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

Schroeter, Hagen; Boyd, Clinton S; Spencer, Jeremy P. E.; Williams, Robert J.; Cadenas, Enrique; Rice‐Evans, Catherine

doi:10.1016/s0197-4580(02)00075-1

Cited by 310 publications

(188 citation statements)

References 230 publications

(293 reference statements)

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“…102,106 The action of flavonoids on the ERK pathway 83,99,107−110 appears to be mediated by interactions with MAPK kinases MEK1 and MEK2 and potentially membrane receptors. 102,111,112 In fact, flavonoids have close structural homology to specific pharmacological modulators of ERK signaling such as PD98059 (2′-amino-3′-methoxyflavone). Moreover, activation of ERK can result in downstream activation of cAMP response element binding protein (CREB), which may lead to changes in synaptic plasticity and memory 113,114 and to upregulation of neuroprotective pathways.…”

Section: ■ Flavonoids and Their Interaction With Signaling Pathwaysmentioning

confidence: 99%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

167

111

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Alzheimer's disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer's therapy taking into account their antiamyloidogenic, antioxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signaling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation, preventing abnormal tau phosphorylation. The interaction of flavonoids with different signaling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer's disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer's disease patients. KEYWORDS: Flavonoids, Alzheimer's disease, amyloid precursor protein, amyloid beta, BACE-1, tau, signaling A lzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia worldwide. The major histopathological hallmarks of AD include proteinous aggregates in the form of neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau 1,2 and extracellular senile plaques, which are deposits of heterogeneously sized small peptides of amyloid-β (Aβ) that are formed via sequential proteolytic cleavages of the amyloid precursor protein (APP) 3 (Figure 1). Dominant mutations in APP, presenilin-1 (PS1) or PS2 are responsible for the early onset or familial form of AD. These mutations have been shown to profoundly alter APP metabolism, favoring the production of aggregation-prone Aβ species, these findings formed the basis for the "amyloid cascade hypothesis" of AD pathogenesis. This broadly accepted hypothesis states that the generation of neurotoxic Aβ peptides by β-secretase and γ-secretase are at the basis of AD pathophysiology. Other hallmarks of this disease, like neurotransmitter changes 4,5 and neuronal and synapse loss in the neocortex and the hippocampus 6,7 develop as a consequence of this event.■ AMYLOID PRECURSOR PROTEIN APP belongs to a protein f...

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Section: ■ Flavonoids and Their Interaction With Signaling Pathwaysmentioning

confidence: 99%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

167

111

View full text Add to dashboard Cite

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“…They may interact with specific proteins involved in intracellular signalling pathways (39) . They can selectively act on protein kinase and lipid kinase signalling cascades such as MAPK, protein kinase C, protein kinase B (PKB/AKT) (serine/threonine kinase), tyrosine kinases and phosphoinositide 3-kinase (PI3K) (for a review, see Williams et al (40) ).…”

Section: Cellular Bioactivities Of Polyphenolsmentioning

confidence: 99%

When nutrition interacts with osteoblast function: molecular mechanisms of polyphenols

2009

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Recent research has provided insights into dietary components that may optimise bone health and stimulate bone formation. Fruit and vegetable intake, as well as grains and other plant-derived food, have been linked to decreased risk of major chronic diseases including osteoporosis. This effect has been partially attributed to the polyphenols found in these foods. Thus, it has been suggested that these compounds may provide desirable bone health benefits through an action on bone cell metabolism. The present review will focus on how some polyphenols can modulate osteoblast function and reports which cellular signalling pathways are potentially implicated. However, to date, despite numerous investigations, few studies have provided clear evidence that phenolic compounds can act on osteoblasts. Polyphenols cited in the present review seem to be able to modulate the expression of transcription factors such as runt-related transcription factor-2 (Runx2) and Osterix, NF-κB and activator protein-1 (AP-1). It appears that polyphenols may act on cellular signalling such as mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP), oestrogen receptor and osteoprotegerin/receptor activator of NF-κB ligand (OPG/RANKL) and thus may affect osteoblast functions. However, it is also important to take in account the possible interaction of these compounds on osteoclast metabolism to better understand the positive correlation reported between the consumption of fruit and vegetables and bone mass.

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“…However, it has been speculated that their classical hydrogen donating antioxidant activity is not the explanation for the bioactivity of flavonoids in vivo. Indeed, it has become evident that flavonoids are more likely to exert their neuroprotective actions by (1) the modulation of intracellular signalling cascades which control neuronal survival, death and differentiation; (2) affecting gene expression and (3) interactions with mitochondria [148,159,185]. This review will highlight some of the interactions of flavonoids with major neuronal intracellular signalling pathways, in particular those that are vital in determining neuronal death, survival, differentiation and proliferation.…”

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confidence: 99%

The interactions of flavonoids within neuronal signalling pathways

2007

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Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects in the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by promoting neurocognitive performance, through changes in synaptic plasticity. It is likely that flavonoids exert such effects in neurons, through selective actions on different components within a number of protein kinase and lipid kinase signalling cascades, such as phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase. This review details the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to affect cellular function through changes in the activation state of target molecules and/or by modulating gene expression. Although, precise sites of action are presently unknown, their abilities to: (1) bind to ATP binding sites on enzymes and receptors; (2) modulate the activity of kinases directly; (3) affect the function of important phosphatases; (4) preserve neuronal Ca 2+ homeostasis; and (5) modulate signalling cascades lying downstream of kinases, are explored. Future research directions are outlined in relation to their precise site(s) of action within the signalling pathways and the sequence of events that allow them to regulate neuronal function in the central nervous system.

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

Cited by 310 publications

References 230 publications

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

When nutrition interacts with osteoblast function: molecular mechanisms of polyphenols

The interactions of flavonoids within neuronal signalling pathways

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