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Discovery of a Novel, Monocationic, Small-Molecule Inhibitor of Scrapie Prion Accumulation in Cultured Sheep Microglia and Rov Cells

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Název: Discovery of a Novel, Monocationic, Small-Molecule Inhibitor of Scrapie Prion Accumulation in Cultured Sheep Microglia and Rov Cells
Autoři: Stanton, James B, Schneider, David A, Dinkel, Kelcey D, Balmer, Bethany F, Baszler, Timothy V, Mathison, Bruce A, Boykin, David W, Kumar, Arvind
Zdroj: PLoS One
PLoS ONE, Vol 7, Iss 11, p e51173 (2012)
Informace o vydavateli: Public Library of Science (PLoS), 2012.
Rok vydání: 2012
Témata: 0301 basic medicine, Curcumin, PrPSc Proteins, Prions, Cells, Science, Pestivirus - drug effects, Furans - pharmacology, Messenger - genetics, PrPSc Proteins - pathogenicity, Small Molecule Libraries, Small Molecule Libraries - chemistry, 03 medical and health sciences, Microglia - metabolism, Cations, Animals, Scrapie - metabolism, RNA, Messenger, Furans, Small Molecule Libraries - pharmacology, Benzimidazoles - chemistry, Cells, Cultured, Furans - chemistry, Cultured, Sheep, Cell Death, Prions - genetics, Prions - metabolism, Messenger - metabolism, Microglia - drug effects, Cell Death - drug effects, Curcumin - pharmacology, Pestivirus, RNA, Medicine, PrPSc Proteins - antagonists & inhibitors, Benzimidazoles, Microglia, Scrapie - pathology, Benzimidazoles - pharmacology, Research Article, Scrapie
Popis: Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrP(C)) to disease-associated prion protein (PrP(Sc)). Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrP(Sc)-specific ELISA we discovered a monocationic phenyl-furan-benzimidazole (DB772), which has previously demonstrated anti-pestiviral activity and represents a chemical category previously untested for anti-prion activity, that inhibited PrP(Sc) accumulation and prion infectivity in primary sheep microglial cell cultures (PRNP 136VV/154RR/171QQ) and Rov9 cultures (VRQ-ovinized RK13 cells). We investigated potential mechanisms of this anti-prion activity by evaluating PrP(C) expression with quantitative RT-PCR and PrP ELISA, comparing the concentration-dependent anti-prion and anti-pestiviral effects of DB772, and determining the selectivity index. Results demonstrate at least an approximate two-log inhibition of PrP(Sc) accumulation in the two cell systems and confirmed that the inhibition of PrP(Sc) accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrP(C) expression is not the mechanism of PrP(Sc) inhibition. PrP(Sc) accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrP(Sc) activity was independent of anti-pestivirus activity. The anti-PrP(Sc) selectivity index in cell culture was approximately 4.6 in microglia and 5.5 in Rov9 cells. The results describe a new chemical category that inhibits ovine PrP(Sc) accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0051173
Přístupová URL adresa: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0051173&type=printable
https://pubmed.ncbi.nlm.nih.gov/23226483
https://doaj.org/article/eece9982e5e540a78fb8bf7bf72928a2
https://dx.plos.org/10.1371/journal.pone.0051173
http://ui.adsabs.harvard.edu/abs/2012PLoSO...751173S/abstract
https://www.ncbi.nlm.nih.gov/pubmed/23226483
https://pubmed.ncbi.nlm.nih.gov/23226483/
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051173
http://europepmc.org/articles/PMC3511409
Rights: CC 0
CC BY
Přístupové číslo: edsair.doi.dedup.....b7a7bf80485fe9082e53bc455563594f
Databáze: OpenAIRE
Popis
Abstrakt:Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrP(C)) to disease-associated prion protein (PrP(Sc)). Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrP(Sc)-specific ELISA we discovered a monocationic phenyl-furan-benzimidazole (DB772), which has previously demonstrated anti-pestiviral activity and represents a chemical category previously untested for anti-prion activity, that inhibited PrP(Sc) accumulation and prion infectivity in primary sheep microglial cell cultures (PRNP 136VV/154RR/171QQ) and Rov9 cultures (VRQ-ovinized RK13 cells). We investigated potential mechanisms of this anti-prion activity by evaluating PrP(C) expression with quantitative RT-PCR and PrP ELISA, comparing the concentration-dependent anti-prion and anti-pestiviral effects of DB772, and determining the selectivity index. Results demonstrate at least an approximate two-log inhibition of PrP(Sc) accumulation in the two cell systems and confirmed that the inhibition of PrP(Sc) accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrP(C) expression is not the mechanism of PrP(Sc) inhibition. PrP(Sc) accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrP(Sc) activity was independent of anti-pestivirus activity. The anti-PrP(Sc) selectivity index in cell culture was approximately 4.6 in microglia and 5.5 in Rov9 cells. The results describe a new chemical category that inhibits ovine PrP(Sc) accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.
ISSN:19326203
DOI:10.1371/journal.pone.0051173