PHARMACOLOGICAL STUDIES OF A NEW DERIVATIVE OF AMPHOTERICIN-B, MS-8209, IN MOUSE AND HAMSTER SCRAPIE

Transmissible subacute spongiform encephalopathies (TSSE) are neurodeg enerative diseases characterized by the presence of a modified, partia lly proteinase-resistant host protein, PrPSc, which accumulates in the brains of infected individuals. Recently it has been reported that am photericin B (AmB) treatment of hamsters infected with scrapie strain 263K prolongs the incubation period of the disease, and dissociates in vivo replication of the scrapie agent from PrPSc accumulation. We rep ort here on data obtained after treatment with AmB and one of its deri vatives, MS-8209, in experimental scrapie of mouse and hamster. Treatm ent was carried out by the intraperitoneal route 6 days per week, at t hree different dosages initiated at the time of infection. Two regimen s were used: during the early time of infection or throughout the expe rimental infection. Results indicate that MS-8209 was as efficient as AmB in prolonging the incubation time and decreasing PrPSc accumulatio n in the hamster scrapie model. A dose-dependent response was observed in mice treated early after experimental infection. At a dose of 2.5 mg/kg, MS-8209 significantly prolonged the incubation period (by 11.9% ). In longterm treatment of mice, MS-8209 and AmB markedly reduced PrP Sc levels in the preclinical stage of the disease. These data demonstr ate that the effect of AmB is not restricted to one model (hamster-263 K). This regimen leads to an inversion of the PrPSc to proteinase-sens itive protein (PrPSens) ratio, suggesting PrPSens (presumably cellular PrPC) accumulation occurs before its conversion into PrPSc. As it has been shown that AmB does not modify the infectivity titre, we conclud e that the drugs could act by inhibiting either the interaction of the scrapie agent with PrPSens during the early times of infection or the conversion of PrPSens into PrPSe.