β-Dicarbonyl enolates: A new class of neuroprotectants

Richard M. Lopachin, Terrence Gavin, Brian C. Geohagen, Lihai Zhang, Diana Casper, Rukmani Lekhraj, David S. Barber

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Curcumin, phloretin and structurally related phytopolyphenols have well-described neuroprotective properties that appear to be at least partially mediated by 1,3-dicarbonyl enol substructures that form nucleophilic enolates. Based on their structural similarities, we tested the hypothesis that enolates of simple 1,3-dicarbonyl compounds such as acetylacetone might also possess neuroprotective actions. Our results show that the β-diketones, particularly 2-acetylcyclopentanone, protected rat striatal synaptosomes and a neuronal cell line from thiol loss and toxicity induced by acrolein, an electrophilic α,β-unsaturated aldehyde. The 1,3-dicarbonyl compounds also provided substantial cytoprotection against toxicity induced by hydrogen peroxide in a cellular model of oxidative stress. Initial chemical characterization in cell-free systems indicated that the 1,3-dicarbonyl compounds acted as surrogate nucleophilic targets that slowed the rate of sulfhydryl loss caused by acrolein. Although the selected 1,3-dicarbonyl congeners did not scavenge free radicals, metal ion chelation was a significant property of both acetylacetone and 2-acetylcyclopentanone. Our data suggest that the 1,3-dicarbonyl enols represent a new class of neuroprotectants that scavenge electrophilic metal ions and unsaturated aldehydes through their nucleophilic enolate forms. As such, these enols might be rational candidates for treatment of acute or chronic neurodegenerative conditions that have oxidative stress as a common molecular etiology.

Original languageEnglish (US)
Pages (from-to)132-143
Number of pages12
JournalJournal of Neurochemistry
Volume116
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • acrolein
  • curcumin
  • neurodegenerative diseases
  • neuroprotection
  • oxidative stress
  • phytopolyphenols

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Lopachin, R. M., Gavin, T., Geohagen, B. C., Zhang, L., Casper, D., Lekhraj, R., & Barber, D. S. (2011). β-Dicarbonyl enolates: A new class of neuroprotectants. Journal of Neurochemistry, 116(1), 132-143. https://doi.org/10.1111/j.1471-4159.2010.07091.x