title: Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms.
abstract: BACKGROUND
  The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier.
  
  
  METHODS
  Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestatic rats, or bile acid treatment, in the presence of a Rac1 inhibitor.
  
  
  RESULTS
  Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability.
  
  
  CONCLUSIONS
  These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions.
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: McMillin
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Galindo
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Pae
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA; Digestive Disease Research Center, Scott & White Hospital, USA; Central Texas Veterans Health Care System, Temple, TX, USA. Electronic address: demorrow@medicine.tamhsc.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000097:blood* / Q000494:pharmacology; D002779:Cholestasis / Q000503:physiopathology*; D003840:Deoxycholic Acid / Q000097:blood* / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells; D008026:Ligation; D008297:Male; D055806:Microvessels / Q000378:metabolism*; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000378:metabolism*; D046509:Tissue Culture Techniques; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D062827:Zonula Occludens-2 Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; C487513:NSC 23766; D062793:Occludin; D011743:Pyrimidines; D012333:RNA, Messenger; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: Bile duct ligation; Occludin; Rac1; Tight junction proteins