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In vitro synergistic anti-prion effect of cholesterol ester modulators

Christina Doriana Orrù¹, Maria Dolores Cannas¹, Sarah Vascellari¹, Fabrizio Angius¹, Pier Luigi Cocco¹, Claudia Norfo¹, Antonella Mandas², Paolo La Colla¹, Sandra Dessì¹ & Alessandra Pani¹

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1. Department of Biomedical Science and Technology, University of Cagliari
2. Department of Internal Medicine, University of Cagliari

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Document Type:

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Date:

Received 21 October 2009 13:06 UTC; Posted 21 October 2009

Subjects:

Microbiology, Neuroscience, Pharmacology

Tags:

• prions
• cholesterol esters
• cholesterol metabolism
• prion inhibitors
• drug combinations
• antiprion synergism

Abstract:

Background. Our studies on the role of cholesterol in prion infection/replication showed that brains and peripheral cells of sheep susceptible to or suffering from Scrapie were characterized by an altered cholesterol homeostasis compared to animals with a scrapie-resistant genotype, and that drugs influencing cholesterol esterification were endowed with selective anti-prion activity in N2a cell lines infected with the 22L and RML prion strains.
Results. In prion-infected N2a cell lines we now report increased anti-prion activity of dual-drug combinations consisting of cholesterol ester modulators associated with prion inhibitors Synergism was obtained with the cholesterol ester modulators everolimus, pioglitazone, progesterone, and verapamil associated with the anti-prion chlorpromazine, and with everolimus and pioglitazone associated with the anti-prion quinacrine. Comparative lipid analyses in prion-infected and non-infected N2a cells by colorimetric, enzymatic, and chemical means, clearly demonstrated a derangement of type and distribution of cholesterol esters, free cholesterol, and triglycerides in the infected N2a cells. Although single-drug treatments influenced lipid syntheses, only the combined-drug treatments appeared to restore a lipid profile similar to that of untreated-uninfected cells.
Conclusions. We conclude that the anti-prion synergistic effect of cholesterol ester modulators with the cholesterol metabolism interfering anti-prion drugs chlorpromazine and quinacrine may arise from the ability of combined drugs to re-establish the intracellular lipid profile of untreated-uninfected cells. Overall, these data suggest that inhibition of prion replication can be readily potentiated by combinatorial drug treatments, and that steps of cholesterol/cholesterol ester metabolism may represent suitable targets.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Orrù, Christina Doriana, Cannas, Maria Dolores , Vascellari, Sarah, Angius, Fabrizio, Cocco, Pier Luigi , Norfo, Claudia, Mandas, Antonella, La Colla, Paolo, Dessì, Sandra, and Pani, Alessandra. In vitro synergistic anti-prion effect of cholesterol ester modulators . Available from Nature Precedings <http://hdl.handle.net/10101/npre.2009.3883.1> (2009)

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