Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models
Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models
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DOI：
10.1128/jvi.78.10.4999-5006.2004
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发表时间：
2004-05-01
影响因子：
5.4
通讯作者：
Iwaki, T
中科院分区：
文献类型：
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作者：
Doh-Ura, K;Ishikawa, K;Iwaki, T
在脑内感染263 K羊瘙痒病病原体的转基因小鼠中评估了直接药物输注到脑（传染性海绵状脑病的靶器官）中的治疗效果。戊聚糖多硫酸酯（PPS）的潜伏期最显着延长，和阿替霉素B有中等效果，但抗疟药，如奎纳克林没有显着延长。在感染的早期或晚期阶段用最高剂量的PPS治疗分别使潜伏期延长了对照小鼠的2.4或1.7倍。PPS输注不仅减少了异常朊蛋白沉积，而且减少了神经退行性病变和感染性。这些变化在装有脑室内输注插管的大脑半球内观察到，但在对侧半球内未观察到，即使在输注结束后很久的终末期疾病阶段也是如此。PPS的治疗作用也在感染RML因子或Fukuoka-1因子的小鼠中得到证实。然而，在高于提供最大效应的剂量下，脑室内PPS输注引起了不良反应，如实验动物中的血肿形成。这些发现表明，脑室内PPS输注可能有助于治疗人类传染性海绵状脑病，前提是仔细评估治疗剂量。
The therapeutic efficacy of direct drug infusion into the brain, the target organ of transmissible spongiform encephalopathies, was assessed in transgenic mice intracerebrally infected with 263K scrapie agent. Pentosan polysulfate (PPS) gave the most dramatic prolongation of the incubation period, and amphotericin B had intermediate effects, but antimalarial drugs such as quinacrine gave no significant prolongation. Treatment with the highest dose of PPS at an early or late stage of the infection prolonged the incubation time by 2.4 or 1.7 times that of the control mice, respectively. PPS infusion decreased not only abnormal prion protein deposition but also neurodegenerative changes and infectivity. These alterations were observed within the brain hemisphere fitted with an intraventricular infusion cannula but not within the contralateral hemisphere, even at the terminal disease stage long after the infusion had ended. Therapeutic effects of PPS were also demonstrated in mice infected with either RML agent or Fukuoka-1 agent. However, at doses higher than that providing the maximal effects, intraventricular PPS infusion caused adverse effects such as hematoma formation in the experimental animals. These findings indicate that intraventricular PPS infusion might be useful for the treatment of transmissible spongiform encephalopathies in humans, providing that the therapeutic dosage is carefully evaluated.