MS-8209, a new amphotericin B derivative, provides enhanced efficacy in delaying hamster scrapie

Abstract

To test the efficacy of a new amphotericin B derivative, MS-8209, in delaying scrapie, hamsters were infected intracerebrally with the 263K scrapie agent and treated with MS-8209 either early in the course of the disease or continuously. The results show that (i) all treatments lengthened the incubation period of hamster scrapie, (ii) continuous treatment with MS-8209 doubled the length of the incubation period compared with that observed in infected, untreated animals, and (iii) all treatments delayed the accumulation of a proteinaseresistant prion protein and glial fibrillary acidic protein in the brain. These findings suggest that MS-8209 is a powerful tool for investigating the pathogenesis of transmissible subacute spongiform encephalopathies.Experimental scrapie in hamsters is a simple, reproducible model of transmissible spongiform encephalopathies (TSE) which have been described for many mammalian species. TSE include Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats. These fatal diseases are characterized by a long incubation period and histopathological changes such as neuronal vacuolization and astrogliosis in the central nervous system. TSE are caused by as-yet-unknown infectious agents named transmissible spongiform agents, or prions, and characterized by the accumulation of an abnormal proteinase-resistant isoform (PrP-res) of the host-encoded prion protein (PrP), derived from PrP posttranslational modifications (2). The transcriptional accumulation of glial fibrillary acidic protein (GFAP), a specific marker of astrocytes, has also been observed (5).At present, no treatment is available for TSE. Many unsuccessful therapeutic trials have been performed in experimental animal models; the trials have included the use of hormones, antibiotics, antiviral drugs, and antifungal agents (3). Three groups of drugs exhibited relative efficacy against scrapie: polyanions (6), the amyloid-binding dye Congo red (7), and amphotericin B (AmB) (1,12). AmB belongs to the group of polyene antibiotics with a ring structure that includes a hydrophobic region of conjugated double bonds and a hydrophilic region of hydroxyl groups with a mycosamine sugar moiety. AmB is an effective antifungal agent that is widely used for the treatment of systemic fungal infections such as candidiasis, histoplasmosis, and aspergillosis (9). It has been reported to delay the appearance of experimental scrapie in hamsters infected intracerebrally or intraperitoneally with the 263K scrapie strain (11). AmB also delayed PrP-res accumulation in the brain (15), but its effect on scrapie agent replication remains unclear (8, 15). The efficacy of AmB is limited by the absolute need to start the treatment in the early stages of scrapie infection and by its acute toxicity. MS-8209 is a polyene macrolide antibiotic derived from AmB which exhibits identical antifungal properties but in addition possesses greater water solubility and is at least five times less toxic (14). MS-8209 is thus an antiviral drug that might be useful for ex...

A cell line infectible by prion strains from different species

“…To determine whether the multiplication of bank vole-adapted BSE agent was sensitive to pharmacological treatment, infected cultures were incubated for 1 week in the presence of DS 500 and the amphotericin B derivative MS-8209, two molecules known to delay the onset of disease in experimentally infected rodents (Adjou et al, 1995;Ehlers & Diringer, 1984). Fig.…”

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

“…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).…”

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.…”