Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms

Ishige, Kumiko; Schubert, David; Sagara, Yutaka

doi:10.1016/s0891-5849(00)00498-6

Cited by 751 publications

(518 citation statements)

References 62 publications

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“…32 Using more selective inhibitors, we recently suggested a participation of 12-LOX in apoptosis triggered by Ab in cortical neurons. 33 However, inhibitors can only provide circumstantial evidence about the role of LOXs in Ab-induced toxicity, since most of these compounds also possess other characteristics such as proor antioxidant properties, 25,26,[34][35][36] which might lead to LOX-independent effects. In order to assess the protective potential of 12-LOX blockade towards Ab-induced apoptosis, we used here an antisense oligonucleotide-based strategy.…”

Section: Resultsmentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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“…Fisetin was originally identified in a screen for compounds that could prevent oxidative stress-induced nerve cell death [36]. Of the *30 flavonoids tested in this study, only two, fisetin and quercetin, were able to maintain GSH levels in the presence of oxidative stress, indicating that this is not a common property of flavonoids.…”

Section: Introductionmentioning

confidence: 84%

“…Although it is not entirely clear how relevant the antioxidant activity of flavonoids as measured in test tube assays is to their effects in vivo, fisetin is a relatively good antioxidant with a Trolox equivalent antioxidant capacity (TEAC) value of *3 [36,54]. Furthermore, fisetin was also shown to be very good at inhibiting lipid peroxidation and chelating iron [90].…”

Section: Antioxidant Activitymentioning

confidence: 99%

Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin

Maher

2009

Genes Nutr

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Multiple factors have been implicated in the age-related declines in brain function. Thus, it is unlikely that modulating only a single factor will be effective at slowing this decline. A better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Over the last few years, we have identified an orally active, novel neuroprotective and cognition-enhancing molecule, the flavonoid fisetin. Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also maintain mitochondrial function in the presence of oxidative stress. In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of 5-lipoxygenase, thereby reducing the production of lipid peroxides and their pro-inflammatory by-products. This wide range of actions suggests that fisetin has the ability to reduce the age-related decline in brain function.

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“…However, the actions of flavonoids are complex and often seemingly antagonistic or paradoxical. For example, while flavonoids are described as antioxidant agents protecting against oxidative insults to cells and apoptosis [11,13,88], others have found flavonoids to be pro-oxidants and -apoptotic [33,212,221]. Thus, it becomes clear that the effects of flavonoids depend on different factors such as the specific compound used, the cell type, concentrations, experimental design, and the general context in which flavonoids are used.…”

Section: Biological and Cellular Propertiesmentioning

confidence: 99%

“…For example, one of the most intensively investigated flavonoids, quercetin, is often just used as the aglycone in cell culture systems and interesting biological activities such as modulation of the multidrug-resistance protein [118], induction of apoptosis [168], inhibition of the expression of nitric oxide synthase and cyclooxygenase [162], protection against oxidative stress [88] and modulation of the calcium homeostasis [209] have been reported. However, in plants and, therefore, also in all plant-derived foods and beverages, quercetin is always present in a glycosylated form which completely alters its bioactivity.…”

Section: Flavonoids: Neuroprotective Agents In Vivo and In Vitro?mentioning

confidence: 99%

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

Schroeter

Boyd

Spencer

et al. 2002

Neurobiology of Aging

308

178

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Oxidative and nitrosative stress is increasingly associated with the pathology of neurodegeneration and aging. The molecular mechanisms underlying oxidative/nitrosative stress-induced neuronal damage are emerging and appear to involve a mode of death in which mitogen-activated protein kinase (MAPK) signaling pathways are strongly implicated. Thus, attention is turning towards the modulation of intracellular signaling as a therapeutic approach against neurodegeneration. Both endogenous and dietary agents have been suggested as potent modulators of intracellular signal transduction, e.g. nitric oxide and flavonoids, respectively. This review addresses recent findings on the biological effects of flavonoids and nitric oxide in neurodegeneration and aims to elucidate the rationale for their prospective use as modulators of cellular signal transduction. © 2002 Elsevier Science Inc. All rights reserved.Keywords: Apoptosis; Oxidative stress; Neuron; Flavonoids; MAP kinase; JNK; ERK; Epicatechin; Nitric oxide; Mitochondria; Redox status; Polyphenols Abbreviations: AKT, serine/threonine kinase (also known as protein kinase B); AP-1, activator protein-1; Apaf-1, apoptosis protease activating factor-1; ASK1, apoptosis signal-regulating kinase-1; Bad, Bcl-2/BclX Lassociated death promoting protein; Bax, pro-apoptotic protein of the Bcl-2 family; Bcl-2, B-cell lymphoma 2: protein with anti-apoptotic properties; BclX L , long form of Bclx: anti-apoptotic protein of the Bcl-2 family; Caspase, cysteinyl aspartic acid-protease; c-Jun, mammalian equivalent of Jun: part of the AP-1 transcription complex; CREB, cAMP response element binding protein; DIABLO/smac, mitochondria-related pro-apoptotic protein: inhibits XIAP; ERK1/2, extracellular signal-related kinase; Fas, CD95: member of the TNF receptor family; GSHST, glutathione Stransferase; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEK1/2, ERK1/2-specific MAPKK; MKK4/7, JNK-specific MAPKK; MSK1, mitogen-and stress-activated kinase-1; NF-B, nuclear factor of immunoglobulin k locus in B-cells; ONOO − , peroxynitrite anion; p53, pro-apoptotic tumor suppressor gene product; PI3-kinase, phosphoinositol 3-kinase; Ras, small G-protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSK, pp90 ribosomal S6 kinase; SAPK, stressactivated protein kinase; XIAP, X-linked inhibitor of apoptosis: inhibits the activation of caspase-9

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Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms

Cited by 751 publications

References 62 publications

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

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