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

Abstract

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.

Identification of the Heparan Sulfate Binding Sites in the Cellular Prion Protein

“…Not only have direct interactions been demonstrated with PrP (14,15), GAGs have been shown to influence PrP sc accumulation in both cell-culture and in vitro converting experiments (12-13, 17, 18) and to modulate PrP sc propagation and disease onset in animal models for scrapie (8,9). This study has addressed three areas of current interest: the structural features of GAGs that engender PrP-binding ability, the influence of metal ions on GAG binding, and the location of GAG binding domains within PrP.…”

“…On a weight/volume basis this preparation was found to be superior to heparin and at least as effective as pentosan polysulfate (PPS), a polyanion with well-documented anti-prion activities in tissue culture and animal models (7,36). It would be of great interest to compare the inhibitory activity of DS8 with fractions of higher molecular weight such as DS500 (average molecular weight 500,000), which is a particularly effective inhibitor of PrP sc propagation in cell culture (13) and a potent anti-prion agent in animal studies of prion disease (8,9). Using this competition ELISA we also explored the contribution to prion binding of 2-and 6-O sulfate groupings, two of the three types of sulfate that elaborate heparin and HS (Nsulfates were not examined in this study).…”

“…Furthermore, administration of select anionic compounds can restrict both tissue-specific accumulation of PrP Sc and the onset of neurodegenerative features in experimental models of prion disease. In this respect pentosan sulfate and DS500 (dextran sulfate with average molecular weight of 500,000) are particularly effective (7)(8)(9). The basis for the anti-prion activity of these compounds is uncertain; one suggestion is that they compete with endogenous HSPGs for prion, another that they stabilize conformations of PrP sc , which are not favored as templates for PrP c ⅐PrP sc conversion (10).…”

A novel generation of heparan sulfate mimetics for the treatment of prion diseases

“…Because the extent of the vCJD epidemic in forthcoming years is still uncertain (Ghani et al, 2000(Ghani et al, , 2002, and given that no effective treatments are presently available for TSEs, the development of new therapeutic strategies is of crucial importance. One class of molecules that has shown significant efficiency in the treatment of prion diseases is the class of sulfated polyanions, such as dextran sulfate 500 (DS500), pentosane polysulfate and suramin (Farquhar & Dickinson, 1986;Kimberlin & Walker, 1986;Ladogana et al, 1992;Caughey & Raymond, 1993;Beringue et al, 2000;Gilch et al, 2001). However, their use is limited by their toxicity, restricted efficiency and narrow window of intervention following infection (Diringer & Ehlers, 1991;Ladogana et al, 1992).…”

Unswitched immunoglobulin M response prolongs mouse survival in prion disease

“…Time-course analyses of peripheral PrP Sc accumulation in mice confirmed that PrP Sc was detectable in the spleens at 7 days and reached a plateau by 30-40 days after peripheral challenge (Beringue et al, 2000).…”