Treatment of SMB-S15 Cells with Resveratrol Efficiently Removes the PrP(Sc) Accumulation In Vitro and Prion Infectivity In Vivo.

Abstract

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 200μM) reduced and even removed cellular PrP(Sc) in a dose-dependent manner, with EC50 0.61μM. Meanwhile, PrP(Sc) signals in SMB-S15 cells treated with 5 and 10μM 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 10μM resveratrol for 2 and 7days 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 228day post inoculation (dpi), while all mice (n = 9) inoculated with SMB-S15 cells treated with resveratrol for 7days maintained healthy by the end of observations (284dpi). 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.