title: Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.
abstract: The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the "cholinergic anti-inflammatory pathway," defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to alpha7nAChR knockout mice failed to suppress TNF levels, indicating that the alpha7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and alpha7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage.
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA. vpavlov@nshs.edu
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Pavlov
authors.forename: William R
authors.initials: WR
authors.lastname: Parrish
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rosas-Ballina
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.forename: Margot
authors.initials: M
authors.lastname: Puerta
authors.forename: Kanta
authors.initials: K
authors.lastname: Ochani
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Chavan
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000470:Alkaloids; D000704:Analysis of Variance; D000818:Animals; D001286:Atropine Derivatives / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood*; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005702:Galantamine / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010276:Parasympatholytics / Q000008:administration & dosage / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014628:Vagotomy / Q000379:methods; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000470:Alkaloids; D001286:Atropine Derivatives; D002800:Cholinesterase Inhibitors; C579166:Chrna7 protein, mouse; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010276:Parasympatholytics; D011978:Receptors, Nicotinic; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C050426:huperzine A; D005702:Galantamine; C006649:methylatropine; D000110:Acetylcholinesterase