Ilsong Institute of Life Science, Hallym University, Youngdeungpo-gu, Seoul 07247, Republic of Korea.
Il Yang Pharm Co., Ltd., 37, Hagal-ro, 136beon-gil, Giheung-gu, Yongin-si 17096, Republic of Korea.
Int J Mol Sci. 2023 Jul 31;24(15):12241. doi: 10.3390/ijms241512241.
The conversion of cellular prion protein (PrP) into pathogenic prion isoforms (PrP) and the mutation of are definite causes of prion diseases. Unfortunately, without exception, prion diseases are untreatable and fatal neurodegenerative disorders; therefore, one area of research focuses on identifying medicines that can delay the progression of these diseases. According to the concept of drug repositioning, we investigated the efficacy of the c-Abl tyrosine kinase inhibitor radotinib, which is a drug that is approved for the treatment of chronic myeloid leukemia, in the treatment of disease progression in prion models, including prion-infected cell models, 20 and hamster cerebellar slice culture models, and 263K scrapie-infected hamster models. Radotinib inhibited PrP deposition in neuronal ZW13-2 cells that were infected with the 22L or 139A scrapie strains and in cerebellar slice cultures that were infected with the 22L or 263K scrapie strains. Interestingly, hamsters that were intraperitoneally injected with the 263K scrapie strain and intragastrically treated with radotinib (100 mg/kg) exhibited prolonged survival times (159 ± 28.6 days) compared to nontreated hamsters (135 ± 9.9 days) as well as reduced PrP deposition and ameliorated pathology. However, intraperitoneal injection of radotinib exerted a smaller effect on the survival rate of the hamsters. Additionally, we found that different concentrations of radotinib (60, 100, and 200 mg/kg) had similar effects on survival time, but this effect was not observed after treatment with a low dose (30 mg/kg) of radotinib. Interestingly, when radotinib was administered 4 or 8 weeks after prion inoculation, the treated hamsters survived longer than the vehicle-treated hamsters. Additionally, a pharmacokinetic assay revealed that radotinib effectively crossed the blood-brain barrier. Based on our findings, we suggest that radotinib is a new candidate anti-prion drug that could possibly be used to treat prion diseases and promote the remission of symptoms.
细胞朊病毒蛋白（PrP）转化为致病性朊病毒异构体（PrP）和 突变是朊病毒病的确切原因。不幸的是，无一例外，朊病毒病是无法治愈且致命的神经退行性疾病；因此，研究的一个领域集中在确定可以延缓这些疾病进展的药物。根据药物再定位的概念，我们研究了 c-Abl 酪氨酸激酶抑制剂 radotinib 的疗效，radotinib 是一种批准用于治疗慢性髓性白血病的药物，在治疗朊病毒模型中的疾病进展方面，包括感染朊病毒的细胞模型、20 和仓鼠小脑切片培养模型，以及感染 263K 瘙痒病毒的仓鼠模型。Radotinib 抑制了感染 22L 或 139A 瘙痒病毒株的神经元 ZW13-2 细胞和感染 22L 或 263K 瘙痒病毒株的小脑切片培养物中 PrP 的沉积。有趣的是，与未治疗的仓鼠（135 ± 9.9 天）相比，用 263K 瘙痒病毒株腹腔内注射并用 radotinib（100mg/kg）治疗的仓鼠的存活时间延长（159 ± 28.6 天），并且 PrP 沉积减少，病理学得到改善。然而，腹腔内注射 radotinib 对仓鼠的存活率影响较小。此外，我们发现不同浓度的 radotinib（60、100 和 200mg/kg）对存活时间有相似的影响，但在用低剂量（30mg/kg）radotinib 治疗时未观察到这种作用。有趣的是，当 radotinib 在朊病毒接种后 4 或 8 周给予时，治疗的仓鼠比载体治疗的仓鼠存活时间更长。此外，药代动力学测定表明 radotinib 有效地穿过了血脑屏障。基于我们的发现，我们认为 radotinib 是一种新的抗朊病毒候选药物，可能用于治疗朊病毒病并促进症状缓解。
