State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing, 102206, People's Republic of China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310003, People's Republic of China.
Mol Neurobiol. 2016 Oct;53(8):5367-76. doi: 10.1007/s12035-015-9464-z. Epub 2015 Oct 6.
Prion diseases are transmissible and invariably fatal neurodegenerative disorders, which still lack of efficacious prophylactic and therapeutic tools. Our previous study has proposed that the natural phytoalexin, resveratrol, can reduce the amounts of PrP(Sc) in a scrapie-infected cell line SMB-S15. To address its anti-prion efficacy, the inhibitive activity of resveratrol on prion accumulation in vitro and prion infectivity in vivo was analyzed in the present study. Exposure of SMB-S15 cells to various concentrations of resveratrol (0.25 to 200 μM) reduced and even removed cellular PrP(Sc) in a dose-dependent manner, with EC50 0.61 μM. Meanwhile, PrP(Sc) signals in SMB-S15 cells treated with 5 and 10 μM resveratrol maintained undetectable after drug withdrawal, indicating that the removal of PrP(Sc) in SMB-S15 cells by resveratrol is irreversible. Furthermore, the lysates of SMB-S15 cells exposed to 10 μM resveratrol for 2 and 7 days were intracerebrally inoculated into CD1 mice. All mice (n = 9) infected with SMB-S15 cells without treatment of resveratrol appeared typical experimental scrapie symptoms from 155 to 228 day post inoculation (dpi), while all mice (n = 9) inoculated with SMB-S15 cells treated with resveratrol for 7 days maintained healthy by the end of observations (284 dpi). PrP-specific Western blots and neuropathological tests did not identify PrP(Sc) or prion disease-associated pathological abnormality in the brains of mice inoculated with 7-day resveratrol-treated SMB-S15 cells. It indicates that the prion infectivity of SMB-S15 onto CD1 mice is eradicated by 1-week resveratrol treatment. Sensitivity of PrP(Sc) to resveratrol highlights its potential role in prion therapeutics.
朊病毒病是一种可传播且始终致命的神经退行性疾病，目前仍缺乏有效的预防和治疗手段。我们之前的研究表明，天然植物抗毒素白藜芦醇可以减少感染细胞系 SMB-S15 中的 PrP(Sc)含量。为了评估其抗朊病毒功效，本研究分析了白藜芦醇在体外抑制朊病毒积累和体内感染性的作用。暴露于不同浓度白藜芦醇（0.25 至 200 μM）的 SMB-S15 细胞中，PrP(Sc)以剂量依赖性方式减少，甚至消除，EC50 为 0.61 μM。同时，用 5 和 10 μM 白藜芦醇处理的 SMB-S15 细胞中的 PrP(Sc)信号在停药后保持无法检测，表明 SMB-S15 细胞中的 PrP(Sc)被白藜芦醇不可逆地消除。此外，暴露于 10 μM 白藜芦醇 2 和 7 天的 SMB-S15 细胞的裂解物被脑内接种到 CD1 小鼠中。未经白藜芦醇处理的 SMB-S15 细胞感染的所有小鼠（n = 9）在接种后 155 至 228 天（dpi）出现典型的实验性瘙痒症状，而所有用白藜芦醇处理 7 天的 SMB-S15 细胞感染的小鼠在观察结束时（284 dpi）保持健康。PrP 特异性 Western blot 和神经病理学测试未在接种 7 天白藜芦醇处理的 SMB-S15 细胞的小鼠脑中鉴定出 PrP(Sc)或朊病毒病相关的病理异常。这表明 1 周的白藜芦醇治疗消除了 SMB-S15 对 CD1 小鼠的朊病毒感染力。PrP(Sc)对白藜芦醇的敏感性突出了其在朊病毒治疗中的潜在作用。
