title: Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage.
abstract: OBJECTIVE
  Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm.
  
  
  METHODS
  Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery.
  
  
  RESULTS
  In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatin=74+/-22 micro m, SAH-vehicle=52+/-18 micro m, P=0.03; sham-simvastatin=102+/-8 micro m, sham-vehicle=105+/-6 micro m). Pretreatment reduced neurological deficits (SAH-simvastatin=25+/-2, SAH-vehicle=20+/-2, P=0.005; sham-simvastatin and sham-vehicle=27+/-0). Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatin=56+/-12 micro m, SAH-vehicle=45+/-4 micro m, P=0.03; sham-simvastatin=92+/-13 micro m, sham-vehicle=99+/-10 micro m) and reduced neurological deficits (SAH-simvastatin=21+/-1, SAH-vehicle=19+/-2, P=0.009). Simvastatin posttreatment did not significantly increase eNOS protein.
  
  
  CONCLUSIONS
  Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice. The mechanism may be attributable in part to eNOS upregulation.
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Duke University School of Medicine Duke University Medical Center, Durham, NC, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McGirt
authors.forename: John R
authors.initials: JR
authors.lastname: Lynch
authors.forename: Augusto
authors.initials: A
authors.lastname: Parra
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.forename: Robert D
authors.initials: RD
authors.lastname: Pearlstein
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
authors.forename: Dale A
authors.initials: DA
authors.lastname: Pelligrino
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014654:Vascular Patency / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse