Pharmacological studies of a new derivative of amphotericin B, MS-8209, in mouse and hamster scrapie

Demaimay, Rémi; Adjou, Karim; Lasmézas, Corinne Ida; Lazarini, Françoise; Cherifi, K.; Séman, Michel; Deslys, Jean‐Philippe; Dormont, Dominique

doi:10.1099/0022-1317-75-9-2499

Cited by 56 publications

(30 citation statements)

References 21 publications

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“…Animals that did not show any clinical signs of scrapie were all negative for the presence of PrPsc. Compared to the 5 ϫ 10 8 to 5 ϫ 10 9 mean LD 50 per gram in intracerebral-infection challenges, these results indicate that intraperitoneal injection of the C506M3 scrapie strain is 10 3 to 10 4 times less efficient than intracerebral inoculation (8,15). These data are very similar to previous findings with other mouse-adapted scrapie strains (14).…”

Section: Resultssupporting

confidence: 82%

“…The mouse-adapted scrapie strain C506M3 was stabilized and propagated in the C57BL/6 mouse line (17). The inoculum was a brain homogenate at 10% (wt/vol) in 5% glucose solution from a mouse with scrapie at the terminal stage of disease, routinely titrating 5 ϫ 10 8 to 5 ϫ 10 9 50% lethal doses (LD 50 ) per gram in intracerebral-infection challenges (8,15). The mean survival time was around 173 Ϯ 5 (standard deviation [SD]) days after intracerebral infection or 333 Ϯ 7 (SD) days after intraperitoneal challenge (8,17).…”

Section: Methodsmentioning

confidence: 99%

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High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses

Jacquemot

Cuche

Dormont

et al. 2005

J Virol

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To clarify the mechanisms leading to the development of Creutzfeldt-Jakob disease in some recipients of pituitary-derived human growth hormone (hGH), we investigated the effects of repeated injections of low prion doses in mice. The injections were performed, as in hGH-treated children, by a peripheral route at short intervals and for an extended period. Twelve groups of 24 mice were intraperitoneally inoculated one, two, or five times per week for 200 days with 2 ؋ 10 ؊5 to 2 ؋ 10 ؊8 dilutions of brain homogenate containing the mouse-adapted C506M3 scrapie strain. Sixteen control mice were injected once a week for 200 days with a 2 ؋ 10 ؊4 dilution of normal brain homogenate. Of mice injected in a single challenge with a scrapie inoculum of a 2 ؋ 10 ؊4 , 2 ؋ 10 ؊5 , or 2 ؋ 10 ؊6 dilution, 2/10, 1/10, and 0/10 animals developed scrapie, respectively. Control mice remained healthy. One hundred thirty-five of 135 mice injected with repeated prion doses of a 2 ؋ 10 ؊5 or 2 ؋ 10 ؊6 dilution succumbed to scrapie. Of mice injected with repeated scrapie doses of a 2 ؋ 10 ؊7 or 2 ؋ 10 ؊8 dilution, 52/59 and 38/67 animals died of scrapie, respectively. A high incidence of scrapie was observed in mice receiving repeated doses at low infectivity, whereas there was no disease in mice that were injected once with the same doses. Repeated injections of low prion doses thus constitute a risk for development of prion disease even if the same total dose inoculated in a single challenge does not induce the disease.

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Section: Resultssupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses

Jacquemot

Cuche

Dormont

et al. 2005

J Virol

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“…While it is hardly practical to consider complete replacement of conventional animals by PrP knockout counterparts, herds of BSEresistant cattle would be useful as a source for products required for pharmaceutical purposes. Moreover, the fact that Prnp °/+ heterozygous mice show prolonged scrapie incubation times argues that an (as yet conjectural) drug leading to moderate reduction of PrP c synthesis or one retarding the conversion of PrP c to PrP sc [72] might substantially mitigate disease progression in incipient cases of human spongiform encephalopathies.…”

Section: Implications and Outlookmentioning

confidence: 99%

Molecular biology of transmissible spongiform encephalopathies

1996

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The prion, the transmissible agent that causes spongiform encephalopathies such as serapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease, is believed to be devoid of nucleic acid and identical with PrP so, a modified form of the normal host protein PrP ¢ which is encoded by the single cop~v gene Prnp. The 'protein only" hypothesis proposes that PrP ~c, when introduced into a normal host, causes the conversion of PrP c into prpS~; it therefore predicts that an animal devoid of PrP c should be resistant to prion diseases. We generated homozygous Prnp °1° ('PrP knockout') mice and showed that, after inoculation with prions, they remained free of scrapie for at least 2 years while wild-type controls all died within 6 months. There was no propagation of prions in the Prnp °t° animals. Surprisingly, heterozygous Prnp °t+ mice, which express PrP c at about half the normal level, also showed enhanced resistance to scrapie disease despite high levels of infectious agent and PrP ~c in the brain early on. After introduction of murine PrP transgenes Prnp °t° mice became highly susceptible to mouse but not to hamster prions, while the insertion of Syrian hamster PrP transgenes rendered them susceptible to hamster but to a much lesser extent to mouse prions. These complementation experiments paved the way to the application of reverse genetics. We have prepared animals transgenic for genes encoding PrP with amino terminal deletions of various lengths and have found that PrP lacking 48 amino proximal amino acids, which comprise four of the five octa repeats of PrP, is still biologically active.

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“…Among them are polyene antibiotics such as amphotericin B (44) and its more efficient derivative MS-8209 (1-4, 14, 15), polyanions such as dextran sulfate 500 (DS500), heteropolyanions (such as HPA23) or sulfated polyanions (such as SP54) (19,21,23,31,34), and Congo red (CR) (30). Polyene antibiotics and polyanions prolong the survival time of scrapie-infected rodents and transiently reduce brain infectivity and PrPres accumulation (1,4,14,21,44). In addition, sulfated polyanions and CR inhibit PrPres accumulation and infectivity in a model of scrapie-infected mouse neuroblastoma cells (11)(12)(13).…”

mentioning

confidence: 99%

Opposite Effects of Dextran Sulfate 500, the Polyene Antibiotic MS-8209, and Congo Red on Accumulation of the Protease-Resistant Isoform of PrP in the Spleens of Mice Inoculated Intraperitoneally with the Scrapie Agent

Béringue

Adjou

Lamoury

et al. 2000

J Virol

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The mode and the site of action of the major antiscrapie drugs have been studied by investigating their effects on the abnormal protease-resistant isoform of PrP (PrPres) and on its accumulation in mouse spleen. Dayby-day PrPres accumulation in the spleen and in other peripheral organs was first monitored to describe the early steps of scrapie pathogenesis. Three phases were identified: the detection of scrapie inoculum on the day of scrapie infection, a clearance phase, and then the peripheral accumulation of PrPres. In a second step, the effects of the polyene antibiotic MS-8209, the polyanion dextran sulfate 500 (DS500), and Congo red were assessed on these phases, after the drugs were coincubated with scrapie inoculum. Highly different mechanisms and sites of action were apparent. MS-8209 had a weak effect on the accumulation of PrPres in spleen, suggesting another site of intervention for this drug. DS500 delayed the beginning of the clearance phase but then blocked PrPres synthesis for a long period of time, probably because of its immunological effects on the spleen. Surprisingly, Congo red suppressed the clearance phase of scrapie inoculum and then increased transiently accumulation of PrPres in spleen. We showed in vitro that this effect was related to a direct enhancement of the protease resistance of PrPres by the drug.

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Pharmacological studies of a new derivative of amphotericin B, MS-8209, in mouse and hamster scrapie

Cited by 56 publications

References 21 publications

High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses

High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses

Molecular biology of transmissible spongiform encephalopathies

Opposite Effects of Dextran Sulfate 500, the Polyene Antibiotic MS-8209, and Congo Red on Accumulation of the Protease-Resistant Isoform of PrP in the Spleens of Mice Inoculated Intraperitoneally with the Scrapie Agent

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