Structure–activity relationship of tocopherol derivatives suggesting a novel non-antioxidant mechanism in antiprion potency

Abstract

Beneficial effects of tocopherols, or vitamin E, on degenerative brain conditions have been attributed mainly to their antioxidant effects. Non-antioxidant effects of the tocopherols have been shown to be mediated by inhibition of protein kinase C (PKC) signaling. Prion disease is a paradigmatic protein conformational disease characterized by the induced conversion of a normal host protein PrPC to adopt a pathogenic conformation PrPSc. The molecular regulation of prion replication is poorly understood. Here, we show that tocopherols inhibit prion replication by a structure–activity relationship for antiprion activity independent of antioxidant activity with tocopherol succinate (TS) posessing highest EC50 at 7μM. Only TS but not an equally antiprion active PKC inhibitor could be partially antagonized by substochiometric 1nM rapamycin suggesting that there are pathways via mammalian target of rapamycin (mTOR) that interfere with tocopherol's biological effects. Interaction with the mTOR pathway is a yet undescribed characteristic of tocopherol derivatives, potentially significant for pathophysiological processes other than prion propagation.