting that these effects are mediated by peripheral alpha7 nAChRs. A-833834 was also efficacious in suppressing TNF-alpha release in mouse serum following oral administration in zymosan-induced peritonitis. These studies collectively demonstrate that selectively targeting alpha7 nAChRs could offer a novel therapeutic modality to treat acute and chronic inflammatory disease states.