Program

OR4-2

A novel flavonoid-based inhibitor of protein SUMOylation, 2-D08 has a dual anti-aggregatory and protective role against amyloid β fibril formation and neurotoxicity

[Speaker] Dylan T Marsh:1
[Co-author] Masaya Fujitani:2, Ryuji Kato:2, Scott D Smid:1
1:Department of Pharmacology, The University of Adelaide, Australia, 2:Department of Basic Medical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Japan

Background: Flavonoids form a diverse class of naturally occurring polyphenols ascribed various biological activities, including inhibition of amyloid β (Aβ) fibrillisation and neurotoxicity. In this study we evaluated the neuroprotective and anti-aggregative properties of the flavones transilitin, quercetin and the novel semi-synthetic flavone and SUMOylation inhibitor, 2-D08 using neuronal PC-12 cells exposed to Aβ1-42 and in mouse cortical neural stem cells (mNSC).
Methods: Flavone effects on neuronal viability were assessed morphologically using live cell imaging and morphometric analysis in mNSC, and biochemically in PC-12 cells using the MTT assay following incubation with Aβ (0-2 microM), alone or in the presence of each flavone (10-100 microM) for 48 hr. Effects of each flavone on Aβ fibril formation and aggregation were directly assessed using the Thioflavin T (ThT) fluorometric assay and transmission electron microscopy (TEM) over 48 hr.
Results: 2-D08 and transilitin (10-100 microM) evoked concentration-dependent inhibition of neurotoxicity elicited by Aβ (0-2 microM). Quercetin was neuroprotective at the low concentration (10 microM), but evoked intrinsic neurotoxicity at higher concentrations (50-100 microM). Morphometric imaging analysis demonstrated that 2-D08 and transilitin were both non-toxic to mNSCs and confirmed that quercetin was neurotoxic at the higher concentrations. The neuroprotective effects were associated with a marked inhibition of Aβ fibrillisation, as evidenced by attenuated ThT fluorescence kinetics and microscopic evidence of both altered and diminished Aβ aggregate and fibril morphology.
Conclusions: These findings highlight the neuroprotective role of select flavones on Aβ-mediated toxicity associated with an inhibition of Aβ fibrillisation. In particular, the efficacy of the novel flavone 2-D08 in this regard may direct further lead development with multiple biological actions targeting neurodegeneration in Alzheimer's disease.

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