Structure-activity relationship of tocopherol derivatives suggesting a novel non-antioxidant mechanism in antiprion potency.
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 PrP(C) to adopt a pathogenic conformation PrP(Sc). 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 EC(50) at 7 microM. Only TS but not an equally antiprion active PKC inhibitor could be partially antagonized by substochiometric 1 nM 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.
Muyrers
Janine
J
Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Klingenstein
Ralf
R
Stitz
Lothar
L
Korth
Carsten
C
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011328:Prions / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D024505:Tocopherols / Q000737:chemistry* / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000737:chemistry / Q000494:pharmacology
D047908:Intracellular Signaling Peptides and Proteins; D011328:Prions; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D024502:alpha-Tocopherol; D024505:Tocopherols