Rho Kinase Inhibition Blunts Lesion Development and Hemorrhage in Murine Models of Aggressive Pdcd10/Ccm3 Disease
| Autor: | Issam A. Awad, Sean P. Polster, Douglas A. Marchuk, Amy Peiper, Dongdong Zhang, Thomas R. Moore, Robert Shenkar, Seán B. Lyne, Heidy Pardo, James K. Liao, Kiranj K. Chaudagar, Carol J. Gallione, Nicholas Hobson, Rhonda Lightle, Ying Cao, Peter Pytel, Romuald Girard, Laleh Saadat, Janne Koskimäki |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Hemangioma
Cavernous Central Nervous System Simvastatin Atorvastatin Central nervous system Disease Pharmacology Article Hemangioma Lesion Mice 03 medical and health sciences 0302 clinical medicine 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine medicine Animals Enzyme Inhibitors KRIT1 Protein Rho-associated protein kinase 030304 developmental biology Mice Knockout Advanced and Specialized Nursing rho-Associated Kinases 0303 health sciences business.industry Intracellular Signaling Peptides and Proteins nutritional and metabolic diseases X-Ray Microtomography medicine.disease medicine.anatomical_structure Neurology (clinical) Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.symptom Apoptosis Regulatory Proteins Cardiology and Cardiovascular Medicine business Intracranial Hemorrhages 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Stroke. 50:738-744 |
| ISSN: | 1524-4628 0039-2499 |
| Popis: | Background and Purpose— Previously, murine models Krit1 +/− Msh2 −/ − and Ccm2 +/ − Trp53 −/ − showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods— The murine models, Pdcd10 +/ − Trp53 −/ − and Pdcd10 +/ − Msh2 −/ − , were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results— The Pdcd10 +/ − Trp53 −/ − /Msh2 −/ − models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P =0.027) by fasudil, and to 0.0047 ( P =0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions— These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing. |
| Databáze: | OpenAIRE |
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