PMID:20554019

Citation	Arredondo, F, Echeverry, C, Abin-Carriquiry, JA, Blasina, F, Antúnez, K, Jones, DP, Go, YM, Liang, YL and Dajas, F (2010) After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult. Free Radic. Biol. Med. 49:738-47
Abstract	In this work we describe the protective effects of quercetin against H(2)O(2) in 24-h-pretreated neuronal cultures. We explored quercetin availability and subcellular fate through the use of HPLC-Diode Array Detection (DAD), epifluorescence, and confocal microscopy. We focused on quercetin modulation of thiol-redox systems by evaluating changes in mitochondrial thioredoxin Trx2, the levels of total glutathione (GSH), and the expression of the gamma-glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme of GSH synthesis, by the use of Western blot, HPLC, and real-time PCR techniques, respectively. We further explored the activation of the protective NF-E2-related factor 2 (Nrf2)-dependent signaling pathway by quercetin using immunocytochemistry techniques. Our results showed rapid quercetin internalization into neurons, reaching the nucleus after its addition to the culture. Quercetin pretreatment increased total GSH levels, but did not increase Trx2. Interestingly it caused Nrf2 nuclear translocation and significantly increased GCLC gene expression. At the moment of H(2)O(2) addition, intracellular quercetin or related metabolites were undetectable in the cultures although quercetin pretreatment prevented neuronal death from the oxidant exposure. Our findings suggest alternative mechanisms of quercetin neuroprotection beyond its long-established ROS scavenging properties, involving Nrf2-dependent modulation of the GSH redox system.
Links	PubMed Online version:10.1016/j.freeradbiomed.2010.05.020
Keywords	Active Transport, Cell Nucleus/drug effects; Animals; Antioxidants/pharmacokinetics; Antioxidants/pharmacology; Cell Death/drug effects; Cell Nucleus/drug effects; Cell Nucleus/metabolism; Cytoprotection/drug effects; Drug Evaluation, Preclinical; Glutathione/metabolism; Hydrogen Peroxide/toxicity; NF-E2-Related Factor 2/metabolism; Neurons/drug effects; Neurons/metabolism; Neuroprotective Agents/pharmacokinetics; Neuroprotective Agents/pharmacology; Oxidative Stress/drug effects; Oxidative Stress/physiology; Protein Transport/drug effects; Quercetin/pharmacokinetics; Quercetin/pharmacology; Rats; Rats, Sprague-Dawley; Up-Regulation/drug effects
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:NF2L2	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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