Tetracyclines affect prion infectivity.
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 PrP(Sc) 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 PrP(Sc) 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 PrP(Sc). 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 PrP(Sc) 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 PrP(Sc) and are potentially useful for inactivation of BSE- or vCJD-contaminated products and prevention strategies.
Forloni
Gianluigi
G
Istituto di Ricerche Farmacologiche Mario Negri, Istituto Nazionale Neurologico Carlo Besta, and Istituto di Microbiologia e Immunologia Veterinaria, Università degli Studi, 20100 Milano, Italy.
Iussich
Selina
S
Awan
Tazeen
T
Colombo
Laura
L
Angeretti
Nadia
N
Girola
Laura
L
Bertani
Ilaria
I
Poli
Giorgio
G
Caramelli
Maria
M
Grazia Bruzzone
Maria
M
Farina
Laura
L
Limido
Lucia
L
Rossi
Giacomina
G
Giaccone
Giorgio
G
Ironside
James W
JW
Bugiani
Orso
O
Salmona
Mario
M
Tagliavini
Fabrizio
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002417:Cattle; D007562:Creutzfeldt-Jakob Syndrome / Q000209:etiology; D006224:Cricetinae; D004195:Disease Models, Animal; D004318:Doxycycline / Q000031:analogs & derivatives / Q000494:pharmacology; D016643:Encephalopathy, Bovine Spongiform / Q000209:etiology; D019286:Endopeptidase K / Q000378:metabolism; D005839:Gentamicins / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D008647:Mesocricetus; D018620:PrPSc Proteins / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D011489:Protein Denaturation; D012608:Scrapie / Q000209:etiology; D013752:Tetracycline / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D006146:Guanidines; D017879:Isothiocyanates; D018620:PrPSc Proteins; C054435:guanidine isothiocyanate; D019286:Endopeptidase K; D013752:Tetracycline; D004318:Doxycycline