Effectiveness of Anthracycline Against Experimental Prion Disease in Syrian Hamsters

Tagliavini, Fabrizio; McArthur, Robert A.; Canciani, Barbara; Giaccone, Giorgio; Porro, M.; Bugiani, Marianna; Lievens, Patricia; Bugiani, Orso; Peri, E.; Dall’Ara, P.; Rocchi, Mara; Poli, G.; Forloni, Gianluigi; Bandiera, Tiziano; Varasi, Mario; Suarato, A.; Cassutti, P.; Cervini, M. A.; Lansen, J.; Salmona, Mario; Post, Claes

doi:10.1126/science.276.5315.1119

Cited by 158 publications

(70 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This effect might act in conjunction with the higher tissue concentration of the drug. Such a hydrophobic interaction between PrP res and anti-prion drugs like Congo red and iododoxorubicin has been demonstrated previously (Prusiner et al, 1983;Merlini et al, 1995;Tagliavini et al, 1997).…”

Section: Discussionmentioning

confidence: 87%

A novel generation of heparan sulfate mimetics for the treatment of prion diseases

Adjou

Simoneau

Salès

et al. 2003

Journal of General Virology

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 87%

A novel generation of heparan sulfate mimetics for the treatment of prion diseases

Adjou

Simoneau

Salès

et al. 2003

Journal of General Virology

View full text Add to dashboard Cite

“…The animals were observed once a week to detect the onset and progression of clinical signs of disease. The behavioral analysis included the evaluation of reactivity to tactile and acoustic stimulation, posture, balance and coordination, and the presence of tremors as described previously (20). In experiments 1 and 3, three animals per group (randomly selected before inoculation) were killed for neuropathological and biochemical examination when clinical signs of disease were first apparent in the positive controls.…”

Section: In Vitro Conversion Of Protease-resistant Prp To a Protease-mentioning

confidence: 99%

“…These molecules include polyanions (10)(11)(12)(13)(14), polyene antibiotics (15)(16)(17), Congo red (18,19), iododoxorubicin (20), tetrapyrroles (21,22), branched polyamines (23,24), and modified PrP peptides (25). Unfortunately, the suitability of these compounds for therapy is limited, primarily because of inability to cross the blood-brain barrier and͞or severe toxicity.…”

mentioning

confidence: 99%

Tetracyclines affect prion infectivity

Forloni¹,

Iussich²,

Awan³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

179

102

View full text Add to dashboard Cite

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 M 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.

show abstract

“…2D) for CJD treatment began with the investigation of a structurally similar molecule, 4 0 -iodo-4 0 -deoxy-doxorubicin, which binds to amyloid fibrils and induces amyloid resorption in patients with systemic amyloidosis. Tagliavini et al (1997) found a reduction in both protease resistance and infectivity of PrP Sc when co-incubated with 4 0 -iodo-4 0 -deoxy-doxorubicin. Doxycy-cline and other tetracycline compounds were shown to have similar activity against PrP Sc , but with much less toxicity, by a subsequent series of in vitro and in vivo studies (Tagliavini et al 2000;Forloni et al 2002;Barret et al 2003).…”

Section: Doxycyclinementioning

confidence: 99%