Comparison of protease-resistant prion protein inhibitors in cell cultures infected with two strains of mouse and sheep scrapie

Kocisko, David A.; Engel, Abbi; Harbuck, Kristin; Arnold, Kevin; Olsen, Emily A.; Raymond, Lynne D.; Vilette, Didier; Caughey, Byron

doi:10.1016/j.neulet.2005.06.053

Cited by 53 publications

(56 citation statements)

References 28 publications

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“…Thus, it is tempting to speculate that PPS or In-TSP may help prevent the spread of CWD on game farms and in the wild, where most transmissions would be expected to occur via peripheral routes of infection. In addition, our findings attest to the broad inhibitory activities of both sulfated glycans and porphyrins, which differ from some other inhibitors that have strain and/or species specificities (10,22,23). The CWD infection in MDB CWD cells appears to be persistent because PrP CWD production has been stable and robust through 32 serial passes despite the fact that, in the first dilution cloning, 33% of the subclones were apparently negative for PrP CWD .…”

Section: Discussionmentioning

confidence: 62%

“…Numerous inhibitors of PrP-res accumulation have been identified initially using scrapie-infected cell lines, and many of these inhibitors have proven to have at least prophylactic activity against experimental scrapie in rodents. Nonetheless, striking TSE strain and species dependence has been observed with some antiscrapie compounds, and thus, it cannot be assumed that a compound that works against one TSE strain will be effective against others, such as CWD (10,19,23).…”

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confidence: 99%

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Inhibition of Protease-Resistant Prion Protein Formation in a Transformed Deer Cell Line Infected with Chronic Wasting Disease

Raymond¹,

Olsen²,

Lee³

et al. 2006

J Virol

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Section: Discussionmentioning

confidence: 62%

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confidence: 99%

Inhibition of Protease-Resistant Prion Protein Formation in a Transformed Deer Cell Line Infected with Chronic Wasting Disease

Raymond¹,

Olsen²,

Lee³

et al. 2006

J Virol

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“…Quinacrine and chlorpromazine were used as anti-prion agents known to prevent PrP res formation in the endocytic compartment [15], whereas dextran sulphate 500,000 (DX500) and tannic acid (TA) were used as inhibitors acting on PrP res formation at the plasma membrane site. Like PPS, DX500 is a sulphated polyanion which is thought to bind to PrP C or PrP res [16,17], whereas polyphenol tannic acid is known to stabilize plasmamembrane saturated phosphatidylcholine residues, thereby affecting PrP C to PrP res conversion [18]. Our data indicate that, compared to uninfected N2a cells, the prion-infected cultures display general alteration of lipid homeostasis, which can be reverted by treatments with CE modulators combined with the cholesterol-interfering anti-prion drugs chlorpromazine and quinacrine.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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In vitro synergistic anti-prion effect of cholesterol ester modulators in combination with chlorpromazine and quinacrine * E-mail: pania@unica.it°These authors contributed equally to this work. Received 06 October 2009; Accepted 16 December 2009Abstract: 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.© Versita Sp. z o.o.

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“…Biologically distinct prion strains can propagate in the same host (for a review, see reference 9), presumably through the perpetuation of different, specific PrP Sc conformers (47). The search for drugs able to impede infection or prioninduced neuropathology currently relies on various experimental models, including an acellular PrP transconformation assay (27,46), yeast prion systems (2), PrP Sc accumulation in chronically infected mammalian cell lines (28), and assay in TSE animal models (for a review, see reference 51). Among many compounds selected for their ability to prevent PrP Sc accumulation in cultured cells, only some of the most potent inhibitors significantly delay disease onset in prion-infected rodents.…”

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confidence: 99%

Prion Strain- and Species-Dependent Effects of Antiprion Molecules in Primary Neuronal Cultures

Cronier

Béringue

Bellon

et al. 2007

J Virol

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Transmissible spongiform encephalopathies (TSE) arise as a consequence of infection of the central nervous system by prions and are incurable. To date, most antiprion compounds identified by in vitro screening failed to exhibit therapeutic activity in animals, thus calling for new assays that could more accurately predict their in vivo potency. Primary nerve cell cultures are routinely used to assess neurotoxicity of chemical compounds. Here, we report that prion strains from different species can propagate in primary neuronal cultures derived from transgenic mouse lines overexpressing ovine, murine, hamster, or human prion protein. Using this newly developed cell system, the activity of three generic compounds known to cure prion-infected cell lines was evaluated. We show that the antiprion activity observed in neuronal cultures is species or strain dependent and recapitulates to some extent the activity reported in vivo in rodent models. Therefore, infected primary neuronal cultures may be a relevant system in which to investigate the efficacy and mode of action of antiprion drugs, including toward human transmissible spongiform encephalopathy agents.

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Comparison of protease-resistant prion protein inhibitors in cell cultures infected with two strains of mouse and sheep scrapie

Cited by 53 publications

References 28 publications

Inhibition of Protease-Resistant Prion Protein Formation in a Transformed Deer Cell Line Infected with Chronic Wasting Disease

Inhibition of Protease-Resistant Prion Protein Formation in a Transformed Deer Cell Line Infected with Chronic Wasting Disease

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

Prion Strain- and Species-Dependent Effects of Antiprion Molecules in Primary Neuronal Cultures

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