TY - JOUR
T1 - β-Dicarbonyl enolates
T2 - A new class of neuroprotectants
AU - Lopachin, Richard M.
AU - Gavin, Terrence
AU - Geohagen, Brian C.
AU - Zhang, Lihai
AU - Casper, Diana
AU - Lekhraj, Rukmani
AU - Barber, David S.
PY - 2011/1
Y1 - 2011/1
N2 - 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.
AB - 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.
KW - acrolein
KW - curcumin
KW - neurodegenerative diseases
KW - neuroprotection
KW - oxidative stress
KW - phytopolyphenols
UR - http://www.scopus.com/inward/record.url?scp=78650110527&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650110527&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2010.07091.x
DO - 10.1111/j.1471-4159.2010.07091.x
M3 - Article
C2 - 21054388
AN - SCOPUS:78650110527
SN - 0022-3042
VL - 116
SP - 132
EP - 143
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 1
ER -