Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner
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作者:
Kawasaki, Yuri
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机构:Tohoku Univ, Grad Sch Med, Dept Prion Res, Aoba Ku, Sendai, Miyagi 9808575, Japan
Kawasaki, Yuri
Kawagoe, Keiichi
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机构:Tohoku Univ, Grad Sch Med, Dept Prion Res, Aoba Ku, Sendai, Miyagi 9808575, Japan
Kawagoe, Keiichi
Chen, Chun-jen
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机构:Tohoku Univ, Grad Sch Med, Dept Prion Res, Aoba Ku, Sendai, Miyagi 9808575, Japan
Chen, Chun-jen
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Teruya, Kenta
Sakasegawa, Yuji
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机构:Tohoku Univ, Grad Sch Med, Dept Prion Res, Aoba Ku, Sendai, Miyagi 9808575, Japan
Sakasegawa, Yuji
Doh-ura, Katsurni
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机构:Tohoku Univ, Grad Sch Med, Dept Prion Res, Aoba Ku, Sendai, Miyagi 9808575, Japan
Doh-ura, Katsurni
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[1] Tohoku Univ, Grad Sch Med, Dept Prion Res, Aoba Ku, Sendai, Miyagi 9808575, Japan
[2] Daiichi Pharmaceut Co Ltd, Tokyo R&D Ctr, Tokyo, Japan
The establishment of effective therapeutic interventions for prion diseases is necessary. We report on a newly developed amyloidophilic compound that displays therapeutic efficacy when administered orally. This compound inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion strain-dependent manner: effectively for RML prion and marginally for 22L prion and Fukuoka-1 prion. When the highest dose (0.2% [wt/wt] in feed) was given orally to cerebrally RML prion-inoculated mice from inoculation until the terminal stage of disease, it extended the incubation periods by 2.3 times compared to the control. The compound exerted therapeutic efficacy in a prion strain-dependent manner such as that observed in the cell culture study: most effective for RML prion, less effective for 22L prion or Fukuoka-1 prion, and marginally effective for 263K prion. Its effectiveness depended on an earlier start of administration. The glycoform pattern of the abnormal prion protein in the treated mice was modified and showed predominance of the diglycosylated form, which resembled that of 263K prion, suggesting that cliglycosylated forms of abnormal prion protein might be least sensitive or resistant to the compound. The mechanism of the prion strain-dependent effectiveness needs to be elucidated and managed. Nevertheless, the identification of an orally available amyloidophilic chemical encourages the pursuit of chemotherapy for prion diseases.
机构:Rocky Mountain Laboratories, Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana
CAUGHEY, B
;
RACE, RE
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机构:Rocky Mountain Laboratories, Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana
机构:Rocky Mountain Laboratories, Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana
CAUGHEY, B
;
RACE, RE
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机构:Rocky Mountain Laboratories, Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana