NR AECE
AU Forloni,G.; Iussich,S.; Awan,T.; Colombo,L.; Angeretti,N.; Girola,L.; Bertani,I.; Poli,G.; Caramelli,M.; Grazia Bruzzone,M.; Farina,L.; Limido,L.; Rossi,G.; Giaccone,G.; Ironside,J.W.; Bugiani,O.; Salmona,M.; Tagliavini,F.
TI Tetracyclines affect prion infectivity
QU Proceedings of the National Academy of Sciences of the United States of America 2002 Aug 6; 99(16): 10849-54
IA http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=125061
PT journal article
AB Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, protease-resistant forms of the prion protein (PrP) termed PrPsc are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Based on previous findings that tetracyclines revert abnormal physicochemical properties and abolish neurotoxicity of PrP peptides in vitro, we tested the ability of these compounds to interact with PrPsc from patients with the new variant of Creutzfeldt-Jakob disease (vCJD) and cattle with bovine spongiform encephalopathy (BSE). The incubation with tetracycline hydrochloride or doxycycline hyclate at concentrations ranging from 10 microM to 1 mM resulted in a dose-dependent decrease in protease resistance of PrPsc. This finding prompted us to investigate whether tetracyclines affect prion infectivity by using an animal model of disease. Syrian hamsters were injected intracerebrally with 263K scrapie-infected brain homogenate that was coincubated with 1 mM tetracycline hydrochloride, 1 mM doxycycline hyclate, or vehicle solution before 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 magnetic-resonance abnormalities in the thalamus, neuropathological changes, and PrPsc accumulation. When tetracycline was preincubated with highly diluted scrapie-infected inoculum, one third of hamsters did not develop disease. Our data suggest that these well characterized antibiotics reduce prion infectivity through a direct interaction with PrPsc and are potentially useful for inactivation of BSE- or vCJD-contaminated products and prevention strategies.
MH Animal; Antibiotics, Tetracycline/*pharmacology; Brain/metabolism; Cattle; Creutzfeldt-Jakob Syndrome/etiology; Disease Models, Animal; Doxycycline/analogs & derivatives/pharmacology; Encephalopathy, Bovine Spongiform/etiology; Endopeptidase K/metabolism; Gentamicins/pharmacology; Guanidines/pharmacology; Hamsters; Human; Isothiocyanates/pharmacology; Mesocricetus; PrPsc Proteins/*drug effects/metabolism/pathogenicity; Protein Denaturation; Scrapie/etiology; Support, Non-U.S. Gov't; Tetracycline/*pharmacology
AD Gianluigi Forloni, Laura Colombo, Nadia Angeretti, Laura Girola, Ilaria Bertani, Mario Salmona, Istituto di Ricerche Farmacologiche Mario Negri, Universita degli Studi, 20100 Milano, Italy; Selina Iussich, Tazeen Awan, Maria Grazia Bruzzone, Laura Farina, Lucia Limido, Giacomina Rossi, Giorgio Giaccone, Orso Bugiani, Fabrizio Tagliavini, Istituto Nazionale Neurologico Carlo Besta, Universita degli Studi, 20100 Milano, Italy; Giorgio Poli, Istituto di Microbiologia e Immunologia Veterinaria, Universita degli Studi, 20100 Milano, Italy; Maria Caramelli, Istituto Zooprofilattico Sperimentale, 10100 Torino, Italy; James W. Ironside, National CJD Surveillance Unit, Western General Hospital, Edinburgh EH42XV, United Kingdom
SP englisch
PO USA