Effect of the Biphenyl Neolignan Honokiol on Aβ₄₂-Induced Toxicity in Caenorhabditis elegans, Aβ₄₂ Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation

Abstract

The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Aβ) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Aβ as a convenient in vivo system for examining the effect of honokiol against Aβ-induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Aβ oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron(II). Honokiol displayed activity similar to that of resveratrol and (-)-epigallocatechin gallate (EGCG) in delaying Aβ-induced paralysis in C. elegans, and it exhibited moderate-to-weak ability to inhibit Aβ on-pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered.

Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity

“…Presumably, honokiol and tri-hydroxyflavones such as 2-D08 or myricetin might have different modes of interacting with αSA53T, nevertheless, they all result in similar degree of inhibition of amyloidogenic aggregation. Previously, honokiol was reported to be effective against toxicity related to Aβ and calcitonin aggregation (Guo et al, 2015 ; Das et al, 2016 ), and shown to be as effective as resveratrol and EGCG in an in vivo model of Aβ toxicity, inhibition of cholinesterase and metal chelation (Kantham et al, 2017 ). Together, honokiol has as pronounced an effect as the two tri-hydroxyflavones on inhibiting αSA53T aggregation and toxic amyloidogenic formation.…”

Rivastigmine and metabolite analogues with putative Alzheimer’s disease-modifying properties in a Caenorhabditis elegans model

“…We characterise the BBB permeabilities and chemical stabilities of the most promising compounds, showing that some compounds have high permeability and good stability. Finally, we report that these compounds protect against Aβ 42induced toxicity in both SH-SY5Y neuroblastoma cells in vitro and a transgenic Aβ 42 -expressing Caenorhabditis elegans strain 26 in vivo.…”

“…The control strain CL2122 exhibited no paralysis over the time course of the experiment, whereas C. elegans GMC101 expressing Aβ 42 showed a timedependent paralysis 26 . The paralysis of GMC101 nematodes in the presence of 3, 5, 10, 11 and EGCG 26 , was significantly delayed in comparison with that of untreated controls at 16, 20 and 24 h at 25°C. These results are in keeping with NAP analogues 3 and being among the most potent Aβ 42 fibrillation inhibitors identified in earlier in vitro studies, while 10 and 11 are rivastigmine analogues that produce 3 and 5, respectively, upon decarbamylation.…”

“…Strain CL2122 was used as a transgenic control and does not express Aβ 42,43 . Figure 6e shows the fraction of nematodes not paralysed after 16, 20 and 24 h at 25°C, for untreated strains GMC101 and CL2122, and GMC101 grown on media that was pre-treated with 100 µL of 2 mM compound (1-3, 5, 9, 10, 11, (S)-8 or EGCG) 26 . The control strain CL2122 exhibited no paralysis over the time course of the experiment, whereas C. elegans GMC101 expressing Aβ 42 showed a timedependent paralysis 26 .…”

“…Figure 6e shows the fraction of nematodes not paralysed after 16, 20 and 24 h at 25°C, for untreated strains GMC101 and CL2122, and GMC101 grown on media that was pre-treated with 100 µL of 2 mM compound (1-3, 5, 9, 10, 11, (S)-8 or EGCG) 26 . The control strain CL2122 exhibited no paralysis over the time course of the experiment, whereas C. elegans GMC101 expressing Aβ 42 showed a timedependent paralysis 26 . The paralysis of GMC101 nematodes in the presence of 3, 5, 10, 11 and EGCG 26 , was significantly delayed in comparison with that of untreated controls at 16, 20 and 24 h at 25°C.…”