title: Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.
abstract: BACKGROUND
  The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.
  
  
  METHODS
  Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed.
  
  
  RESULTS
  Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).
  
  
  CONCLUSIONS
  The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.
authors.affiliation: SetPoint Medical Corporation, Valencia, California, United States of America.
authors.forename: Yaakov A
authors.initials: YA
authors.lastname: Levine
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Frieda A
authors.initials: FA
authors.lastname: Koopman
authors.affiliation: SetPoint Medical Corporation, Valencia, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Faltys
authors.affiliation: SetPoint Medical Corporation, Valencia, California, United States of America.
authors.forename: April
authors.initials: A
authors.lastname: Caravaca
authors.affiliation: Bolder BioPATH, Inc., Boulder, Colorado, United States of America.
authors.forename: Alison
authors.initials: A
authors.lastname: Bendele
authors.affiliation: SetPoint Medical Corporation, Valencia, California, United States of America.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zitnik
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; Arthrogen BV, Amsterdam, the Netherlands.
authors.forename: Margriet J
authors.initials: MJ
authors.lastname: Vervoordeldonk
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage, United Kingdom; University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul Peter
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000628:therapy*; D001842:Bone and Bones / Q000378:metabolism; D004599:Electric Stimulation Therapy; D004566:Electrodes; D005260:Female; D051381:Rats; D014630:Vagus Nerve / Q000378:metabolism
chemical_list: D000109:Acetylcholine
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