Acetylcholineestarase-inhibiting alkaloids from Lycoris radiata delay paralysis of amyloid beta-expressing transgenic C. elegans CL4176

PLoS One. 2013 May 13;8(5):e63874. doi: 10.1371/journal.pone.0063874. Print 2013.

Abstract

The limited symptom relief and side effects of current Alzheimer's disease (AD) medications warrant urgent discovery and study of new anti-AD agents. The "cholinergic hypothesis" of AD prompts us to search for plant-derived acetylcholineesterase (AChE) inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid β-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Aβ1-42 is induced, to study two natural benzylphenethylamine alkaloids isolated from Lycoris radiata (L' Her.) Herb, galanthamine and haemanthidine, and their synthetic derivatives 1,2-Di-O-acetyllycorine and 1-O-acetyllycorine for their anti-paralysis effects. Our data indicate that these Lycoris compounds effectively delay the paralysis of CL4176 worms upon temperature up-shift, and prolong the lives of these transgenic worms. Lycoris compounds were shown to significantly inhibit the gene expression of ace-1 and ace-2. Additionally, the Lycoris compounds may modulate inflammatory and stress-related gene expressions to combat the Aβ-toxicity in C. elegans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics
  • Amaryllidaceae Alkaloids / isolation & purification
  • Amaryllidaceae Alkaloids / pharmacology*
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / genetics
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Cholinesterase Inhibitors / isolation & purification
  • Cholinesterase Inhibitors / pharmacology*
  • Disease Models, Animal
  • Galantamine / analogs & derivatives
  • Galantamine / isolation & purification
  • Galantamine / pharmacology*
  • Gene Expression
  • Humans
  • Longevity / drug effects
  • Lycoris / chemistry*
  • Oxidative Stress / drug effects
  • Paralysis / prevention & control*
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics
  • Phenanthridines / isolation & purification
  • Phenanthridines / pharmacology*

Substances

  • Amaryllidaceae Alkaloids
  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • Phenanthridines
  • amyloid beta-protein (1-42)
  • Galantamine
  • hemanthidine
  • Acetylcholinesterase

Grants and funding

This work was partially funded by the National Natural Science Foundation of China (31161140345, 31070288, 20972166), and Ministry of Education of China through its 111 and 985 programs (B08044, MUC985-9, MUC98506-01000101). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.