Abstract
On the basis of the structural homologies between ST1859 (1[(2-hydroxy-1-naphtyl)methyl]-2-naphthol) and the anti-prion agents and its anti-amyloidogenic activity, we tested whether this molecule altered the biochemical properties of aggregates formed in vitro by synthetic prion peptides and affected prion infectivity in experimental scrapie. Co-incubation of ST1859 with the peptides PrP 106–126 and PrP 82–146 reduced their fibrillogenic capacity and their resistance to digestion with protease K. Hamsters inoculated with the ST1859-treated homogenate showed a significant delay in the onset of clinical signs of disease and longer survival. Survival was also significantly longer in infected hamsters treated peripherally with ST1859 for the whole post-inoculation period until the onset of clinical symptoms. Similar results were found with the analogue ST1745. Our data indicate that ST1859 reduces prion infectivity and can exert a therapeutic effect in experimental scrapie.
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References
Abdul HM, Calabrese V, Calvani M, Butterfield DA (2006) Acetyl-l-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1–42-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. J Neurosci Res 84:398–408
Bauer M, Langer O, Dal-Bianco P, Karch R, Brunner M, Abrahim A, Lanzenberger R, Hofmann A, Joukhadar C et al (2006) Positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer’s disease. Clin Pharmacol Ther 80:216–227
Caramelli M, Ru G, Acutis P, Forloni G (2006) Prion diseases: current understanding of epidemiology and pathogenesis, and therapeutic advances. CNS Drugs 20:15–28
De Luigi A, Colombo L, Diomede L, Capobianco R, Mangieri M, Miccolo C, Limido L, Forloni G, Tagliavini F, Salmona M (2008) The efficacy of tetracyclines in peripheral and intracerebral prion infection. PLoS ONE 3:e1888
Fioriti L, Angeretti N, Colombo L, De Luigi A, Colombo A, Manzoni C, Morbin M, Tagliavini F, Salmona M, Chiesa R, Forloni G (2007) Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-Sträussler-Scheinker disease amyloid protein. J Neurosci 27:1576–1583
Forloni G, Iussich S, Awan T, Colombo L, Angeretti N, Girola L, Bertani I, Poli G, Caramelli M et al (2002) Tetracyclines affect prion infectivity. Proc Natl Acad Sci USA 99:10849–10854
Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M (2001) Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett 487:404–407
Forloni G, Angeretti N, Smiroldo S (1994) Neuroprotective activity of acetyl-l-carnitine: studies in vitro. J Neurosci Res 37:92–96
Forloni G, Angeretti N, Chiesa R, Monzani E, Salmona M, Bugiani O, Tagliavini F (1993) Neurotoxicity of a prion protein fragment. Nature 362:543–546
Forloni G, Varì MR, Colombo L, Bugiani O, Tagliavini F, Salmona M (2003) Prion diseases: time for a therapy? Curr Med Chem Immun Endocr Metab Agents 3:185–197
Forloni G, Salmona M, Marcon G, Tagliavini F (2009) Tetracycline and prion infectivity. Infect Disord Drug Targets 9:23–30
Korth C, May BC, Cohen FE, Prusiner SB (2001) Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci USA 98:9836–9841
Merlini G, Ascari E, Amboldi N, Bellotti V, Arbustini E, Perfetti V, Ferrari M, Zorzoli I, Marinone MG et al (1995) Interaction of the anthracycline 4′-iodo-4′-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci USA 92:2959–2963
Montgomery SA, Thal LJ, Amrein R (2003) Meta-analysis of double blind randomized controlled clinical trials of acetyl-l-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 18:61–71
Priola SA, Raines A, Caughey WS (2000) Porphyrin and phthalocyanine antiscrapie compounds. Science 287:1503–1506
Prusiner SB (2001) Shattuck lecture—neurodegenerative diseases and prions. N Engl J Med 344:1516–1526
Piccardo P, Dlouhy SR, Lievens PM, Young K, Bird TD, Nochlin D, Dickson DW, Vinters HV, Zimmerman TR et al (1998) Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol 57:979–988
Salmona M, Morbin M, Massignan T, Colombo L, Mazzoleni G, Capobianco R, Diomede L, Thaler F, Mollica L et al (2003) Structural properties of Gerstmann–Straussler–Scheinker disease amyloid protein. J Biol Chem 278:48146–48153
Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, Frattura L, Tiraboschi P et al (1991) Long-term acetyl-l-carnitine treatment in Alzheimer’s disease. Neurology 41:1726–1732
Stewart LA, Rydzewska LHM, Keogh GF, Knight RSG (2008) Systematic review of therapeutic interventions in human prion disease. Neurology 70:1272–1281
Tagliavini F, McArthur RA, Canciani B, Giaccone G, Porro M, Bugiani M, Peri E, Dall’Ara P, Rocchi M et al (1997) Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science 276:1119–1122
Tagliavini F, Forloni G, Colombo L, Rossi G, Girola L, Canciani B, Angeretti N, Giampaolo L, Peressini E et al (2000) Tetracycline affects abnormal properties of synthetic PrP peptides and PrP(Sc) in vitro. J Mol Biol 300:1309–1322
Trevitt CR, Collinge JA (2006) Systematic review of prion therapeutics in experimental models. Brain 129:2241–2246
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Colombo, L., Piovesan, P., Ghirardi, O. et al. ST1859 reduces prion infectivity and increase survival in experimental scrapie. Arch Virol 154, 1539–1544 (2009). https://doi.org/10.1007/s00705-009-0471-0
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DOI: https://doi.org/10.1007/s00705-009-0471-0