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• W2608623599 abstract "Cavernous malformations (CCM) are endothelium-lined sinusoidal channels filled with blood. CCMs have a prevalence 0.4% to 0.6% and exhibit an annual hemorrhage rate of 2.5% (95% CI 1.3%-5.1%).1 Previous hemorrhage has shown to be the most significant hemorrhagic risk factor, while age, sex, location, size, and multiplicity are less relevant. Hyperpermeability of CCM vessels occurs via the inactivation of ccm1, 2, or 3 genes and the subsequent increase in RhoA activity and Rho-associated coiled-coil-forming kinase (ROCK).2 Multiple therapies based on downregulating endothelial CCM genes have been trialed in the past; however, a more recent study specifically targeting Rho proteases has shown higher efficacy.3,4 The authors of the current study previously demonstrated that Fasudil, ROCK inhibitor, decreased CCM lesion burden in a heterozygous murine model.5 Unfortunately, prior studies did not assess either CCM lesion maturation or hemorrhage burden. Two heterozygous allelic CCM murine models, Ccm1+/−Msh2−/− and Ccm2+/−Trp53−/−, were developed by predisposing the animals to somatic mutations by carrying the knockout allele for the tumor suppressor gene Trp53 or Msh2.6 P21 mice were randomized to receive simvastatin (40 mg/kg per day), Fasudil (100 mg/kg per day), or placebo until at least 5 months of age. In contrast to Fasudil, simvastatin has been classically used in the treatment of cavernomas but has nonspecific ROCK inhibition, also inhibiting HMG-CoA reductase, and RhoA lipidation. After treatment, brains were removed, formalin-fixed, and cut into 5-μm slices, fixed, and assessed for number of stage 1 prelesions (single capillaries >100 μm in diameter) and stage 2 lesions (mature and multicavernous). In the Fasudil-treated Ccm1+/−Msh2−/− group, the number of stage 2 lesions per mouse was decreased by 74% compared to placebo group (0.68 ± 0.30 vs 0.18 ± 0.24, P = .02). Although not statistically significant, the Ccm2+/−Trp53−/− had a 58% decrease in stage 2 lesions when treated with placebo vs Fasudil (0.78 ± 0.33 vs 0.33 ± 0.41, P = .25; Figure).6 The decrease in stage 2 lesion counts correlates with an increase in stage 1 counts without a change in the total number of lesions per mouse, demonstrating Fasudil's effect on CCM lesion maturation. Furthermore, the simvastatin group showed no decrease in stage 2 lesions compared to the placebo group. Cross-sectional area was unaffected in either group; however, the Fasudil group trended towards a smaller stage 2 lesional area. Both simvastatin and Fasudil decreased nonheme iron in the Ccm1+/−Msh2−/− stage 2 lesions; however, only simvastatin decreased nonheme iron of stage 2 lesions of the Ccm2+/−Trp53−/− model.Figure.: Lesion burden Ccm models with Fasudil (F) and simvastatin (S) treatment. A, F (n = 16 placebo [P], n = 22 F-treated mice), but not S (n = 20, P, n = 28 S-treated mice), decreased the multicavernous stage 2 lesion burden in the Ccm1+/−Msh2−/− murine model. B, Neither F (n = 18 P, n = 19 F-treated mice) nor S (n = 11 P, n = 12 S-treated mice), significantly affected lesion burden in Ccm2+/−Trp53−/ mice. Meta-analysis of combined effect in the 2 models showed that incidence of stage 2 lesions is decreased with F C, but now with the S D. The Der-Simonian and Laird method used for the meta-analyses considers the relative contribution of effect by the 2 models (weight %) and their different penetrance (incidence rate ratio). CCM indicates cerebral cavernous malformation; and CI, confidence interval. Figure and legend reprinted from Shenkar R, Shi C et al. RhoA kinase inhibition with fasudil versus simvastatin in murine models of cerebral cavernous malformations. Stroke. 2017;48:187–194,6 http://stroke.ahajournals.org/.By measuring the percentage of cells that were phosphorylated myosin light chain positive, the authors were able to measure stage 2 lesion endothelial cell ROCK activity in the Ccm1+/−Msh2−/− group. They showed a decrease from 68.7% to 51.9% in the placebo vs Fasudil-treated group (P = .01) and to 57% in the simvastatin treatment arm. The authors went on to prove that there was a survival benefit among the Fasudil treated Ccm1+/−Msh2−/− group (P = .05) compared to placebo. Previous studies have shown the effect that ROCK inhibition has on CCM genesis; however, the current authors6 used a chronic heterozygous model that more closely modeled the CCM human disease process. Stage 2 lesions have only been associated with hemorrhagic risk and Fasudil, unlike simvastatin, decreased the number of multicavernous lesions, and improved survival. Further work is necessary in order to optimize the efficacy of ROCK inhibition and better define pharmacological safety parameters of Fasudil administration." @default.
• W2608623599 created "2017-05-05" @default.
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• W2608623599 date "2017-04-21" @default.
• W2608623599 modified "2023-10-17" @default.
• W2608623599 title "Fasudil Slows Development of Cavernous Malformations" @default.
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• W2608623599 doi "https://doi.org/10.1093/neuros/nyx100" @default.
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