Role of α7 nicotinic acetylcholine receptors in regulating tumor necrosis factor-α (TNF-α) as revealed by subtype selective agonists

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 alpha 7 nicotinic acetylcholine receptor (alpha 7 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 alpha 7 nAChRs in the regulation of TNF-alpha release was investigated using high affinity and selective alpha 7 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 alpha 7 nAChR agonist, A-833834 (5-[6-(5-Methylhexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole), and that effect was attenuated by alpha 7 nAChR antagonist methyllycaconitine. The inhibitory effect of A-833834 on LPS-induced INF-alpha release was also observed in human whole blood in vitro. I.v. LPS-induced INF-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 alpha 7 nAChR agonist with limited brain penetration, suggesting that these effects are mediated by peripheral alpha 7 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 alpha 7 nAChRs could offer a novel therapeutic modality to treat acute and chronic inflammatory disease states. (C) 2011 Elsevier B.V. All rights reserved.