title: Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm.
abstract: OBJECTIVE
  Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH.
  
  
  METHODS
  New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy.
  
  
  RESULTS
  In vehicle treated rabbits, mean +/- standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 +/- 0.08 mm versus 0.75 +/- 0.03 mm, P < 0.01). After SAH, mean +/- standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 +/- 0.04 mm versus 0.49 +/- 0.08 mm, P < 0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean +/- standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 +/- 2; SAH-vehicle 90 +/- 27; P < 0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 +/- 13; SAH vehicle, 90 +/- 27; P < 0.001).
  
  
  CONCLUSIONS
  Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.
authors.affiliation: Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McGirt
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pradilla
authors.forename: Federico G
authors.initials: FG
authors.lastname: Legnani
authors.forename: Quoc-Anh
authors.initials: QA
authors.lastname: Thai
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Recinos
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Tamargo
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clatterbuck
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D011817:Rabbits; D019821:Simvastatin / Q000008:administration & dosage*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000473:pathology*; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*
chemical_list: D019821:Simvastatin