R. Demaimay et al., PHARMACOLOGICAL STUDIES OF A NEW DERIVATIVE OF AMPHOTERICIN-B, MS-8209, IN MOUSE AND HAMSTER SCRAPIE, Journal of General Virology, 75, 1994, pp. 2499-2503
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.