title: RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations.
abstract: We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease.
  
  
  
  Two heterozygous murine models, Ccm1+/-Msh2-/-and Ccm2+/-Trp53-/-, were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity.
  
  
  
  Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1+/-Msh2-/-mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1+/-Msh2-/-mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of Ccm1+/-Msh2-/-mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1+/-Msh2-/-mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2+/-Trp53-/-mice alone, and Fasudil benefit seemed limited to males.
  
  
  
  ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Robert
authors.initials: R
authors.lastname: Shenkar
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Changbin
authors.initials: C
authors.lastname: Shi
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Cecilia
authors.initials: C
authors.lastname: Austin
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Thomas
authors.initials: T
authors.lastname: Moore
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Rhonda
authors.initials: R
authors.lastname: Lightle
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Meijing
authors.initials: M
authors.lastname: Wu
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Zeineddine
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Romuald
authors.initials: R
authors.lastname: Girard
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: David A
authors.initials: DA
authors.lastname: McDonald
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Autumn
authors.initials: A
authors.lastname: Rorrer
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Carol
authors.initials: C
authors.lastname: Gallione
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk).
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.affiliation: From the Section of Neurosurgery (R.S., C.S., C.A., T.M., R.L., Y.C., L.Z., M.W., H.A.Z., R.G., I.A.A.), Department of Pathology (P.P.), Section of Cardiology (J.K.L.), Biological Sciences Division, University of Chicago, IL; and the Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC (D.A. McDonald, A.R., C.G., D.A. Marchuk). iawad@uchicago.edu.
authors.forename: Issam A
authors.initials: IA
authors.lastname: Awad
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000188:drug therapy* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019821:Simvastatin; D054460:rho-Associated Kinases; C049347:fasudil
keywords: Fasudil; hemangioma, cavernous; hemangioma, cavernous, central nervous system; rho-associated kinases; simvastatin; therapeutics