title: Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation.
abstract: Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer's disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases.
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Mauricio
authors: M
authors: Rosas-Ballina
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Sergio I
authors: SI
authors: Valdés-Ferrer
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Meghan E
authors: ME
authors: Dancho
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Mahendar
authors: M
authors: Ochani
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: David
authors: D
authors: Katz
authors: Laboratory of Medicinal Chemistry, Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Kai Fan
authors: KF
authors: Cheng
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Peder S
authors: PS
authors: Olofsson
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Sangeeta S
authors: SS
authors: Chavan
authors: Laboratory of Medicinal Chemistry, Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Yousef
authors: Y
authors: Al-Abed
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States.
authors: Kevin J
authors: KJ
authors: Tracey
authors: Laboratory of Biomedical Science, Center for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United States. Electronic address: vpavlov@nshs.edu.
authors: Valentin A
authors: VA
authors: Pavlov
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000502:physiology; D055809:Illness Behavior / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides; D008297:Male; D008807:Mice, Inbred BALB C; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists; D018805:Sepsis / Q000401:mortality / Q000517:prevention & control*; D013154:Spleen / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D016019:Survival Analysis; D013830:Thiadiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha; C075257:xanomeline
keywords: Brain muscarinic acetylcholine receptors; Cytokines; Endotoxemia; Inflammation; Sepsis; Sickness behavior; Splenic nerve; Vagus nerve; Xanomeline