title: Effects of a peripheral cholinesterase inhibitor on cytokine production and autonomic nervous activity in a rat model of sepsis.
abstract: OBJECTIVE
  Recently, cholinergic anti-inflammatory pathway manipulation has been proposed as a new strategy to control cytokine production in sepsis. We investigated whether hypercytokinemia can be controlled via this pathway in an animal model of sepsis, with concomitant monitoring of autonomic nervous activity involving heart rate variability (HRV) analysis of electrocardiographic R-R intervals.
  
  
  METHODS
  Sixty-eight adult male Sprague-Dawley rats were used (28 for examination of cytokine production and autonomic nervous activity; 40 for survival analysis). Each part of the study involved four animal groups, including two control groups without drug administration. Sepsis was induced by cecal ligation and puncture (CLP). Distigmine bromide, a peripheral, non-selective cholinesterase inhibitor (0.01mg/kg), was administered subcutaneously 90 min after surgery. Continuous electrocardiograms were recorded for 5 min before and after surgery (at intervals of 5h) in CLP and sham-operated animals for HRV analysis. Blood samples were collected 20 h after surgery for serum cytokine and catecholamine assay.
  
  
  RESULTS
  On HRV analysis, distigmine inhibited reduction of total power and high-frequency components in CLP animals (P<0.05). Distigmine significantly inhibited cytokine induction (IL-6 and IL-10) (P<0.01) as well as increase in serum levels of noradrenaline and dopamine (P<0.05). Distigmine did not significantly improve CLP animal survival rate.
  
  
  CONCLUSIONS
  The cholinesterase inhibitor distigmine inhibited induction of inflammatory cytokines and catecholamines as well as HRV suppression in a rat CLP model, suggesting that an agent modulating the cholinergic anti-inflammatory pathway can control excess cytokine production involved in the pathogenesis of severe sepsis/septic shock.
authors.affiliation: Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba City, Chiba, Japan. iki_saikou@hotmail.co.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Setoguchi
authors.forename: Henry
authors.initials: H
authors.lastname: Yatsuki
authors.forename: Tomohito
authors.initials: T
authors.lastname: Sadahiro
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yo
authors.initials: Y
authors.lastname: Hirayama
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tateishi
authors.forename: Shigeto
authors.initials: S
authors.lastname: Oda
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000473:pathology*; D002395:Catecholamines / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D004195:Disease Models, Animal; D008026:Ligation; D008297:Male; D011677:Punctures; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D002395:Catecholamines; D002800:Cholinesterase Inhibitors; D016207:Cytokines; D011726:Pyridinium Compounds; C084645:distigmine