The M1 muscarinic acetylcholine receptor agonist xanomeline suppresses lethal inflammation

We have recently indicated a role for brain muscarinic acetylcholine receptors in controlling systemic inflammatory responses (Proc Natl Acad Sci USA, 2006, 5219; Brain Behav Immun, Epub). Here we studied whether xanomeline, a centrally‐acting M1 muscarinic receptor agonist, suppresses the systemic cytokine response and improves survival during lethal endotoxemia. This drug has been studied in the context of Alzheimer's disease, but its anti‐inflammatory effects have not been previously reported. Peripheral drug (5 or 20 mg/kg, i.p.) administration 1h prior to endotoxin (6 mg/kg, i.p.) dose‐dependently suppressed serum TNF levels and significantly improved survival in mice. Pharmacological blockade of brain muscarinic receptors, but not peripheral muscarinic receptors abrogated the survival‐improving drug effect, thus demonstrating that central muscarinic receptors mediated the effect of xanomeline. In addition, administration of xanomeline (20 mg/kg, i.p.) 20h prior to endotoxin significantly reduced serum TNF levels and improved survival. Together these findings demonstrate the long‐lasting anti‐inflammatory efficacy of xanomeline, acting through a brain muscarinic receptor‐dependent mechanism, and indicate the therapeutic potential of centrally‐acting muscarinic M1 agonists in the treatment of inflammatory diseases. This study was funded in part by NIH/NIGMS.