1887

Abstract

Diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders. A thioflavin derivative, 2-[4′-(methylamino)phenyl] benzothiazole (BTA-1) and a Congo red derivative, (, ),-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) are representative chemicals of these probes. In this report, the two chemicals were studied in transmissible spongiform encephalopathies (TSE). Both BTA-1 and BSB selectively bound to compact plaques of prion protein (PrP), not only in the brain specimens of certain types of human TSE, but also in the brains of TSE-infected mice when the probes were injected intravenously. The chemicals bound to plaques in the brains were stable and could be detected for more than 42 h post-injection. In addition, the chemicals inhibited abnormal PrP formation in a cellular model of TSE with IC values of 4 nM for BTA-1 and 1·4 μM for BSB. In an experimental mouse model, the intravenous injection of 1 mg BSB prolonged the incubation period by 14 %. This efficacy was only observed against the RML strain and not the other strains examined. These observations suggest that these chemicals bind directly to PrP aggregates and inhibit new formation of abnormal PrP in a strain-dependent manner. Both BTA-1 and BSB can be expected to be lead chemicals not only for imaging probes but also for therapeutic drugs for TSEs caused by certain strains.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.19754-0
2004-06-01
2024-11-07
Loading full text...

Full text loading...

/deliver/fulltext/jgv/85/6/vir851785.html?itemId=/content/journal/jgv/10.1099/vir.0.19754-0&mimeType=html&fmt=ahah

References

  1. Bacskai B. J., Klunk W. E., Mathis C. A., Hyman B. T. 2002; Imaging amyloid- β deposits in vivo . J Cereb Blood Flow Metab 22:1035–1041
    [Google Scholar]
  2. Caughey B., Raymond G. J. 1993; Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. J Virol 67:643–650
    [Google Scholar]
  3. Caughey B., Ernst D., Race R. E. 1993; Congo red inhibition of scrapie agent replication. J Virol 67:6270–6272
    [Google Scholar]
  4. Demaerel P., Baert A. L., Vanopdenbosch L., Robberecht W., Dom R. 1997; Diffusion-weighted magnetic resonance imaging in Creutzfeldt–Jakob disease. Lancet 349:847–848
    [Google Scholar]
  5. Doh-ura K., Mekada E., Ogomori K., Iwaki T. 2000; Enhanced CD9 expression in the mouse and human brains infected with transmissible spongiform encephalopathies. J Neuropathol Exp Neurol 59:774–785
    [Google Scholar]
  6. Engler H., Nordberg A., Blomqvist G. 11 other authors 2002; First human study with a benzothiazole amyloid-imaging agent in Alzheimer's disease and control subjects. Neurobiol Aging 23:S429
    [Google Scholar]
  7. Fischer M., Rulicke T., Raeber A., Sailer A., Moser M., Oesch B., Brandner S., Aguzzi A., Weissmann C. 1996; Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15:1255–1264
    [Google Scholar]
  8. Hamad A., Hamad A., Sokrab T. E., Momeni S., Brown P. 2001; Iatrogenic Creutzfeldt–Jakob disease at the millennium. Neurology 56:987 [CrossRef]
    [Google Scholar]
  9. Ingrosso L., Ladogana A., Pocchiari M. 1995; Congo red prolongs the incubation period in scrapie-infected hamsters. J Virol 69:506–508
    [Google Scholar]
  10. Mathis C. A., Bacskai B. J., Kajdasz S. T. 8 other authors 2002; A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 12:295–298 [CrossRef]
    [Google Scholar]
  11. Murakami-Kubo I., Doh-Ura K., Ishikawa K., Kawatake S., Sasaki K., Kira J., Ohta S., Iwaki T. 2004; Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies. J Virol 78:1281–1288 [CrossRef]
    [Google Scholar]
  12. Murata T., Shiga Y., Higano S., Takahashi S., Mugikura S. 2002; Conspicuity and evolution of lesions in Creutzfeldt–Jakob disease at diffusion-weighted imaging. Am J Neuroradiol 23:1164–1172
    [Google Scholar]
  13. Nishida N., Harris D. A., Vilette D., Laude H., Frobert Y., Grassi J., Casanova D., Milhavet O., Lehmann S. 2000; Successful transmission of three mouse-adapted scrapie strains to murine neuroblastoma cell lines overexpressing wild-type mouse prion protein. J Virol 74:320–325 [CrossRef]
    [Google Scholar]
  14. Priola S. A., Raines A., Caughey W. S. 2000; Porphyrin and phthalocyanine antiscrapie compounds. Science 287:1503–1506 [CrossRef]
    [Google Scholar]
  15. Prusiner S. B. 1991; Molecular biology of prion diseases. Science 252:1515–1522 [CrossRef]
    [Google Scholar]
  16. Race R. E., Caughey B., Graham K., Ernst D., Chesebro B. 1988; Analyses of frequency of infection, specific infectivity, and prion protein biosynthesis in scrapie-infected neuroblastoma cell clones. J Virol 62:2845–2849
    [Google Scholar]
  17. Race R. E., Priola S. A., Bessen R. A., Ernst D., Dockter J., Rall G. F., Mucke L., Chesebro B., Oldstone M. B. 1995; Neuron-specific expression of a hamster prion protein minigene in transgenic mice induces susceptibility to hamster scrapie agent. Neuron 15:1183–1191 [CrossRef]
    [Google Scholar]
  18. Skovronsky D. M., Zhang B., Kung M. P., Kung H. F., Trojanowski J. Q., Lee V. M. 2000; In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 97:7609–7614 [CrossRef]
    [Google Scholar]
  19. Supattapone S., Nishina K., Rees J. R. 2002; Pharmacological approaches to prion research. Biochem Pharmacol 63:1383–1388 [CrossRef]
    [Google Scholar]
  20. Will R. G., Ironside J. W., Zeidler M. 7 other authors 1996; A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347:921–925 [CrossRef]
    [Google Scholar]
  21. Yokoyama T., Kimura K. M., Ushiki Y., Yamada S., Morooka A., Nakashiba T., Sassa T., Itohara S. 2001; In vivo conversion of cellular prion protein to pathogenic isoforms, as monitored by conformation-specific antibodies. J Biol Chem 276:11265–11271 [CrossRef]
    [Google Scholar]
/content/journal/jgv/10.1099/vir.0.19754-0
Loading
/content/journal/jgv/10.1099/vir.0.19754-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error