Properties of scyllo–inositol as a therapeutic treatment of AD-like pathology

Abstract

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.

scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

“…The mechanism of polyQ-Htt modulation may vary between compounds and be independent of direct interaction of the compound with mutant Htt. The decrease in polyQ-Htt aggregation after SI treatment is consistent with previous studies on A␤ peptide aggregation that demonstrated a decrease in A␤ oligomer and fibril formation in vitro (19,54), stabilization of preformed oligomers in vitro (54), and decreased oligomers and prevention of amyloid plaques in vivo (55)(56)(57). The lack of toxicity detected in this study is also in agreement with the SI-induced decrease in ␣-synuclein toxicity in an inducible neuronal cell model (21) and in amyloid-␤ peptide toxicity in the 7PA2 cell line (54).…”

A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease

“…5,7 Scyllo-inositol also appears to neutralize toxic effects of A␤ oligomers, 6 including amelioration of oligomerinduced synaptic loss, LTP inhibition, and memory deficits. 8,9 A prior amyloid antiaggregation agent failed to demonstrate efficacy in phase 3 trials, 10 but several other amyloid-targeted therapies are currently being studied.…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[36] scyllo-Inositol is not incorporated into phospholipids in mammals. [37] The analogue 1-deoxy-1-fluoro-scyllo-inositol (96 Figure 3) inhibits the incorporation of myo-inositol into phosphatidylinositols. [38] scyllo-Inositol inhibits the incorporation of myo-inositol into lipid-soluble phosphoinositides and water-soluble inositol phosphates in the developing rat conceptus (causing dysmorphogenesis) and also impairs phosphoinositide hydrolysis.…”

“…[78] Intracellular scyllo-inositol levels in rat brain extracts have been analysed by micellar electrokinetic chromatography. [79] 4.6 scyllo-Inositol Phosphates scyllo-Inositol is not incorporated into phospholipids in mammals [37] but scyllo-inositolcontaining phosphatidylinositol has been detected in non-mammalian species -see the Supporting Information (SI_2) for details.…”