Abstract W P415: A Comparison between Fasudil and Simvastatin Treatment in Two Murine Models with Cerebral Cavernous Malformation

Abstract

Objective: To compare therapeutic effect on cerebral cavernous malformation (CCM) genesis and maturation of fasudil (specific RhoA kinase inhibitor) and simvastatin (with pleiotropic effects including Rho inhibition) in two heterozygous murine models. Methods: The murine models Ccm1 +/- Msh2 -/- and Ccm2 +/- Trp53 -/- were treated from weaning to 5 months of age with fasudil (100 mg/kg/day administered in drinking water), simvastatin (40 mg/kg/day administered in chow) or with placebo. Brains were removed, fixed, embedded and blindly analyzed for lesion count and size, and for iron leak by Perls staining. Results: Fasudil, but not simvastatin, improved survival in Ccm1 +/- Msh2 -/- mice ( P =0.05). Both drugs did not affect attrition in Ccm2 +/- Trp53 -/- mice. Fasudil decreased mature CCM lesion burden and total lesional area per animal in Ccm1 +/- Msh2 -/- mice ( P =0.007, P =0.18, respectively), more in males ( P =0.04, P =0.05, respectively) than in females ( P =0.10, P =0.81, respectively) when compared to mice given placebo. In the same model, simvastatin decreased total lesion count less significantly ( P =0.09), with no decrease in lesional area. Integrated iron density per area of CCM lesions was decreased in mice treated with fasudil ( P <0.01) or simvastatin ( P =0.09) compared to mice given placebo. In contrast, both fasudil and simvastatin treatment of Ccm2 +/- Trp53 -/- mice (with less aggressive phenotype) did not significantly affect attrition, lesion count or lesional area. No decrease in iron density was observed in Ccm2 +/- Trp53 -/- mice given fasudil. Conclusions: The ROCK inhibitor fasudil was more efficacious than simvastatin in the longitudinal treatment of Ccm1 +/- Msh2 -/- mice, decreasing lesion formation, maturation, and iron leak. The favorable, although weaker benefit of simvastatin, including decreased iron leak, would suggest a need for higher statin dose to accomplish a same effect as fasudil. There was no effect by either drug in Ccm2 +/- Trp53 -/- mice, likely in part because of milder phenotype in this model. Treatment with higher statin dose and effects on more aggressive Ccm3 +/ - models are being assessed in ongoing research.