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In vitro synergistic anti-prion effect of cholesterol ester modulators in combination with chlorpromazine and quinacrine

  • Research Article
  • Published:
Central European Journal of Biology

Abstract

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, and that drugs affecting cholesterol ester pool were endowed with selective anti-prion activity in N2a cell lines infected with the 22L and RML prion strains. In these 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. In addition, comparative lipid analyses in prion-infected vs. uninfected N2a cells, demonstrated a derangement of type and distribution of cholesterol ester, free cholesterol, and triglyceride pools in the infected cells. Single-drug treatments differently affected synthesis of the various lipid forms, whereas combined drug treatments appeared to restore a lipid profile similar to that of the untreated-uninfected cells. We conclude that the anti-prion synergistic effects of cholesterol ester modulators associated with the cholesterol-interfering anti-prion drugs chlorpromazine and quinacrine may arise from the ability of combined drugs to re-establish lipid homeostasis in the prion-infected 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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Abbreviations

PrPres :

PK-resistant prion protein

TL:

total lipids

TC:

total cholesterol

FC:

free cholesterol

NL:

neutral lipids

CE:

cholesterol esters

TG:

triglycerides

PL:

phospholipids

DX 500:

dextran sulphate 500,000

TA:

tannic acid

CP:

chlorpromazine

Q:

quinacrine

EVE:

everolimus

PIO:

pioglitazone

PG:

progesterone

VP:

verapamil

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Authors and Affiliations

  1. Department of Biomedical Science and Technology, University of Cagliari, 09042, Monserrato (CA), Italy

    Christina D. Orrù, M. Dolores Cannas, Sarah Vascellari, Fabrizio Angius, Pier Luigi Cocco, Claudia Norfo, Paolo La Colla, Giacomo Diaz, Sandra Dessì & Alessandra Pani

  2. Department of Internal Medicine, University of Cagliari, 09042, Monserrato (CA), Italy

    Antonella Mandas

Authors
  1. Christina D. Orrù
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  2. M. Dolores Cannas
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  3. Sarah Vascellari
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  4. Fabrizio Angius
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  5. Pier Luigi Cocco
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  6. Claudia Norfo
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  7. Antonella Mandas
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  8. Paolo La Colla
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  9. Giacomo Diaz
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  10. Sandra Dessì
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  11. Alessandra Pani
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Correspondence to Alessandra Pani.

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These authors contributed equally to this work.

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Orrù, C.D., Cannas, M.D., Vascellari, S. et al. In vitro synergistic anti-prion effect of cholesterol ester modulators in combination with chlorpromazine and quinacrine. cent.eur.j.biol. 5, 151–165 (2010). https://doi.org/10.2478/s11535-009-0070-9

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  • DOI: https://doi.org/10.2478/s11535-009-0070-9

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