NR AOZQ
AU Tagliavini,F.; Forloni,G.; Bugiani,O.; Salmona,M.
TI Anti-Prion Activity of Tetracyclic Compounds
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-34
PT Konferenz-Vortrag
AB Prion diseases are transmissible neurodegenerative disorders for which no effective treatment is available. Evidence indicates that abnormal forms of PrP, termed PrPsc, are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. The urgency to develop anti-prion agents has remarkably increased following the appearance of a new variant of Creutzfeldt-Jakob disease (vCJD) which is causally linked to BSE. Based on the observation that tetracyclines have structural homologies with anti-prion compounds (in particular, with the aglycone moiety of iododoxorubucin) we tested the ability of several congeners selected on QSAR basis to alter the biochemical properties of PrPsc and PrP amyloid peptides in vitro, and to reduce prion infectivity. We found that tetracyclines bind to and disrupt PrP amyloid fibrils, and revert the protease resistance of PrPsc extracted from brain tissue of BSE-affected cattle and patients with sporadic, genetic or acquired forms of CJD, including vCJD. On these grounds, tetracyclines were tested in an animal model of prion disease. Syrian hamsters were injected intracerebrally with 263K scrapie-infected brain homogenate which was co-incubated with tetracycline, doxicycline or vehicle solution prior to inoculation. Hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. These effects were paralleled by a delay in the appearance of MRI abnormalities, neuropathological changes (i.e., spongiosis and gliosis) and accumulation of PrPsc. When tetracycline was pre-incubated with high dilution of the scrapie-infected inoculum, one third of hamsters did not develop disease. Our data suggests that these well-characterized antibiotics reduce prion infectivity through a direct interaction with PrPsc and are potentially useful for inactivation of BSE-vCJD contaminated products and prevention strategies.
AD Fabrizio Tagliavini, Orso Bugiani, Istituto Nazionale Neurologico Carlo Besta, Milano, Italy; Gianluigi Forloni, Mario Salmona, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
SP englisch
PO Deutschland