Ameliorating effect of luteolin on memory impairment in an Alzheimer's disease model

Wang, Huimin; Wang, Huiling; Cheng, Huixin; Che, Zhenyong

doi:10.3892/mmr.2016.5052

Cited by 128 publications

(78 citation statements)

References 44 publications

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“…The onset and progression of AD is multifactorial. Underlying mechanisms that may lead to cognitive impairment involve cellular injury from β-amyloid (Aβ), tau, excitotoxicity, mitochondrial damage, acetylcholine loss, astrocytic cell injury, oxidative stress, and cellular metabolic dysfunction [ 10 – 20 ]. In light of the multiple pathways that may be responsible for the onset of AD, developing therapies are designed to focus on a variety of targets that include DNA methylation, deployment of monoclonal antibodies against Aβ, prevention of Aβ and tau aggregation, increased cytokine and growth factor signal transduction, mammalian target of rapamycin (mTOR) modulation, and the application of metal chelators [ 14 , 15 , 17 , 18 , 21 – 27 ].…”

Section: Assessing the Role Of Foxo Transcription Factors For Alzheimmentioning

confidence: 99%

Forkhead transcription factors: new considerations for alzheimer’s disease and dementia

Maiese¹

2016

J Transl Sci

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Life expectancy of individuals in both developed and undeveloped nations continues to rise at an unprecedented rate. Coupled to this increase in longevity for individuals is the rise in the incidence of chronic neurodegenerative disorders that includes Alzheimer’s disease (AD). Currently, almost ten percent of the population over the age of 65 suffers from AD, a disorder that is presently without definitive therapy to prevent the onset or progression of cognitive loss. Yet, it is estimated that AD will continue to significantly increase throughout the world to impact millions of individuals and foster the escalation of healthcare costs. One potential target for the development of novel strategies against AD and other cognitive disorders involves the mammalian forkhead transcription factors of the O class (FoxOs). FoxOs are present in “cognitive centers” of the brain to include the hippocampus, the amygdala, and the nucleus accumbens and may be required for memory formation and consolidation. FoxOs play a critical role in determining survival of multiple cell types in the nervous system, drive pathways of apoptosis and autophagy, and control stem cell proliferation and differentiation. FoxOs also interface with multiple cellular pathways that include growth factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that ultimately may control FoxOs and determine the fate and function of cells in the nervous system that control memory and cognition. Future work that can further elucidate the complex relationship FoxOs hold over cell fate and cognitive function could yield exciting prospects for the treatment of a number of neurodegenerative disorders including AD.

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Section: Assessing the Role Of Foxo Transcription Factors For Alzheimmentioning

confidence: 99%

Forkhead transcription factors: new considerations for alzheimer’s disease and dementia

Maiese¹

2016

J Transl Sci

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“…In addition, it has shown robust anti-inflammatory effects by reducing the production of LPS-induced pro-inflammatory cytokines in intestinal epithelial cells, mouse bone marrow-derived dendritic cells [ 21 ], rat fibroblasts [ 22 ], and human gingival fibroblasts [ 23 ]. Moreover, it has been demonstrated that luteolin exerted anti-amnesic effects against Aβ-induced toxicity [ 24 , 25 , 26 ]. In our previous studies, we demonstrated that the improvement in cognition and neuroprotective effects of luteolin included regulating microvascular function and protecting to BBB ultrastructure [ 24 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways

et al. 2017

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Amyloid-β peptides (Aβ) exist in several forms and are known as key modulators of Alzheimer’s disease (AD). Fibrillary Aβ (fAβ) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAβ1–40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAβ1–40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAβ1–40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAβ1–40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAβ1–40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAβ1–40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAβ1–40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAβ1–40-induced injury.

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“…In addition to this direct anti-oxidant properties, luteolin was also reported to inhibit LPS-induced activation of NF-κB and MAPK pathways, but its mode of action was not understood 27 . Luteolin is blood-brain barrier permeable and was reported to have a neuroprotective effect in drug-induced Alzheimer’s rat model 38 . These properties would be therefore in line with a role for PKR in impairment of cognition through inflammation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT

Dabo

Maillard

Rodríguez

et al. 2017

Sci Rep

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PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome.

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Ameliorating effect of luteolin on memory impairment in an Alzheimer's disease model

Cited by 128 publications

References 44 publications

Forkhead transcription factors: new considerations for alzheimer’s disease and dementia

Forkhead transcription factors: new considerations for alzheimer’s disease and dementia

Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways

Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT

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