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Proc Natl Acad Sci U S A. 2017 May 23;114(21):5503-5508. doi: 10.1073/pnas.1702942114. Epub 2017 May 12.

Combined HMG-COA reductase and prenylation inhibition in treatment of CCM.

Author information

1
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520.
2
Department of Biomedical Engineering, Yale University, New Haven, CT 06520.
3
Yale Systems Biology Institute, Yale University, West Haven, CT 06516.
4
Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516.
5
Department of Drug Discovery, Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Tampa, FL 33612.
6
Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612.
7
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520; angeliki.louvi@yale.edu murat.gunel@yale.edu.
8
Department of Neuroscience, Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06520.
9
Department of Genetics, Yale School of Medicine, New Haven, CT 06520.

Abstract

Cerebral cavernous malformations (CCMs) are common vascular anomalies that develop in the central nervous system and, more rarely, the retina. The lesions can cause headache, seizures, focal neurological deficits, and hemorrhagic stroke. Symptomatic lesions are treated according to their presentation; however, targeted pharmacological therapies that improve the outcome of CCM disease are currently lacking. We performed a high-throughput screen to identify Food and Drug Administration-approved drugs or other bioactive compounds that could effectively suppress hyperproliferation of mouse brain primary astrocytes deficient for CCM3. We demonstrate that fluvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase and the N-bisphosphonate zoledronic acid monohydrate, an inhibitor of protein prenylation, act synergistically to reverse outcomes of CCM3 loss in cultured mouse primary astrocytes and in Drosophila glial cells in vivo. Further, the two drugs effectively attenuate neural and vascular deficits in chronic and acute mouse models of CCM3 loss in vivo, significantly reducing lesion burden and extending longevity. Sustained inhibition of the mevalonate pathway represents a potential pharmacological treatment option and suggests advantages of combination therapy for CCM disease.

KEYWORDS:

cerebral cavernous malformations; fluvastatin; high-throughput screen; mevalonate pathway; zoledronic acid

PMID:
28500274
PMCID:
PMC5448170
DOI:
10.1073/pnas.1702942114
[Indexed for MEDLINE]
Free PMC Article

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