Transmissible
subacute spongiform encephalopathies (TSSE) are
neurodegenerative diseases characterized by the presence of a modified, partially
proteinase-resistant host
protein, PrPSc, which accumulates in the brains of infected individuals. Recently it has been reported that
amphotericin 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 report here on data obtained
after treatment with AmB and one of its derivatives,
MS-8209, in experimental
scrapie of mouse and hamster. Treatment was carried out by the intraperitoneal route 6 days per week, at three different dosages initiated at the time of
infection. Two regimens were used: during the early time of
infection or throughout the experimental
infection. Results indicate that
MS-8209 was as efficient as AmB in prolonging the incubation time and decreasing PrPSc accumulation 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 long-term treatment of mice,
MS-8209 and AmB markedly reduced PrPSc levels in the preclinical stage of the disease. These data demonstrate that the effect of AmB is not restricted to one model (hamster-263K). This regimen leads to an inversion of the PrPSc to
proteinase-sensitive
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 conclude 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 PrPSc.