Quercetin supplementation: insight into the potentially harmful outcomes of neurodegenerative prevention.
Dietary antioxidant supplements have been considered for the prevention of neuronal oxidative injury and death. Recent studies indicate that excessive antioxidants could exert adverse effects, thereby questioning the safety of prolonged supplementation. The aim of our study was to investigate the effects of quercetin (up to 150 μM), the ubiquitous plant-derived flavonoid and highly potent scavenger of reactive oxygen species (ROS) on healthy P19 neurons, in order to assess the efficacy and safety of its long-term use in neurodegenerative prevention. Although exposure for 24 h to quercetin did not compromise neuronal survival, morphological examination revealed diminished neuronal branching, a finding probably related to an observed decrease in lactate dehydrogenase activity. Using 2',7'-dichlorofluorescin diacetate and dot-blot analysis, we found reduced basal levels of ROS and 4-hydroxy-2-nonenal, a biomarker of lipid peroxidation, confirming the antioxidative mechanism of quercetin action. Unexpectedly, quercetin also depleted intracellular glutathione content. Reverse transcriptase PCR and western blot analysis showed depletion of total RNA amount and changes in the expression of cell survival regulating genes Bcl-2, p53, and c-fos. Nuclear condensation and caspase-3/7 activity, phenomena related to programmed cell death cascade, were not affected. The potential risk of observed changes indicates that quercetin-enriched supplements should be taken with caution. The diversity of quercetin effects and complexity of possible intracellular interactions between affected genes pointed out the necessity for additional pharmacological and toxicological studies in order to better elucidate the mechanisms of quercetin action and to recognize its potential side effects at higher doses and during long-term administration.
Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10 000, Zagreb, Croatia. jazvin@irb.hr
Maja
M
Jazvinšćak Jembrek
Ana
A
Čipak Gašparović
Lidija
L
Vuković
Josipa
J
Vlainić
Neven
N
Žarković
Nada
N
Oršolić
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D012313:RNA / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012313:RNA; D011794:Quercetin; D007770:L-Lactate Dehydrogenase; D005978:Glutathione