NR ATGG
AU Salmona,M.; Colombo,L.; De Luigi,A.; Capobianco,R.; Mangieri,M.; Miccolo,C.; Forloni,G.; Tagliavini,F.
TI Tetracylines are effective in the treatment of peripheral prion infection
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-37
PT Konferenz-Vortrag
AB We previously showed that tetracyclines have the ability to (i) bind to synthetic peptides homologous to residues 82-146 and 106-126 of human PrP, (ii) hinder assembly of these peptides into amyloid fibrils, (iii) revert protease resistance of PrPsc extracted from brain tissue of patients with sporadic and variant CJD and cattle with BSE, (iv) prevent neuronal death and astrocyte proliferation induced by PrP peptides in vitro, and (v) reduce prion infectivity of scrapie-infected tissue by co-incubation. To investigate the effectiveness of these compounds as therapeutic agents, we carried out an initial experiment in Syrian hamsters that were inoculated in the gastrocnemius muscle with 100 µl of a 10-4 dilution of 263K-infected brain homogenate. The animals received a first dose of doxycycline (10 mg/kg) i.p. 1 h after infection, and then three subsequent doses every two days. Drug treatment significantly prolonged survival from 215±15 (mean± sem) days to 289±21 days (P<0.05). On this ground, a larger experiment was designed using the same scrapie model and the following treatment schedules with 10 mg/kg of compound i.p.: (1) tetracycline or doxycycline 1h after infection and then three times/week until day 40; (2) tetracycline or doxycycline 24 h after infection and then three times/week until day 40; (3) doxycycline 4 days after infection and then three times/week until day 44; (4) doxycycline 1 h after infection and then three times/week until day 40, followed by minocycline three times/week for the remaining life-span of the animals. Control animals for each treatment group received vehicle solution alone. At the time of writing the experiments have been in progress for 280 days. The initial results confirm the pilot study, showing that tetracyclines significantly delay the onset of clinical signs of disease, while the survival time is now being determined. These data indicate that tetracyclines are useful candidates for treatment of peripheral prion infection.
AD Mario Salmona, Laura Colombo, Ada De Luigi, Gianluigi Forloni, Istituto di Ricerche Farmacologiche "Mario Negri"; Raffaella Capobianco, Michela Mangieri, Claudia Miccolo, Fabrizio Tagliavini, Istituto Nazionale Neurologico "Carlo Besta"
SP englisch
PO Deutschland