title: Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss.
abstract: BACKGROUND
  Systemic inflammation and oxidative stress are crucial in mediating blood-brain barrier (BBB) integrity loss during sepsis. Simvastatin possess potent anti-inflammation and antioxidation capacity. We sought to elucidate whether an acute bolus of simvastatin could mitigate BBB integrity loss in a rodent model of polymicrobial sepsis.
  
  
  METHODS
  A total of 96 adult male rats (200-250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus simvastatin, sham operation, or sham operation plus simvastatin (n = 24 in each group). After maintaining for 24 h, BBB integrity in the surviving rats was determined.
  
  
  RESULTS
  CLP significantly induced BBB integrity loss, as grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels in rats receiving CLP were significantly higher than those receiving sham operation. In contrast, grading of Evans blue staining (P = 0.020), BBB permeability to Evans blue dye (P = 0.031), and brain edema levels (P = 0.009) in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP alone. Tight junction proteins claudin-3 and claudin-5 in endothelial cells are major structural components of BBB. Our data revealed that concentrations of claudin-3 and claudin-5 in rats receiving CLP were significantly lower than those receiving CLP plus simvastatin (P = 0.010 and 0.007). Immunohistochemistry further revealed significant fragmentation of claudin-3 and claudin-5 in rats receiving CLP. Moreover, levels of claudin-3 and claudin-5 fragmentation in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP.
  
  
  CONCLUSIONS
  Simvastatin mitigates BBB integrity loss in a rodent model of polymicrobial sepsis.
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chen-Hsien
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ming-Chan
authors.initials: MC
authors.lastname: Kao
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ping-Cheng
authors.initials: PC
authors.lastname: Shih
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Kuang-Yao
authors.initials: KY
authors.lastname: Li
authors.affiliation: Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Tsai
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan. Electronic address: huangcj1112@gmail.com.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D001927:Brain Diseases / Q000209:etiology / Q000517:prevention & control*; D054426:Chemokine CXCL2 / Q000097:blood; D062465:Claudin-3 / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications* / Q000188:drug therapy; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D054426:Chemokine CXCL2; D062465:Claudin-3; D062507:Claudin-5; C513296:Cxcl2 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D008315:Malondialdehyde; D019821:Simvastatin
keywords: Cecal ligation and puncture; Evans blue dye; Inflammation; Rat; Tight junction