Late treatment with polyene antibiotics can prolong the survival time of scrapie-infected animals

Abstract

Amphotericin B (AmB) is one of the few drugs able to prolong survival times in experimental scrapie and delays the accumulation of PrPres, a specific marker of this disease in the brain in vivo. Previous reports showed that the AmB effect is observed only if the drug is administered around the time of infection. In the present study, intracerebrally infected mice were treated with AmB or one of its derivatives, MS-8209, between 80 and 140 days postinoculation. We observed an increased incubation time and a delay in PrPres accumulation and glial fibrillary acidic protein gene expression. Treatment starting at 80 days postinoculation was as efficient as long-term treatment starting the day of inoculation. Our results indicate that polyene antibiotics may interfere, throughout the course of the experimental disease, with the propagation of the scrapie agent. MATERIALS AND METHODS Animals. Mice used in the study were purchased from IFFA-CREDO (St. Germain d'Arbresle, France). C57BL/6 females were 4 weeks old at the time of inoculation. Animals were sacrificed by cervical column disruption. The central nervous system, including cerebellum, was dissected, rapidly frozen in liquid nitrogen, and kept at Ϫ80°C until use. Groups of three animals were sacrificed for molecular analysis. Animals were regularly monitored for clinical signs. Survival times were statistically analyzed by a nonparametric (Mann-Whitney) test. Scrapie strain. The C506M3 scrapie strain was a gift from P. Brown and D. C. Gajdusek (National Institutes of Health, Bethesda, Md.) and was passaged seven times in our laboratory. The scrapie inoculum had been titrated in vivo by limiting dilution 50% lethal dose (LD 50) assay. Twenty microliters of 1% (wt/vol) homogenate, 1.6 ϫ 10 8 LD 50 , was injected into the right cerebral hemisphere.

Approaches to Therapy of Prion Diseases

“…Many compounds, representative examples of which are listed in Table 1, prolong the incubation time in animals when administered before or soon after infection. Among these are sulfated polyanions (121)(122)(123)(124)(125), Congo red D (126), polyene antibiotics (125,(127)(128)(129), tetracyclic compounds (130), and tetrapyrroles (111,131,132). Copper added to the drinking water of scrapie-infected hamsters has been reported to delay clinical disease (133), but a similar effect was reported for the copper chelator D-(-)-penicillamine in scrapie-infected mice (134); such is life in the prion field.…”

Past, Present and Potential Future Prion Disease Treatment Strategies

“…Of the most commonly examined small molecule candidate therapies, many have not stood up to scrutiny when their in vitro efficacy was tested in vivo. This includes quinacrine, pentosan poylsufate, Congo red, amphotericin B, anthracyclines, and memantine [32][33][34][35][36][37][38][39]. Moreover, a subset of these compounds has been shown to extend the lives of prion-infected animals [40][41][42].…”

Oral toxicity study of an antiprion compound <i>N</i>,<i>N</i><i>’</i>-[(cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] in rats and cynomolgus monkeys

“…To date, numerous compounds that inhibit the accumulation of PrP Sc in TSE-infected cells have been identified (Cashman and Caughey, 2004;Sim and Caughey, 2009). However, only a limited number of compounds, including amphotericin B and its derivative (Demaimay et al, 1997), pentosan polysulfate (Doh-ura et al, 2004), and porphyrin derivatives (Kocisko et al, 2006), have been reported to be effective in TSE-infected animals. The inadequacy of most antiprion compounds as therapeutic agents can be attributed to their strain-dependent activity, low blood-brain barrier permeability, and toxicity (Zerr, 2009).…”