Tetracyclines affect prion infectivity

Gianluigi Forloni, Selina Iussich, Tazeen Awan, Laura Colombo, Nadia Angeretti, Laura Girola, Ilaria Bertani, Giorgio Poli, Maria Caramelli, Maria Grazia Bruzzone, Laura Farina, Lucia Limido, Giacomina Rossi, Giorgio Giaccone, James W. Ironside, Orso Bugiani, Mario Salmona, Fabrizio Tagliavini

Research output: Contribution to journalArticle

Abstract

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 μM 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.

Original languageEnglish
Pages (from-to)10849-10854
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number16
DOIs
Publication statusPublished - Aug 2002

ASJC Scopus subject areas

  • Genetics
  • General

Fingerprint Dive into the research topics of 'Tetracyclines affect prion infectivity'. Together they form a unique fingerprint.

  • Cite this

    Forloni, G., Iussich, S., Awan, T., Colombo, L., Angeretti, N., Girola, L., Bertani, I., Poli, G., Caramelli, M., Bruzzone, M. G., Farina, L., Limido, L., Rossi, G., Giaccone, G., Ironside, J. W., Bugiani, O., Salmona, M., & Tagliavini, F. (2002). Tetracyclines affect prion infectivity. Proceedings of the National Academy of Sciences of the United States of America, 99(16), 10849-10854. https://doi.org/10.1073/pnas.162195499