The Efficacy of Tetracyclines in Peripheral and Intracerebral Prion Infection

Ada De Luigi,Raffaella Capobianco,Gianluigi Forloni,Michela Mangieri,Claudia Miccolo,Laura Colombo,Lucia Limido,Fabrizio Tagliavini,Luisa Diomede,Mario Salmona,Mark R Cookson

doi:10.1371/journal.pone.0001888

Abstract

We have previously shown that tetracyclines interact with and reverse the protease resistance of pathological prion protein extracted from scrapie-infected animals and patients with all forms of Creutzfeldt-Jakob disease, lowering the prion titre and prolonging survival of cerebrally infected animals. To investigate the effectiveness of these drugs as anti-prion agents Syrian hamsters were inoculated intramuscularly or subcutaneously with 263K scrapie strain at a 10−4 dilution. Tetracyclines were injected intramuscularly or intraperitoneally at the dose of 10 mg/kg. A single intramuscular dose of doxycycline one hour after infection in the same site of inoculation prolonged median survival by 64%. Intraperitoneal doses of tetracyclines every two days for 40 or 44 days increased survival time by 25% (doxycycline), 32% (tetracycline); and 81% (minocycline) after intramuscular infection, and 35% (doxycycline) after subcutaneous infection. To extend the therapeutic potential of tetracyclines, we investigated the efficacy of direct infusion of tetracyclines in advanced infection. Since intracerebroventricular infusion of tetracycline solutions can cause overt acute toxicity in animals, we entrapped the drugs in liposomes. Animals were inoculated intracerebrally with a 10−4 dilution of the 263K scrapie strain. A single intracerebroventricular infusion of 25 µg/ 20 µl of doxycycline or minocycline entrapped in liposomes was administered 60 days after inoculation, when 50% of animals showed initial symptoms of the disease. Median survival increased of 8.1% with doxycycline and 10% with minocycline. These data suggest that tetracyclines might have therapeutic potential for humans.

Highlights

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that cause extensive loss of cerebral neurons with formation of vacuoles, giving a ‘‘sponge-like’’ appearance to the tissue
Many classes of molecules have been screened in experimental therapy [4,5,6,7], some showing promising anti-prion activity, but most of them suffer the limitation of poor passage through the bloodbrain barrier (BBB) and severe toxicity
We report the efficacy of tetracycline, doxycycline and minocycline in prolonging the survival of hamsters infected intramuscularly, subcutaneously or intracerebrally with the 263K scrapie strain and showed that the drugs are active when administered at the appearance of the first symptoms

Summary

Introduction

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that cause extensive loss of cerebral neurons with formation of vacuoles, giving a ‘‘sponge-like’’ appearance to the tissue. They include several diseases with different causes (infectious/iatrogenic, sporadic or genetic origin), recognized both in humans and animals as variations of the same disorder [1,2]. The precise pathogenic mechanism is still not understood, prion diseases involve the deposition of aggregates of disease-related isoforms (PrPSc) of a host-encoded protein (PrPC) in the central nervous system. There is no therapy for prion diseases in humans. Pentosan polysulfate [8,9], quinacrine [10,11] and flupirtrine [12], are currently used in the clinical management of human prion diseases, none of them have yet been proved to be effective, reinforcing the importance of identifying new treatment strategies

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