PMID- 19945507
OWN - NLM
STAT- MEDLINE
DCOM- 20100309
LR  - 20211203
IS  - 1872-7972 (Electronic)
IS  - 0304-3940 (Linking)
VI  - 469
IP  - 1
DP  - 2010 Jan 18
TI  - Structure-activity relationship of tocopherol derivatives suggesting a novel 
      non-antioxidant mechanism in antiprion potency.
PG  - 122-6
LID - 10.1016/j.neulet.2009.11.057 [doi]
AB  - 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.
CI  - (c) 2009 Elsevier Ireland Ltd. All rights reserved.
FAU - Muyrers, Janine
AU  - Muyrers J
AD  - Department of Neuropathology, Heinrich Heine University Dusseldorf, Moorenstrasse 
      5, 40225 Dusseldorf, Germany.
FAU - Klingenstein, Ralf
AU  - Klingenstein R
FAU - Stitz, Lothar
AU  - Stitz L
FAU - Korth, Carsten
AU  - Korth C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091127
PL  - Ireland
TA  - Neurosci Lett
JT  - Neuroscience letters
JID - 7600130
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Prions)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H4N855PNZ1 (alpha-Tocopherol)
RN  - R0ZB2556P8 (Tocopherols)
SB  - IM
MH  - Animals
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Mice
MH  - Phosphorylation
MH  - Prions/*antagonists & inhibitors
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases
MH  - Tocopherols/*chemistry/*pharmacology
MH  - alpha-Tocopherol/chemistry/pharmacology
EDAT- 2009/12/01 06:00
MHDA- 2010/03/10 06:00
CRDT- 2009/12/01 06:00
PHST- 2009/08/11 00:00 [received]
PHST- 2009/11/06 00:00 [revised]
PHST- 2009/11/20 00:00 [accepted]
PHST- 2009/12/01 06:00 [entrez]
PHST- 2009/12/01 06:00 [pubmed]
PHST- 2010/03/10 06:00 [medline]
AID - S0304-3940(09)01548-1 [pii]
AID - 10.1016/j.neulet.2009.11.057 [doi]
PST - ppublish
SO  - Neurosci Lett. 2010 Jan 18;469(1):122-6. doi: 10.1016/j.neulet.2009.11.057. Epub 
      2009 Nov 27.