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

Proceedings of the National Academy of Sciences of the United States of America
Sayoko NishimuraMurat Günel

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 opti...Continue Reading

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Citations

May 3, 2018·Critical Reviews in Biochemistry and Molecular Biology·Angela JeongLing Li
Sep 6, 2018·EMBO Molecular Medicine·Cécile OttenSalim Abdelilah-Seyfried
Jan 30, 2020·Stroke; a Journal of Cerebral Circulation·Cécile CardosoGwénola Boulday
Jul 28, 2020·Angiogenesis·Matthew R DetterDouglas A Marchuk
Oct 26, 2018·Circulation Research·Matthew R DetterDouglas A Marchuk

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