Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner
Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner
复制标题
DOI：
10.1128/jvi.01563-07
复制
发表时间：
2007-12-01
影响因子：
5.4
通讯作者：
Doh-ura, Katsurni
中科院分区：
文献类型：
--
作者：
Kawasaki, Yuri;Kawagoe, Keiichi;Doh-ura, Katsurni
建立有效的朊病毒病治疗干预措施是必要的。我们报告了一种新开发的淀粉样蛋白化合物，口服给药时显示治疗效果。该化合物以朊病毒株依赖性方式抑制朊病毒感染的神经母细胞瘤细胞中异常朊病毒蛋白的形成：有效抑制RML朊病毒，轻微抑制22 L朊病毒和Fukuoka-1朊病毒。当从接种至疾病终末期对脑RML朊病毒接种小鼠经口给予最高剂量（饲料中0.2% [wt/wt]）时，与对照组相比，其潜伏期延长了2.3倍。该化合物以朊病毒株依赖性方式发挥治疗功效，如在细胞培养研究中观察到的：对RML朊病毒最有效，对22 L朊病毒或Fukuoka-1朊病毒效果较差，对263 K朊病毒效果甚微。其有效性取决于较早开始管理。治疗小鼠中异常朊病毒蛋白的糖型模式被改变，并显示出二糖基化形式的优势，这类似于263 K朊病毒，表明二糖基化形式的异常朊病毒蛋白可能对该化合物最不敏感或耐药。朊病毒株依赖的有效性的机制需要阐明和管理。尽管如此，一种口服可利用的淀粉样蛋白化学物质的鉴定鼓励了对朊病毒疾病的化疗的追求。
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.