Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology.
Inositol is a simple polyol with eight naturally occurring stereoisomers. myo-Inositol, D-chiro- and epi-inositol have been examined as potential therapeutic agents for various diseases, with favorable results, but treatment with scyllo-inositol has not been previously investigated. Our laboratory has shown that scyllo-inositol inhibits cognitive deficits in TgCRND8 mice and significantly ameliorates disease pathology, suggesting it might be effective in treating Alzheimer's disease (AD). In this paper, we show that scyllo-inositol has a sustained ability to treat animals at advanced stages of AD-like pathology. Significant decreases in insoluble Abeta40, Abeta42, and plaque accumulation were observed in the brains of treated versus untreated TgCRND8 mice. The growth of plaques of all sizes was inhibited by scyllo-inositol administration. To demonstrate that the scyllo-inositol effects were within the CNS, gas chromatography/mass spectrometry was used to examine myo- and scyllo-inositol concentrations after oral administration. Further, we examined how closely scyllo- and myo-inositol are inter-regulated in the CNS and whether scyllo-inositol, if elevated within the CNS, would incorporate into phosphatidylinositol lipids. Cerebral spinal fluid levels of scyllo-inositol increased after scyllo-inositol treatment but not myo-inositol treatment. scyllo-Inositol treatment also caused increased levels of scyllo-inositol in the brain. We further show that scyllo-inositol, even at elevated levels, does not incorporate into the phosphatidylinositol family of lipids. These combined results demonstrate that scyllo-inositol accumulates within the CNS up to tenfold endogenous levels and does not interfere with phosphatidylinositol lipid production.
Fenili
Daniela
D
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, M5S 3H2, Canada.
Brown
Mary
M
Rappaport
Rebecca
R
McLaurin
JoAnne
J
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007294:Inositol / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000187:drug effects
D016229:Amyloid beta-Peptides; C009217:scyllitol; D007294:Inositol