title: Cytidine-5-diphosphocholine reduces microvascular permeability during experimental endotoxemia.
abstract: BACKGROUND
  Microvascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality. No effective pharmacological therapy is currently available to restore microvascular barrier function in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects during inflammation. Cytidine-5-diphosphocholine (CDP-choline) is an extensively studied cholinergic drug due to its brain protective characteristics in cerebrovascular diseases. This study evaluated the effect of CDP-choline on microvascular permeability and leukocyte adhesion during endotoxemia.
  
  
  METHODS
  Macromolecular leakage, leukocyte adhesion, and venular wall shear rate were examined in mesenteric postcapillary venules of rats by using intravital microscopy (IVM). Lipopolysaccharide (LPS) (4 mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0 min. IVM was repeated after 60 and 120 min in endotoxemic and nonendotoxemic animals. CDP-choline (100 mg/kg) was applied as an i.v. bolus. Animals received either saline alone, CDP-choline alone, CDP-choline 10 min before or 30 min after LPS administration, or LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunn's multiple comparisons test were used for data analysis. Data were considered statistically significant at p < 0.05.
  
  
  RESULTS
  Treatment with LPS alone significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. CDP-choline significantly reduced microvascular permeability in animals treated with LPS. Leukocyte adhesion and venular wall shear rate were not affected by CDP-choline during endotoxemia.
  
  
  CONCLUSIONS
  CDP-choline has a protective effect on microvascular barrier function during endotoxemia. Considering the excellent pharmacologic safety profile of CDP-choline, its use could be an approach for the treatment of capillary leakage in sepsis.
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. karsten.schmidt@med.uni-heidelberg.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Ludwigshafen, University of Heidelberg, Heidelberg, Germany. JFHernekamp@bgu-ludwigshafen.de.
authors.forename: Jochen Frederick
authors.initials: JF
authors.lastname: Hernekamp
authors.affiliation: Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany. miriam.doerr@med.uni-heidelberg.de.
authors.forename: Miriam
authors.initials: M
authors.lastname: Doerr
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. aleksandar.zivkovic@med.uni-heidelberg.de.
authors.forename: Aleksandar R
authors.initials: AR
authors.lastname: Zivkovic
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. thorsten.brenner@med.uni-heidelberg.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Department of Anesthesiology, Katharinenhospital, Stuttgart, Germany. A.Walther@klinikum-stuttgart.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Walther
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. markus.weigand@med.uni-heidelberg.de.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Weigand
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. stefan.hofer@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hofer
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D008070:Lipopolysaccharides; D018697:Nootropic Agents; D003566:Cytidine Diphosphate Choline