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.
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. Day-by-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.
Beringue
V
V
CEA, Service de Neurovirologie, DRM/DSV, CRSSA, Fontenay aux Roses, France. v.beringue@ic.ac.uk
Adjou
K T
KT
Lamoury
F
F
Maignien
T
T
Deslys
J P
JP
Race
R
R
Dormont
D
D
D000666:Amphotericin B / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003224:Congo Red / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006224:Cricetinae; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019286:Endopeptidase K / Q000378:metabolism; D005260:Female; D007274:Injections, Intraperitoneal; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009928:Organ Specificity; D018620:PrPSc Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D012608:Scrapie / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D018620:PrPSc Proteins; D020033:Protein Isoforms; C074660:MS 8209; D003224:Congo Red; D000666:Amphotericin B; D016264:Dextran Sulfate; D019286:Endopeptidase K