Suppression of scrapie infection in mice by heteropolyanion 23, dextran sulfate, and some other polyanions

Abstract

Studies of polyanions that suppress scrapie have been done to pinpoint the cell types in the lymphoreticular system which are important in pathogenesis and to suggest possible prophylactic or therapeutic strategies for the unconventional slow viruses. A regime of three daily injections of the inorganic heteropolyanion HPA-23 reduced the effective scrapie dose by more than 99%; i.e., some mice survived peripherally injected doses of 100 50% lethal dose units. The effect was greatest when the first dose of HPA-23 was given 4 h ifter injecting scrapie, but it declined rapidly as this interval was increased, and there was virtually no effect 2 days after infection. A single dose of high-molecular-weight organic polyanions such as carrageenan or dextran sulfate (DS-500) greatly reduced (i.e., >99%) the efficiency of scrapie infection. In contrast to HPA-23, DS-500 was equally effective whether given 4 days before or 8 h after the time of infection. The antiscrapie effect of DS-500 appeared to be independent of its activity as a B-cell mitogen and of its ability to produce a cytotoxic blockade of phagocytic cells. DS-500 probably caused the aggregation and loss from blood of scrapie inoculum which was present immediately after injection, but it had additional effects on scrapie at later times.

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

“…2b). Comparison of the effect of HMs with DS500, another sulfated polyanion proven to be effective in vivo (Farquhar & Dickinson, 1986;Kimberlin & Walker, 1986;Beringue et al, 2000), showed a similar reduction in PrP res levels in our in vitro model at 1 and 10 mg ml 21 (Fig. 2c).…”

“…It has been shown that PrP can bind specifically to heparan sulfate-like molecules (Gabizon et al, 1993;Brimacombe et al, 1999;Gonzalez-Iglesias et al, 2002;Warner et al, 2002) and that some of them exhibit anti-prion properties (Ehlers & Diringer, 1984;Farquhar & Dickinson, 1986;Kimberlin & Walker, 1986;Ladogana et al, 1992;Caughey & Raymond, 1993;Farquhar et al, 1999;Beringue et al, 2000). For these reasons, various HMs developed initially for their properties to enhance tissue repair were screened to identify inhibitors of PrP res accumulation.…”

“…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).…”

Chemoprophylaxis of scrapie in mice

“…However, unconventional viruses do not elicit an immune reaction and immunostimulatory substances used to alter scrapie pathogenesis have been shown to shorten rather than to lengthen incubation periods (Dickinson et al, 1978;Kimberlin & Cunnington, 1978). Furthermore, evidence that the inhibitory effects of DS 500 on scrapie infection are not due to its action as a B cell mitogen has been published (Kimberlin & Walker, 1986).…”

Tetracyclines affect prion infectivity

“…These molecules include polyanions (10)(11)(12)(13)(14), polyene antibiotics (15)(16)(17), Congo red (18,19), iododoxorubicin (20), tetrapyrroles (21,22), branched polyamines (23,24), and modified PrP peptides (25). Unfortunately, the suitability of these compounds for therapy is limited, primarily because of inability to cross the blood-brain barrier and͞or severe toxicity.…”