title: Simvastatin in traumatic brain injury: effect on brain edema mechanisms.
abstract: OBJECTIVE
  Traumatic brain injury causes deleterious brain edema, leading to high mortality and morbidity. Brain edema exacerbates neurologic deficits and may be attributable to the breakdown of endothelial cell junction protein, leukocyte infiltration, and matrix metalloproteinase activation. These all contribute to loss of blood-brain barrier integrity. The pleiotropic effects of statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, may inhibit posttraumatic brain edema. We therefore investigated the effect of acute simvastatin on neurologic deficits, cerebral edema, and its origins.
  
  
  METHODS
  Randomized laboratory animal study.
  
  
  METHODS
  University-affiliated research laboratory.
  
  
  METHODS
  Male Sprague-Dawley rats.
  
  
  METHODS
  Rats were subjected to lateral fluid percussion traumatic brain injury. Our preliminary dose-effect study indicated that 37.5 mg/kg simvastatin, administered orally 1 hr and 6 hrs after traumatic brain injury, has the greatest anti-edematous effect. This dose was used to study its effects on brain edema and on its mechanisms.
  
  
  RESULTS
  We first assessed the effects of simvastatin 24 hrs after traumatic brain injury on brain edema, brain claudin-5 expression, and the vascular endothelial-cadherin (pTyr731)/total vascular endothelial-cadherin ratio, matrix metalloproteinase-9 activity, intercellular adhesion molecule-1 expression, and polymorphonuclear neutrophil infiltration. We also evaluated blood-brain barrier permeability by measuring Evans blue and fluorescein sodium salt extravasation into the cerebral parenchyma. We then investigated whether simvastatin reduces neurologic deficits, edema, and blood-brain barrier permeability earlier than 24 hrs; these effects were evaluated 6 hrs after traumatic brain injury. The anti-edematous effect of simvastatin 24 hrs after traumatic brain injury was associated with increased claudin-5 and decreased intercellular adhesion molecule-1, polymorphonuclear neutrophil infiltration, and blood-brain barrier permeability, with no effect on matrix metalloproteinase-9 activity or vascular endothelial-cadherin phosphorylation. Earlier, 6-hrs after traumatic brain injury, simvastatin reduced neurologic deficits, cerebral edema, and blood-brain barrier permeability.
  
  
  CONCLUSIONS
  Simvastatin could be a new therapy for reducing posttraumatic edema by preventing damage to tight junctions and neutrophil infiltration into the parenchyma, thus preserving blood-brain barrier integrity.
authors.affiliation: Université Paris Descartes, Laboratoire de Pharmacologie de la Circulation Cérébrale EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Béziaud
authors.forename: Xiao
authors.initials: X
authors.lastname: Ru Chen
authors.forename: Nelly
authors.initials: N
authors.lastname: El Shafey
authors.forename: Magalie
authors.initials: M
authors.lastname: Fréchou
authors.forename: Fei
authors.initials: F
authors.lastname: Teng
authors.forename: Bruno
authors.initials: B
authors.lastname: Palmier
authors.forename: Virginie
authors.initials: V
authors.lastname: Beray-Berthat
authors.forename: Mathieu
authors.initials: M
authors.lastname: Soustrat
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
authors.forename: Michel
authors.initials: M
authors.lastname: Plotkine
authors.forename: Catherine
authors.initials: C
authors.lastname: Marchand-Leroux
authors.forename: Valérie C
authors.initials: VC
authors.lastname: Besson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001812:Blood-Brain Barrier / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001930:Brain Injuries / Q000150:complications*; D015820:Cadherins / Q000096:biosynthesis; D062507:Claudin-5; D042783:Endothelial Cells / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; D008565:Membrane Proteins; D019821:Simvastatin; D000099152:Cadherin 5; C107466:CLDN5 protein, human