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The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer´s disease model mice

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... Maria et al. reported that QC improves cognitive and behavioral skills in the aged triple transgenic AD mice model. QC decreases intracellular NFTs and extracellular deposition of Aβ peptides in the hippocampus and the amygdala in these mice [222]. One of the underlying mechanisms mediated by QC is the interaction of QC and acetylcholinesterase (AChE). ...
... At the same time, the released QC from QCIONP inhibits inflammation, apoptosis [248], protein aggregation [222,227], and regulates antioxidant pathways to restore oxidative balance [181,240]. Besides, QC via iron chelation and radical scavenging prevents iron overload raised from the metabolism of its carrier, Fenton reaction, and inhibits neuronal death (Fig. 7). ...
... Under this condition, low levels of GSH contribute to the arylation of other thiol proteins by QQ and cell damage [293,297]. However, various studies indicated optimal concentrations of QC increase GSH levels [222,224,238]. Besides, in vitro studies reported shortterm treatment with QC exerts antioxidant effects via a decrease in H 2 O 2 , whereas extending treatment duration represents prooxidant activity of QC via an increase in O 2 − , which was accompanied by a decrease in GSH levels [294,295]. ...
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Iron oxide nanoparticles (IONPs) have been proposed as targeted carriers to deliver therapeutic molecules in the central nervous system (CNS). However, IONPs may damage neural tissue via free iron accumulation, protein aggregation, and oxidative stress. Neuroprotective effects of quercetin (QC) have been proven due to its antioxidant and anti-inflammatory properties. However, poor solubility and low bioavailability of QC have also led researchers to make various QC-involved nanoparticles to overcome these limitations. We wondered how high doses or prolonged treatment with quercetin conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) could improve cognitive dysfunction and promote neurogenesis without any toxicity. It can be explained that the QC inhibits protein aggregation and acts against iron overload via iron-chelating activity, iron homeostasis genes regulation, radical scavenging, and attenuation of Fenton/Haber–Weiss reaction. In this review, first, we present brain iron homeostasis, molecular mechanisms of iron overload that induced neurotoxicity, and the role of iron in dementia-associated diseases. Then by providing evidence of IONPs neurotoxicity, we discuss how QC neutralizes IONPs neurotoxicity, and finally, we make a brief comparison between QC and conventional iron chelators. In this review, we highlight that QC as supplementation and especially in conjugated form reduces iron oxide nanoparticles neurotoxicity in clinical application.
... En esta investigación se evaluó el aprendizaje, la memoria espacial y conductas a través del laberinto en cruz elevado, en donde se obtuvo que la quercetina indujo un mejor rendimiento en tareas de aprendizaje y memoria espacial y un mayor comportamiento de evaluación de riesgo basado en la prueba del laberinto en cruz y en la prueba del laberinto de agua de Morris; para entender más globalmente el ¿por qué de estas respuestas? se evaluaron algunos tejidos de distintas del cerebro a través de pruebas como el ELISA, Western Blot y la IHC (Sabogal-Guáqueta et al, 2015). Empero, con la utilización de IHC se evaluaron las regiones que incluyen el CA1 y el subículo (hipocampo), la corteza entorrinal (EC) y la amígdala, en donde se observó una pérdida de densidad celular en el subículo en los ratones 3xTg-AD tratados con vehículo, y el tratamiento con quercetina aumentó la densidad celular en el subículo a un nivel similar al de los ratones no transgénicos tratados con vehículo o quercetina (Sabogal-Guáqueta et al, 2015). ...
... se evaluaron algunos tejidos de distintas del cerebro a través de pruebas como el ELISA, Western Blot y la IHC (Sabogal-Guáqueta et al, 2015). Empero, con la utilización de IHC se evaluaron las regiones que incluyen el CA1 y el subículo (hipocampo), la corteza entorrinal (EC) y la amígdala, en donde se observó una pérdida de densidad celular en el subículo en los ratones 3xTg-AD tratados con vehículo, y el tratamiento con quercetina aumentó la densidad celular en el subículo a un nivel similar al de los ratones no transgénicos tratados con vehículo o quercetina (Sabogal-Guáqueta et al, 2015). Como conclusión, sugirieron que, según estos hallazgos la quercetina revierte las características histológicas del Alzheimer y protege la función cognitiva y emocional en ratones 3xTg-AD de edad avanzada. ...
... Como conclusión, sugirieron que, según estos hallazgos la quercetina revierte las características histológicas del Alzheimer y protege la función cognitiva y emocional en ratones 3xTg-AD de edad avanzada. (Sabogal-Guáqueta et al, 2015) En el contexto colombiano existen varios laboratorios que emplean la técnica de inmunohistoquímica dentro de sus investigaciones comportamentales, algunos de estas están liderados por el PhD Javier Rico, la PhD Marisol Lamprea, el PhD Efraín, la PhD Elena García, el PhD Fernando Cárdenas, la PhD Patricia Cardona, la PhD Liliana Francis, entre otros. ...
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This dissertation aims to offer a reflection on the possible use of Immunohistochemistry and Immunofluorescence techniques in behavioral research. For this purpose, a brief context of the current user that is being given to both techniques in psychology, both alone and in interdisciplinary research, will be shown. In addition, you will find an agenda that will present brief answers on what is immunohistochemistry? what is immunofluorescence? What types of immunohistochemical and immunofluorescence techniques are used? what are antibodies? What kind of antibodies exists? etc., which will serve as a starting point to understanding these immunostaining techniques. In addition to the above, certain disadvantages and sales that each technique has when used by the researcher to obtain information on their tissues of interest are also discussed. Moreover, a protocol for performing immunohistochemistry and another for taking pictures of the tissues and quantifying them in ImageJ is presented. Finally, culminates with the aforementioned reflection on the use of immunohistochemistry in scientific research in psychology.
... With this in mind, GSK-3β inhibitors could represent a promising treatment strategy for AD. gliosis in the hippocampus and amygdala of 3xTg-AD mice, decreasing the number of paired helical filaments (PHF), Aβ levels, and BACE1-mediated cleavage of APP [171,172]. In quercetin-treated 3xTg-AD mice, reactive microglia and Aβ aggregates were reduced [173], and the oral administration of quercetin increased brain apolipoprotein E (ApoE) and decreased Aβ levels in the cerebral cortex of 5xFAD mice model [174]. ...
... In accordance, senile plaques were reduced by quercetin in the cerebral cortex and hippocampus of APP/PS1 mice [170]. Other in vivo studies revealed that quercetin decreased extracellular β-amyloidosis, tauopathy, astrogliosis, and microgliosis in the hippocampus and amygdala of 3xTg-AD mice, decreasing the number of paired helical filaments (PHF), Aβ levels, and BACE1-mediated cleavage of APP [171,172]. In quercetin-treated 3xTg-AD mice, reactive microglia and Aβ aggregates were reduced [173], and the oral administration of quercetin increased brain apolipoprotein E (ApoE) and decreased Aβ levels in the cerebral cortex of 5xFAD mice model [174]. ...
... Another study also showed that a quercetin-enriched diet during the early-middle pathology stages ameliorated cognitive dysfunction in APP/PS1 mice [175]. In addition, beneficial effects of quercetin in learning, memory deficits, and cognitive function were demonstrated in APP/PS1, APP23, and 3xTg-AD transgenic mice models of AD [170][171][172]219]. Furthermore, quercetin administration in Aβ-induced amnesic mice enhanced learning and memory performance [206,209,270]. ...
Article
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting elderly people worldwide. Currently, there are no effective treatments for AD able to prevent disease progression, highlighting the urgency of finding new therapeutic strategies to stop or delay this pathology. Several plants exhibit potential as source of safe and multi-target new therapeutic molecules for AD treatment. Meanwhile, Eucalyptus globulus extracts revealed important pharmacological activities, namely antioxidant and anti-inflammatory properties, which can contribute to the reported neuroprotective effects. This review summarizes the chemical composition of essential oil (EO) and phenolic extracts obtained from Eucalyptus globulus leaves, disclosing major compounds and their effects on AD-relevant pathological features, including deposition of amyloid-β (Aβ) in senile plaques and hyperphosphorylated tau in neurofibrillary tangles (NFTs), abnormalities in GABAergic, cholinergic and glutamatergic neurotransmission, inflammation, and oxidative stress. In general, 1,8-cineole is the major compound identified in EO, and ellagic acid, quercetin, and rutin were described as main compounds in phenolic extracts from Eucalyptus globulus leaves. EO and phenolic extracts, and especially their major compounds, were found to prevent several pathological cellular processes and to improve cognitive function in AD animal models. Therefore, Eucalyptus globulus leaves are a relevant source of biological active and safe molecules that could be used as raw material for nutraceuticals and plant-based medicinal products useful for AD prevention and treatment.
... Moreover, MMP-13 hydrolyses many other proteins including type I, type II, type III, type IV, type XIV, and type X collagen (12). The up-regulation of MMP-13 has been demonstrated in several disorders such as tooth decay, periodontitis, Alzheimer's disease, and cancer progression (1)(2)(3)(4)(13)(14)(15)(16). Therefore, the inhibition of MMP-13 may result in the prevention of mentioned disorders. ...
... The physical and chemical features of the compounds were studied based on the RO5 as described by Lipinski et al (20). According to RO5, an appropriate compound must illustrate a molecular mass of ≤500 g/mol, logarithm of the partition coefficient between n-octanol and water (LogP) ≤ 5, a hydrogen bond acceptor count ≤10, and a hydrogen bond donor count ≤ 5 (12)(13)(14)(15)(24)(25)(26). According to the results, all four compounds were in agreement with the RO5 and considered to be drug-like molecules for oral use. ...
Article
Background: Foeniculum vulgare (Fennel) has a wide range of applications. Previous studies revealed the presence of different compounds in the essential oil (EO) of fennel fruit (FF). Matrix metalloproteinase-13 (MMP-13) participates in several human biological processes including the degradation of extracellular matrix proteins, activation or degradation of some significant regulatory proteins, and tumor cell invasion. Furthermore, the up-regulation of MMP-13 is associated with many disorders such as tooth caries and periodontitis, as well as the degradation of enamel and tissues around the implant and Alzheimer’s disease. Therefore, the aims of the present study were to investigate the compounds of the EO of FF (EOFF) from the Hamedan district, along with performing molecular docking analysis to assess the binding affinity of four compounds originated from F. vulgare with the MMP-13. Finally, the study focused on evaluating the pharmacokinetic and toxicity characteristics of the compounds. Methods: Hydrodistillation method was used for obtaining the EO from FF. Then, gas chromatography-mass spectrometry was applied to identify the components of the EO. Molecular docking analysis was carried out using AutoDock software. Eventually, the pharmacokinetic and toxicity features of compounds were evaluated using bioinformatics webservers. Results: The results revealed the presence of fourteen compounds, among which e-anethole (86.86%), fenchone (743%), estragole (165%), and thymol (1.21%) were the main components. Based on the results, thymol, fenchone, e-anethole, and estragole could potentially bind to the MMP-13 active site, respectively. Conclusion: Regardless of several studies on the chemical constituents of EOFF, the subject has its own pharmacognostical importance. According to computational studies, EOFF has the potential for study on several human disorders such as cancer, tooth decay, and Alzheimer’s disease.
... Moreover, quercetin deceases ROS which is a major contributor to AD (Zaplatic et al., 2019). It also decreases extracellular Aβ, AChE level, tau toxicity, and microgliosis (Sabogal-Guaqueta et al., 2015). Additionally, quercetin improved learning and memory function in aged 3xTg-AD mice determined through the elevated plus-maze test (Orhan et al., 2007;Sabogal-Guaqueta et al., 2015). ...
... It also decreases extracellular Aβ, AChE level, tau toxicity, and microgliosis (Sabogal-Guaqueta et al., 2015). Additionally, quercetin improved learning and memory function in aged 3xTg-AD mice determined through the elevated plus-maze test (Orhan et al., 2007;Sabogal-Guaqueta et al., 2015). ...
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Alzheimer’s disease (AD) is characterized by the excessive deposition of extracellular amyloid-beta peptide (Aβ) and the build-up of intracellular neurofibrillary tangles containing hyperphosphorylated tau proteins. This leads to neuronal damage, cell death and consequently results in memory and learning impairments leading to dementia. Although the exact cause of AD is not yet clear, numerous studies indicate that oxidative stress, inflammation, and mitochondrial dysfunction significantly contribute to its onset and progression. There is no effective therapeutic approach to stop the progression of AD and its associated symptoms. Thus, early intervention, preferably, pre-clinically when the brain is not significantly affected, is a better option for effective treatment. Natural polyphenols (PP) target multiple AD-related pathways such as protecting the brain from Aβ and tau neurotoxicity, ameliorating oxidative damage and mitochondrial dysfunction. Among natural products, the cereal crop sorghum has some unique features. It is one of the major global grain crops but in the developed world, it is primarily used as feed for farm animals. A broad range of PP, including phenolic acids, flavonoids, and condensed tannins are present in sorghum grain including some classes such as proanthocyanidins that are rarely found in others plants. Pigmented varieties of sorghum have the highest polyphenolic content and antioxidant activity which potentially makes their consumption beneficial for human health through different pathways such as oxidative stress reduction and thus the prevention and treatment of neurodegenerative diseases. This review summarizes the potential of sorghum PP to beneficially affect the neuropathology of AD.
... Quercetin is a flavonol mainly found in black and green tea that can also activate AMPK. Recent studies showed that quercetin administration reduced Aβ deposition and tau hyperphosphorylation and ameliorated cognitive function in a triple transgenic AD mouse model [344]. Moreover, long-term treatment with quercetin was shown to be preventive in neurodegeneration if administered prior to the appearance of AD histopathological alterations in the same model [344]. ...
... Recent studies showed that quercetin administration reduced Aβ deposition and tau hyperphosphorylation and ameliorated cognitive function in a triple transgenic AD mouse model [344]. Moreover, long-term treatment with quercetin was shown to be preventive in neurodegeneration if administered prior to the appearance of AD histopathological alterations in the same model [344]. The possible modulation of autophagy by resveratrol or quercetin in AD supports further research as therapeutic strategies. ...
Article
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Macroautophagy, a quality control mechanism, is an evolutionarily conserved pathway of lysosomal degradation of protein aggregates, pathogens, and damaged organelles. As part of its vital homeostatic role, macroautophagy deregulation is associated with various human disorders, including neurodegenerative diseases. There are several lines of evidence that associate protein misfolding and mitochondrial dysfunction in the etiology of Alzheimer's, Parkinson's, and Huntington's diseases. Macroautophagy has been implicated in the degradation of different protein aggregates such as Aβ, tau, alpha-synuclein (α-syn), and mutant huntingtin (mHtt) and in the clearance of dysfunctional mitochondria. Taking these into consideration, targeting autophagy might represent an effective therapeutic strategy to eliminate protein aggregates and to improve mitochondrial function in these disorders. The present review describes our current understanding on the role of macroautophagy in neurodegenerative disorders and focuses on possible strategies for its therapeutic modulation.
... In the meantime, it inhibits secretase enzymes and reduces the production of amyloid proteins (Shimmyo et al., 2008;Khan et al., 2009). This has been confirmed in AD mouse models where quercetin decreases the level of amyloid proteins in the extracellular space, inhibits tau phosphorylation, and ameliorates neuroinflammation evidenced by attenuated microglial and astrocyte activation (Sabogal-Guáqueta et al., 2015). It is known that activated microglial cells can secrete TNF-α, interleukins and interferon-V. ...
... A recent study has shown that quercetin ameliorates memory impairment in scopolamine treated mice through protecting against neurodegeneration and neuroinflammation (Olayinka et al., 2022). Collectively, quercetin mainly exerts anti-AD effects through the following pathological mechanisms: 1) inhibition of Aβ production, aggregation and tau phosphorylation; 2) inhibition of the activity of AChE; 3) attenuation of oxidative stress and neuroinflammation (Paris et al., 2011;Qureshi et al., 2011;Abdalla et al., 2013;Sabogal-Guáqueta et al., 2015;Costa et al., 2016). Calycosin is the most abundant one among flavonoids isolated from AR. ...
Article
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Astragalus mongholicus Bunge (Fabaceae) (also known as Astragali radix-AR), a widely used herb by Traditional Chinese Medicine practitioners, possesses a wide range of pharmacological effects, and has been used to treat Alzheimer’s disease (AD) historically. Its bioactive compounds are categorized into four families: saponins, flavonoids, polysaccharides, and others. AR’s bioactive compounds are effective in managing AD through a variety of mechanisms, including inhibiting Aβ production, aggregation and tau hyperphosphorylation, protecting neurons against oxidative stress, neuroinflammation and apoptosis, promoting neural stem cell proliferation and differentiation and ameliorating mitochondrial dysfunction. This review aims to shed light upon the chemical constituents of AR and the mechanisms underlying the therapeutic effect of each compound in manging AD. Also presented are clinical studies which reported successful management of AD with AR and other herbs. These will be helpful for drug development and clinical application of AR to treat AD.
... Additionally, it improved many age-related symptoms in an Ercc1 −/∆ mouse model of premature aging, including cardiovascular function, bone density, and physical endurance [18] (Table 1). In the CNS, quercetin reduced neurodegenerative burden in a triple-transgenic mouse model of AD by decreasing amyloid-β expression and alleviating some of the pathology associated with microgliosis and astrogliosis [75]. The dual combination reduced SA-β-Gal expression, several cytokine secretions, the number of reactive microglia, and amyloid-β plaque formation in the hippocampus of the APP/PS1 AD mouse model [52] (Table 1). ...
Article
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Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.
... Though there are several senolytic compounds which have been identified and are being further studied (e.g., fisetin and other flavonoids) for their associations with improvements in cognition and reductions in AD-relevant pathology (36,(49)(50)(51)(52), D+Q was selected for use in this first AD relevant trial as it is the most well established. Indeed, testing these first generation senolytics in early AD is a necessary and critical step in carefully moving this field forward. ...
Article
Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer’s disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer’s disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer’s disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer’s disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).
... A major challenge for the use of these agents for therapy is thought to be their poor bioavailability after ingestion and inability to cross the BBB [123,124]. The most studied polyphenols that may be beneficial for AD include curcumin [125,126], resveratrol [127][128][129], quercetin [130,131], (-)-epigallactocatechin-3gallate (EGCG) [132], and fisetin [133]. Many polyphenols exert favorable effects on mitochondria in terms of biogenesis and integrity [134]. ...
Article
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Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neurodegenerative disorders including Alzheimer’s disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bioactive food components, known as nutraceuticals, may serve as such agents to combat AD. Urolithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, anti-inflammatory, anti-atherogenic, anti-Aβ, and pro-mitophagy properties are increasingly recognized. However, the underlying mechanisms of urolithin A in inducing mitophagy is poorly understood. This review discusses the mitophagy deficits in AD and examines potential molecular mechanisms of its activation. Moreover, the current knowledge of urolithin A is discussed, focusing on its neuroprotective properties and its potential to induce mitophagy. Specifically, this review proposes potential mechanisms by which urolithin A may activate and promote mitophagy.
... Flavonoids have been reported having beneficial effects in the prevention of neurodegenerative disorders like Alzheimer's disease. The molecular investigation has shown that the administration of quercetin significantly decreases extracellular b-amyloidosis in the hippocampus by downregulating the β-site APP cleaving enzyme 1 (BACE1) [22]. The oral consumption of rutin can combat oxidative stress and enhance antioxidant pathways resulting in attenuation in cognitive impairments. ...
Article
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Treatment with valproic acid (VPA) deteriorates hippocampal neurogenesis, which leads to memory impairment. Hesperidin (Hsd) is a plant-based bioflavonoid that can augment learning and memory. This study aimed to understand the effect of Hsd on the impairment of hippocampal neurogenesis and memory caused by VPA. The VPA (300 mg/kg) was administered by intraperitoneal injection twice daily for 14 days, and Hsd (100 mg/kg/day) was administered by oral gavage once a day for 21 days. All rats underwent memory evaluation using the novel object location (NOL) and novel object recognition (NOR) tests. Immunofluorescent staining of Ki-67, BrdU/NeuN, and doublecortin (DCX) was applied to determine hippocampal neurogenesis in cell proliferation, neuronal survival, and population of the immature neurons, respectively. VPA-treated rats showed memory impairments in both memory tests. These impairments resulted from VPA-induced decreases in the number of Ki-67-, BrdU/NeuN-, and DCX-positive cells in the hippocampus, leading to memory loss. Nevertheless, the behavioral expression in the co-administration group was improved. After receiving co-administration with VPA and Hsd, the numbers of Ki-67-, BrdU/NeuN-, and DCX-positive cells were improved to the normal levels. These findings suggest that Hsd can reduce the VPA-induced hippocampal neurogenesis down-regulation that results in memory impairments.
... In addition, wogonin (5,7-dihydroxy-8-methoxyflavone), a novel inhibitor for mammalian target of rapamycin (mTOR) signaling pathway, strengthens the autophagy to effectively clear Aβ and suppresses Tau protein phosphorylation (Zhu and Wang, 2015). Quercetin (3,3 ,4 ,5,7-pentahydroxyflavone) decreases β-amyloidosis and tauopathy and protects the cognitive function in APP, PS1, and Tau triple-transgenic AD mouse model (3 × Tg-AD mice) (Sabogal-Guáqueta et al., 2015;Pérez-Corredor et al., 2019). Studies have shown that apigenin (4 ,5,7-trihydroxyflavone) ameliorates learning and memory impairment through relieving Aβ burden, suppressing amyloidogenic process, and restoring ERK/CREB/BDNF pathway in APP and PS1 double transgenic AD mice (Zhao et al., 2013). ...
Article
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and cognitive decline. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein are one of the pathological hallmarks of several neurodegenerative diseases including AD. Heat shock protein family B (small) member 1 (HSPB1) is a molecular chaperone that promotes the correct folding of other proteins in response to environmental stress. Nuclear factor erythroid 2-like 2 (NRF2), a redox-regulated transcription factor, is the master regulator of the cellular response to excess reactive oxygen species. Tropomyosin-related kinase B (TRKB) is a membrane-bound receptor that, upon binding brain-derived neurotrophic factor (BDNF), phosphorylates itself to initiate downstream signaling for neuronal survival and axonal growth. In this study, four natural flavones such as 7,8-dihydroxyflavone (7,8-DHF), wogonin, quercetin, and apigenin were evaluated for Tau aggregation inhibitory activity and neuroprotection in SH-SY5Y neuroblastoma. Among the tested flavones, 7,8-DHF, quercetin, and apigenin reduced Tau aggregation, oxidative stress, and caspase-1 activity as well as improved neurite outgrowth in SH-SY5Y cells expressing ΔK280 Tau RD -DsRed folding reporter. Treatments with 7,8-DHF, quercetin, and apigenin rescued the reduced HSPB1 and NRF2 and activated TRKB-mediated extracellular signal-regulated kinase (ERK) signaling to upregulate cAMP-response element binding protein (CREB) and its downstream antiapoptotic BCL2 apoptosis regulator (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of these three flavones. Our results suggest 7,8-DHF, quercetin, and apigenin targeting HSPB1, NRF2, and TRKB to reduce Tau aggregation and protect cells against Tau neurotoxicity and may provide new treatment strategies for AD.
... Moreover, both animal (Rahvar, Owji, & Mashayekhi, 2018) and human studies (Neshatdoust et al., 2016) showed that quercetin may affect BDNF levels through regulation of gene expression (Rahvar et al., 2018) and improve synthesis of nerve growth factor (NGF) and neurite outgrowth via an increase in intracellular Cl(−) by activating the Na(+)/ K(+)/2Cl(−) cotransporter isoform 1 (NKCC1) without any increase in the expression level of NKCC1 protein (Nakajima, Niisato, & Marunaka, 2011). Additional mechanism for the neuroprotective activity of quercetin and its cognitive-enhancing effect (Sriraksa et al., 2012) relates to the modulation of autophagy (Qu, Liang, Gu, & Liu, 2014;Regitz, Dußling, & Wenzel, 2014), the inhibition of Aβ aggregation (Sato et al., 2013) and prevention of Tau phosphorylation (Sabogal-Guáqueta et al., 2015), the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) (Abdalla et al., 2014), G. Caruso, S.A. Torrisi, M.P. Mogavero et al. Pharmacology & Therapeutics xxx (xxxx) xxx the reduction of neuroinflammatory phenomena through the downregulation of iNOS, COX-2, TNF-α, IL-6, IL-1β, and interferon-γ (IFNγ) in microglia and macrophages Qureshi et al., 2011;Testa et al., 2014), and the activation of sirtuin 1 (SIRT1), which in turn would lead to the suppression of B-cell lymphoma 2 (BCL2)-associated X protein (Bax)-dependent apoptosis as well as the inhibition of several additional pro-apoptotic transcription factors (Leyton et al., 2015). ...
Article
Dietary polyphenols have been the focus of major interest for their potential benefits on human health. Several preclinical studies have been conducted to provide a rationale for their potential use as therapeutic agents in preventing or ameliorating cognitive decline. However, results from human studies are scarce and poorly documented. The aim of this review was to discuss the potential mechanisms involved in age-related cognitive decline or early stage cognitive impairment and current evidence from clinical human studies conducted on polyphenols and the aforementioned outcomes. The evidence published so far is encouraging but contrasting findings are to be taken into account. Most studies on anthocyanins showed a consistent positive effect on various cognitive aspects related to aging or early stages of cognitive impairment. Studies on cocoa flavanols, resveratrol, and isoflavones provided substantial contrasting results and further research is needed to clarify the therapeutic potential of these compounds. Results from other studies on quercetin, green tea flavanols, hydroxycinnamic acids (such as chlorogenic acid), curcumin, and olive oil tyrosol and derivatives are rather promising but still too few to provide any real conclusions. Future translational studies are needed to address issues related to dosage, optimal formulations to improve bioavailability, as well as better control for the overall diet, and correct target population.
... In addition, vitamin E is an antioxidant that could compete for oxidative stress status, such as neurodegenerative diseases [22]. Hence, NG and vitamin E could successfully alleviate learning and cognition deficits induced by lipopolysaccharide and aesthesia, neurotoxicity, chronic stress in Alzheimer's disease model and diabetic rats [23][24][25][26][27][28]. Moreover, NG mitigated anxiety-like effects induced by iron and hypoxic stress in rats [29,30]. ...
Article
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Nicotine is the major alkaloid present in cigarettes that induces various biochemical and behavioral changes. Nanonaringenin (NNG) and vitamin E are antioxidants that are reported to mitigate serious impairments caused by some toxins and oxidants. Thus, we aimed to investigate the efficacy of NNG, vitamin E, and their combinations to ameliorate behavioral, biochemical, and histological alterations induced by nicotine in rats. Adult male albino rats were randomly grouped into six equal groups (10 rats/group): control, N (nicotine 1 mg/kg b.w./day S/C from 15th to 45th day, 5 days a week), NNG (25 mg/kg b.w./day orally for 45 days), N + NNG, N + E (nicotine + vitamin E 200 mg/kg b.w./day orally), and N + NNG + E (nicotine + NNG + vitamin E at the aforementioned doses). Behavioral tests were conducted on day 15 and 30 postnicotine injection, while memory tests, brain neurotransmitters, antioxidants, and histopathological examination were examined at day 30 only. As a result, nicotine impaired rats’ activity (hypoactivity and hyperactivity) and memory, induced anxiolytic and anxiogenic effects on rats, and altered neurotransmitters (acetylcholinesterase, serotonin, and dopamine), and redox markers (MDA, H2O2, GSH, and catalase) levels in brain homogenates. Thickening and congestion of the meninges and degeneration of the cerebral neurons and glia cells were observed. Cosupplementation with NNG, vitamin E, and their combination with nicotine was beneficial in the alleviation of activity impairments and improved short memory and cognition defects and exploratory behaviors. Our results indicate the antioxidant potential of NNG and vitamin E by modulating redox markers and neurotransmitters in the brain. Thus, data suggest that the prophylactic use of NNG, vitamin E, and/or their combination for (45 days) may have a successful amelioration of the disrupted behavior and cognition and biochemical and histopathological alterations induced by nicotine.
... It can also determine mitochondrial regulation of complex 1 activity in deteriorated dopaminergic neurons and impede mitochondrial injury (Karuppagounder et al. 2013); in addition, its administration, in a triple transgenic AD model, may considerably lower extracellular β-amyloidosis, tauopathy, astrogliosis, and microgliosis in the hippocampus and amygdala. Additional molecular research indicated that the administration of quercetin generated the downregulation of BACE1-mediated APP cleavage and a considerable decline in Aβ1-40, Aβ1-42, and paired helical filament (PHF) (Rodrigues et al. 2007;Sabogal-Guáqueta et al. 2015). ...
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Alzheimer’s disorder (AD) is very difficult to manage and treat. The complexity of the brain, the blood–brain barrier influencing a multitude of parameters/biomarkers, as well as numerous other factors involved often contribute to the decline in the chances of treatment success. Development of the new drug moiety also takes time, being necessary to consider both its toxicity and related issues. As a strategic plan, a combined strategy is being developed and considered to address AD pathology using several approaches. A combination of vitamin E, quercetin, and basil oil in a nano-based formulation is designed to be administered nasally. The antioxidant present in these natural-based products helps to treat and alleviate AD if a synergistic approach is considered. The three active substances mentioned above are well known for the treatment of neurodegenerative disorders. The nanoformulation helps the co-delivery of the drug moiety to the brain through the intranasal route. In this review, a correlation and use of vitamin E, quercetin, and basil oil in a nano-based formulation is described as an effective way to treat AD. The intranasal administration of drugs is a promising approach for the treatment of neurodegenerative and mental disorders, as this route is non-invasive, enhances the bioavailability, allows a drug dose reduction, bypasses the blood–brain barrier, and reduces the systemic undesired effect. The use of natural products is generally considered to be just as safe; therefore, by using this combined approach, the level of toxicity can be minimized.
... Tauopathies commonly lay their roots in the brain's hippocampal region, hampering the cognitive abilities related to the region and further expanding to other regions of the brain. QC decreased tau phosphorylation and the formation of NFTs (Sabogal-Guáqueta et al. 2015). Kinases and phosphatases play a regulatory role in tau hyperphosphorylation. Protein phosphatases keep a check on kinase activity, and the imbalance between the two can cause AD progression. ...
Book
This book talks about the multidimensional biological etiology of Alzheimer’s disease and autism spectrum disorder which leads to distinctive ways of perception, thinking and learning in affected individuals. It provides a deeper emphasis on the need for early diagnosis, continuous assessment of patients and the proper educational methods and environment required towards enabling people affected with these disorders capable of evolving and learning. This book explores alternative solutions for autism spectrum disorder based on the theory of brain plasticity, the relationship between the gut microbiota and the central nervous system along with genetic factors and toxic metal exposures which are responsible for the oxidative damage resulting in a decreased ability of the patients to use objects or response to auditory stimuli. It also identifies and provides the latest research towards dealing with memory loss, which is the first sign of cognitive impairment followed by behavioral disturbances. These symptoms are associated with a rigorous neuronal decline and the appearance of two brain lesions, senile plaques and neurofibrillary tangles, which are mainly composed of Aβ and hyper phosphorylated tau protein respectively. This book also provides the latest research towards reducing autism disorder severity such as targeting the disease with symptomatic treatments such as cholinesterase inhibitors, NMDA receptor antagonist, β-secretase and γ-secretase inhibitors, α-secretase stimulators, tau inhibitors, immunotherapy, nutraceuticals, and nano drugs. This book will not only be a good resource for professors and lecturers teaching in the area of neuroscience, medicine, biochemistry, neuroinformatics, and nanotechnology, etc. but also for professionals working in the field of occupational therapy and geriatric clinics and rehabilitation.
... Tauopathies commonly lay their roots in the brain's hippocampal region, hampering the cognitive abilities related to the region and further expanding to other regions of the brain. QC decreased tau phosphorylation and the formation of NFTs (Sabogal-Guáqueta et al. 2015). Kinases and phosphatases play a regulatory role in tau hyperphosphorylation. Protein phosphatases keep a check on kinase activity, and the imbalance between the two can cause AD progression. ...
Chapter
Psychotic illness is a major health burden at the present world. Common psychotic disorders like autism spectrum disorders and schizophrenia frequently share clinical manifestations caused by brain dysfunction. However, there is a clear distinction between early- and late-onset psychotic illnesses. Despite appreciable advancement in identifying the genetic risk factors for most psychiatric illnesses, it is still unknown how these genetic variants interact with epigenetic risk factors and environmental factors that predispose risk for these clinically distinct disorders. In this chapter, we tried to trace the clinical features of psychotic illnesses and the relationship between these disorders with genetic insight. Furthermore, we reviewed the common therapeutic targets for these conditions. From the discussion, it is clear that psychotic illnesses share a genetic overlap and the therapeutic target of these abnormalities relies on the same pipeline. Therefore, prospects will be to develop more specific therapies for treating psychotic illnesses.
... Reduction of immunoreactivity of degenerating neurons In vivo [223] Parkinson's disease In vivo [224] Apoptosis on neural cells via PI3K/Akt signal pathway In vitro [225] Cerebrovascular disorders In vivo [226] Alzheimer's disease (AD) prevention In vivo [227] Defense of oxidative Stress via PKCinactivation/ERK1/2 activation In vivo [228] Neuropathic pain reliever In vitro [229] Inhibiting oxidative stress and inflammation in brain injury In vivo [230] Hypoxic-ischemic brain injury In vivo [231] Alzheimer's disease prevention In vitro [232] Anti-neuroinflammatory In vitro [233] Enhanced neuronal mitochondrial performance In vitro [234] Brain therapy, hypoxia In vivo [235] Anti-inflammatory, antioxidant, and anti-acetylcholinesterase activities in In vitro [236] Reduction in oxidative-stress-mediated neurodegeneration In vivo [237] Prevention of Parkinson's disease by gene expression In vitro [238] Anti-brain ischemic/reperfusion injury using Akt pathway In vivo [239] In neuron survival In vitro [240] Cognitive function In vivo [241] Antioxidative stress, neuronal damage, In vivo [242] Protection of human brain cells In vitro [243] Spatial memory dysfunctions improvement In vivo [244] Protection of cognitive and emotional functions In vivo [245] Reduction of cell apoptosis of oxidant-stressed neuroblastoma (SK-N-MC) cells In vitro [246] Protects the weakening of memory and anxiogenic behavior In vitro [247] Locomotor activities, neurotransmission In vivo [248] Spinal cord injury treatment In vitro [249] Perinatal cerebral hypoxia-ischemia In vivo [250] Protection from oxidative stress and brain edema In vivo [251] Brain protection In vivo and in vitro [252] Retinal neuroprotection In vivo [253] Brain injury treatment In vivo [254] Neurolemmocytes damage prevention In vivo [255] Protection of PC12 neural cells In vitro [256] Multiple therapeutic molecular targets of Alzheimer diseases In vitro [257] ...
Article
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Quercetin, a bioactive secondary metabolite, holds incredible importance in terms of bioactivities, which has been proved by in vivo and in vitro studies. The treatment of cardiovascular and neurological diseases by quercetin has been extensively investigated over the past decade. Quercetin is present naturally in appreciable amounts in fresh produce (fruits and vegetables). However, today, corresponding to the growing population and global demand for fresh fruits and vegetables, a paradigm shift and focus is laid towards exploring industrial food wastes and/or byproducts as a new resource to obtain bioactive compounds such as quercetin. Based on the available research reports over the last decade, quercetin has been suggested as a reliable therapeutic candidate for either treating or alleviating health issues, mainly those of cardiovascular and neurological diseases. In the present review, we have summarized some of the critical findings and hypotheses of quercetin from the available databases foreseeing its future use as a potential therapeutic agent to treat cardiovascular and neurological diseases. It is anticipated that this review will be a potential reference material for future research activities to be undertaken on quercetin obtained from fresh produce as well as their respective processing wastes/byproducts that rely on the circular concept.
... Tauopathies commonly lay their roots in the brain's hippocampal region, hampering the cognitive abilities related to the region and further expanding to other regions of the brain. QC decreased tau phosphorylation and the formation of NFTs (Sabogal-Guáqueta et al. 2015). Kinases and phosphatases play a regulatory role in tau hyperphosphorylation. Protein phosphatases keep a check on kinase activity, and the imbalance between the two can cause AD progression. ...
... Tauopathies commonly lay their roots in the brain's hippocampal region, hampering the cognitive abilities related to the region and further expanding to other regions of the brain. QC decreased tau phosphorylation and the formation of NFTs (Sabogal-Guáqueta et al. 2015). Kinases and phosphatases play a regulatory role in tau hyperphosphorylation. Protein phosphatases keep a check on kinase activity, and the imbalance between the two can cause AD progression. ...
Chapter
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Neurodegenerative diseases are becoming more common in the people of old age. Numerous complications have occurred in the treatment of neurodegenerative diseases, some of which are multi-systemic in nature. Since the structure, efflux pumps, and expression of the blood-brain barrier’s (BBB) metabolism are limited, traditional drug delivery systems are ineffective for treating neurodegenerative disorders. Nanotechnology has the potential to significantly improve neurodegenerative disease treatment by bioengineered systems that interact with biological systems on a molecular level. This chapter discusses the applications of nanoparticles in the treatment of Alzheimer’s disease.
... Cinnamic acid have acetylcholinesterase inhibition, antioxidant and anti-inflammatory activities (Lan et al. 2017;Kong et al. 2009). Other detected phytochemicals in electroscopy ionization mass spectrometry negative mode like Caffeic acid in amyloid beta peptide induced AD mouse model recovered spatial memory and cognitive abilities (Kim et al. 2015a;Wang et al. 2016), quercetin have neuroprotective effect through modulation of multiple antioxidant mechanistic pathways like Nrf2, MAPK and PI3K/Akt signaling cascades in transgenic AD mouse model (Zaplatic et al. 2019;Sabogal-Guáqueta et al. 2015), 5-p-coumaroyl quinic acid, p-Coumaric acid, pachyaximine, kaempferol, ferulic acid and quercitrin exhibited anti-inflammatory, antioxidant and neuroprotective pharmacological actions (Farrukh et al. 2022a;Bakr et al. 2016;Kumar et al. 2015;Beg et al. 2018;Nabavi et al. 2015;Sgarbossa et al. 2015;Rattanajarasroj and Unchern 2010). ...
Article
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Sarcococca saligna is a valuable source of bioactive secondary metabolites exhibiting antioxidant, anti-inflammatory and acetylcholinesterase inhibitory activities. The study was intended to explore the therapeutic pursuits of S. saligna in amelioration of cognitive and motor dysfunctions induced by D-galactose and linked mechanistic pathways. Alzheimer’s disease model was prepared by administration of D-galactose subcutaneous injection100 mg/kg and it was treated with rivastigmine (100 mg/kg, orally) and plant extract for 42 days. Cognitive and motor functions were evaluated by behavioral tasks and oxidative stress biomarkers. Level of acetylcholinesterase, reduced level of glutathione, protein and nitrite level, and brain neurotransmitters were analyzed in brain homogenate. The level of apoptosis regulator Bcl-2, Caspases 3 and heat shock protein HSP-70 in brain homogenates were analyzed by ELISA and colorimetric method, respectively. AChE, IL-1β, TNF-α, IL-1α and β secretase expressions were analyzed by RT-PCR. S. saligna dose dependently suppressed the neurodegenerative effects of D-galactose induced behavioral and biochemical impairments through modulation of antioxidant enzymes and acetylcholinesterase inhibition. S. saligna markedly (P<0.05) ameliorated the level of brain neurotransmitters, Bcl-2, HSP-70 and Caspases-3 level. S. saligna at 500-1000 mg/kg considerably recovered the mRNA expression of neurodegenerative and neuro-inflammatory biomarkers, also evident from histopathological analysis. These findings suggest that S. saligna could be applicable in cure of Alzheimer’s disease.
... The latest study by Sabogal-Guáqueta et al., in an aged triple-transgenic AD model mouse, has explored quercetin in reversing β-amyloidosis, astrogliosis, and microgliosis in the hippocampus and amygdala via reducing Aβ (1-40) and Aβ (1-42) levels. In parallel, an improvement in cognition and emotional function in the mouse model to quercetin intake was also observed (Sabogal-Guáqueta et al. 2015 ). Reduced number of acetylcholine (ACh) receptors and increased activity of acetylcholinesterase (AChE) cause depletion of ACh in AD. ...
Article
Neurodegenerative disorders are often life threatening and hired as an economic burden to the health-care system. Nutritional interventions principally involving polyphenols were practiced to arrest or reverse the age-related health disorders. Flavonoids, a class of dietary polyphenols, are rising to super-stardom in preventing brain disorders with their potent antioxidant defense mechanism. Quercetin is a ubiquitous fl avonoid reported to have all-natural myriad of health benefi ts. Citrus fruits, apple, onion, parsley, berries, green tea, and red wine comprise the major dietary supplements of quercetin apart from some herbal remedies like Ginkgo biloba. Appositeness of quercetin in reducing risks of neurodegenerative disorders, cancer, cardiovascular diseases, allergic disorders, thrombosis, atherosclerosis, hypertension, and arrhythmia, to name a few, is attributed to its highly pronounced antioxidant and anti-infl ammatory properties. Neurodegeneration, characterized by progressive deterioration of the structure and function of neurons, is crucially accompanied by severe cogni-tive defi cits. Aging is the major risk factor for neurodegenerative disorders in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) being coequal high hands. Oxidative stress and mitochondrial dysfunction are the key players in triggering neurodegeneration. The upsurge of neurode-generative disorders is always appalling since there exists a paucity in effective treatment practices. Past few years' studies have underpinned the mechanisms through which quercetin boons the brain health in many aspects including bet-terment in cognitive output. Undoubtedly, quercetin will be escalating as an arable fi eld, both in scientifi c research and in pharmacological and clinical applications.
... Being localized mainly in mitochondria, PON2 decreases oxidative stress by preventing the formation of superoxide, a free radical, at the inner mitochondrial membrane [202]. Quercetin has also been reported to cause a reduction in neuroinflammation and neurodegeneration, a decrease in astrogliosis, and recovery in cognition disabilities in mouse models of AD [92,93]. ...
Article
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Honey is the principal premier product of beekeeping familiar to Homo for centuries. In every geological era and culture, evidence can be traced to the potential usefulness of honey in several ailments. With the advent of recent scientific approaches, honey has been proclaimed as a potent complementary and alternative medicine for the management and treatment of several maladies including various neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, etc. In the literature archive, oxidative stress and the deprivation of antioxidants are believed to be the paramount cause of many of these neuropathies. Since different types of honey are abundant with certain antioxidants, primarily in the form of diverse polyphenols, honey is undoubtedly a strong pharmaceutic candidate against multiple neurological diseases. In this review, we have indexed and comprehended the involved mechanisms of various constituent polyphenols including different phenolic acids, flavonoids, and other phytochemicals that manifest multiple antioxidant effects in various neurological disorders. All these mechanistic interpretations of the nutritious components of honey explain and justify the potential recommendation of sweet nectar in ameliorating the burden of neurological disorders that have significantly increased across the world in the last few decades.
... Also, rutin as a physiological compound of EFEL decreased the expression of TNF-α, IL-1β, IL-6, p-ERK, and p-JNK and decreased the expression level of IκB in LPS-induced lung injury mice [69]. Quercetin contained in Eucommia ulmoides decreased the expression levels of p-ERK, p-JNK, and p-p65 in okadaic acid-induced hippocampal neurons and reduced the expression levels of amyloid-β 1-42 and phosphorylation tau protein in aged triple transgenic Alzheimer's disease model mice [70,71]. In this study, EFEL down-regulated the expression levels of p-JNK, p-IκBα, caspase-1, IL-1β, and TNF-α in the lung and the expression levels of p-JNK, p-IκBα, caspase-1, IL-1β, and TNF-α in olfactory bulb caused by PM 2.5 toxicity. ...
Article
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This study aimed to evaluate the protective effect of the ethyl acetate from Eucommia ulmoides leaves (EFEL) on PM2.5-induced cognitive impairment in BALB/c mice. EFEL improved PM2.5-induced cognitive decline by improving spontaneous alternative behavioral and long-term memory ability. EFEL increased ferric reducing activity power (FRAP) in serum. In addition, EFEL increased superoxide dismutase (SOD) and reduced glutathione (GSH) contents and inhibited the production of malondialdehyde (MDA) in lung and brain tissues. EFEL also restored the mitochondrial function by regulating reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) level, and ATP level in lung and brain tissues. EFEL ameliorated the cholinergic system by regulating the acetylcholine (ACh) content and acetylcholinesterase (AChE) activity in the brain tissue and the expression of AChE and choline acetyltransferase (ChAT) in the whole brain and hippocampal tissues. EFEL reduced PM2.5-induced excessive expression of inflammatory protein related to the lung, whole brain, olfactory bulb, and hippocampus. Physiological compounds of EFEL were identified as 5-O-caffeolyquinic acid, rutin, quercetin, and quercetin glycosides. As a result, EFEL has anti-inflammation and anti-amnesic effect on PM2.5-induced cognitive impairment by regulating the inflammation and inhibiting the lung and brain tissue dysfunction, and its effect is considered to be due to the physiological compounds of EFEL.
... It has also shown therapeutic potentials in neurodegenerative disorders [193,194]. It has been shown that quercetin reduces intracellular tau and gliosis in the amygdala and hippocampus during AD [195]. As mentioned earlier, radiation elevates inflammatory and apoptotic mediators [57], while quercetin ameliorates astrogliosis in AD by inhibiting COX-2, iNOS, NO, IL-1β, TNF-α, and prostaglandin E2. ...
Article
The radiation for therapeutic purposes has shown positive effects in different contexts; however, it can increase the risk of many age-related and neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and Parkinson’s disease (PD). These different outcomes highlight a dose-response phenomenon called hormesis. Prevailing studies indicate that high doses of radiation could play several destructive roles in triggering oxidative stress, neuroapoptosis, and neuroinflammation in neurodegeneration. However, there is a lack of effective treatments in combating radiation-induced neurodegeneration, and the present drugs suffer from some drawbacks, including side effects and drug resistance. Among natural entities, polyphenols are suggested as multi-target agents affecting the dysregulated pathogenic mechanisms in neurodegenerative disease. This review discusses the destructive effects of radiation on the induction of neurodegenerative diseases by dysregulating oxidative stress, apoptosis, and inflammation. We also describe the promising effects of polyphenols and other candidate phytochemicals in preventing and treating radiation-induced neurodegenerative disorders, aiming to find novel/potential therapeutic compounds against such disorders.
... APP and Aβ co-localize in mitochondria; Aβ inhibits the respiratory chain, and altered mitochondrial function can result in changes in APP and eventual alterations in the production of amyloidogenic derivatives [138]. Nevertheless, quercetin reduced Aβ and BACE1-mediated cleavage of APP in a murine triple transgenic AD model (3xTg-AD) [139]. Treatment with quercetin also decreased ROS levels and restored normal mitochondrial morphology in hippocampal neurons affected by H 2 O 2 -induced neuronal toxicity and Aβ-induced neurodegeneration this suggests that quercetin could prevent neuronal mitochondrial dysfunction [140]. ...
Article
Full-text available
Multi-factorial mitochondrial damage exhibits a “vicious circle” that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.
... Tauopathies commonly lay their roots in the brain's hippocampal region, hampering the cognitive abilities related to the region and further expanding to other regions of the brain. QC decreased tau phosphorylation and the formation of NFTs (Sabogal-Guáqueta et al. 2015). Kinases and phosphatases play a regulatory role in tau hyperphosphorylation. Protein phosphatases keep a check on kinase activity, and the imbalance between the two can cause AD progression. ...
Chapter
Alzheimer’s disease (AD) is a degenerative brain disease that is the leading cause of dementia among the human population. AD is characterized by accumulating amyloid plaques which are insoluble deposits of a 4 kDa peptide of ~40–42 amino acids in length, known as amyloid-β (Aβ). The imbalance between Aβ generation and clearance in the brain leads to the progression of AD. AD pathology is characterized by the deposition of oligomeric and fibrillar forms of amyloid-β (Aβ) in the neuropil and cerebral vessel walls. Neurofibrillary tangles are composed mainly of hyperphosphorylated tau and neurodegeneration. Polyphenols are the most abundant antioxidants in the diet. More than 8000 naturally occurring polyphenols exist. Numerous studies have indicated that high consumption of fruits and vegetables rich in flavonoids and other polyphenols reduces the risk/incidence of age-related neurodegenerative disorders, highlighting the importance of these polyphenols as neuroprotective agents. Due to polyphenols’ ability to influence and modulate multiple targets in the cascade of the pathogenesis of neurodegenerative diseases, they are considered a candidate with a promising result against neurodegeneration, halting the progression of the disease. There is now substantial evidence indicating that oxidative damage to the brain is an early AD pathogenesis event. Oxidative stress and damage to brain macromolecules are vital processes in neurodegenerative diseases. The antioxidant properties of many polyphenols are purported to provide neuroprotection. There are pieces of evidence that some of the polyphenols can easily cross the blood-brain barrier (BBB). This chapter will provide deeper insights into various polyphenols that play a pivotal role in AD and shed light on the roles of these in the context of AD therapeutics.
... Tauopathies commonly lay their roots in the brain's hippocampal region, hampering the cognitive abilities related to the region and further expanding to other regions of the brain. QC decreased tau phosphorylation and the formation of NFTs (Sabogal-Guáqueta et al. 2015). Kinases and phosphatases play a regulatory role in tau hyperphosphorylation. Protein phosphatases keep a check on kinase activity, and the imbalance between the two can cause AD progression. ...
Article
Full-text available
Alzheimer's disease (AD) is the most common form of dementia with a growing incidence rate primarily among the elderly. It is a neurodegenerative, progressive disorder leading to significant cognitive loss. Despite numerous pieces of research, no cure for halting the disease has been discovered yet. Phytoestrogens are nonestradiol compounds classified as one of the endocrine-disrupting chemicals (EDCs), meaning that they can potentially disrupt hormonal balance and result in developmental and reproductive abnormalities. Importantly, phytoestrogens are structurally, chemically, and functionally akin to estrogens, which undoubtedly has the potential to be detrimental to the organism. What is intriguing, although classified as EDCs, phytoestrogens seem to have a beneficial influence on Alzheimer's disease symptoms and neuropathologies. They have been observed to act as antioxidants, improve visual-spatial memory, lower amyloid-beta production, and increase the growth, survival, and plasticity of brain cells. This review article is aimed at contributing to the collective understanding of the role of phytoestrogens in the prevention and treatment of Alzheimer's disease. Importantly, it underlines the fact that despite being EDCs, phytoestrogens and their use can be beneficial in the prevention of Alzheimer's disease.
Article
Quercetin is reported to be beneficial to or pose hazards to the health of animals, the inconsistence remains to be recognized and debated. This work was conducted to understand the neuroprotective or neurotoxic properties of quercetin, and investigate the different action mechanisms between low- and high-level quercetin. Therefore, we evaluated brain oxidative stress and monoamine neurotransmitters in adult zebrafish (Danio rerio) after exposure to 1 and 1000 μg/L quercetin. In addition, the brain transcriptional profiles were analyzed to identify genes and pathways that were differentially regulated in the brains. The results of oxidative stress and neurotransmitters suggest that low-level quercetin might be beneficial to nervous system, while high-level quercetin might exert detrimental effects. Furthermore, transcriptional profiles also suggested different toxic mechanisms occurred between low- and high-level quercetin. At 1 μg/L quercetin, enrichment analysis of differently expressed genes (DEGs) revealed that the fanconi anemia pathway might be an important mechanism in neuroprotective effects. At 1000 μg/L quercetin, the up-regulated DEGs were enriched in many Gene Ontology (GO) terms related to neuronal synapses, indicating potential neuroprotective effects; however, enrichment of up-regulated DEGs in GO terms of response to stimulus and the MAPK signaling pathway was also found, which indicated increases of stress. Notably, at 1000 μg/L quercetin, the down-regulated DEGs were enriched in several GO terms related to the proteostasis and the proteasome pathway, indicating impairment of proteasome functions which was involved in neurodegenerative diseases. Moreover, several hub genes involved in the pathology of neurodegenerative diseases were identified by Protein-protein interaction analysis at 1000 μg/L quercetin. Thus, high-level quercetin might pose potential risk inducing neurodegenerative diseases, which should receive more attention in the future. Additionally, our findings may provide awareness to society and researchers about toxicity possibilities of phytochemicals on wildlife and human.
Article
The traditional Mediterranean diet (MedDiet), rich in minimally processed plant foods and fish, has been widely recognized to be one of the healthiest diets. Data from multiple randomized clinical trials have demonstrated its powerful effect against oxidative stress, inflammation and the development and progression of cardiovascular disease, type 2 diabetes, and other metabolic conditions that play a crucial role in the pathogenesis of neurodegenerative diseases. The protecting effects of the MedDiet against cognitive decline have been investigated in several observational and experimental studies. Data from observational studies suggest that the MedDiet may represent an effective dietary strategy for the early prevention of dementia, although these findings require further substantiation in clinical trials which have so far produced inconclusive results. Moreover, as we discuss in this review, accumulating data emphasizes the importance of: 1) maintaining an optimal nutritional and metabolic status for the promotion of healthy cognitive aging, and 2) implementing cognition-sparing dietary and lifestyle interventions during early time-sensitive windows before the pathological cascades turn into an irreversible state. In summary, components of the MedDiet pattern, such as essential fatty acids, polyphenols and vitamins, have been associated with reduced oxidative stress and the current evidence from observational studies seems to assign to the MedDiet a beneficial role in promoting brain health; however, results from clinical trials have been inconsistent. While we advocate for longitudinal analyses and for larger and longer clinical trials to be conducted, we assert our interim support to the use of the MedDiet as a protective dietary intervention for cognitive function based on its proven cardiovascular and metabolic benefits.
Article
Aims Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder characterized by declined cognitive functions in the elderly. Quercetin (Q) is a potent flavonol that has neuroprotective effects on AD derangements. The present study aimed to evaluate the α-secretase stimulatory function of Q through activation of ADAM10 and ADAM17 gene expression in the aluminum chloride (AlCl3)-induced AD rat model. Main methods After induction of AD in rats by oral administration of AlCl3 (50 mg/kg) for 28 days, the Q doses (25 and 50 mg/kg) were orally administered for 28 days. Rats performed the behavioral assessments during the last week of the treatment period. Hippocampi were harvested for assessments of the neurochemical and histopathological examinations and gene expression analysis. Key findings Administration of Q to AlCl3-induced AD rat model attenuated behavioral deficits, improved cholinergic and dopaminergic dysfunctions, and diminished insoluble amyloid β (Aβ) plaques aggregation in the hippocampus. These ameliorative effects of Q were associated with down-regulation of APP, BACE1, APH1, and PSEN1 and up-regulation of ADAM10 and ADAM17 gene expression levels in the hippocampus. Significance The present study suggests that Q might attenuate neurotransmission impairment, Aβ aggregation in the hippocampus, and behavioral deficits in the AlCl3-induce AD rat model via up-regulating ADAM 10 and ADAM 17 (α-secretase) gene expression, leading to the inhibition of the amyloidogenic pathway. In support of the present finding, we suggest that ADAM10 and ADAM17 activation might be potential drug targets for AD to counteract the Aβ aggregation and cognitive deterioration.
Chapter
Neurodegenerative diseases are globally one of the leading causes of death and represent an enormous burden in human suffering, social distress, and economic costs. Recent data expanded on the initial antioxidant-based mechanism of polyphenols’ action by showing that they can modulate several cell-signaling pathways and mediators. The proposed benefits of polyphenols, either as protective/prophylactic substances or as therapeutic molecules, may be achieved by consuming a natural polyphenol-enriched diet by using food supplements nutraceuticals. It has also been proved that polyphenols’ health effects depend on the consumed amount and their bioavailability. This chapter addresses the impacts of food polyphenols and focuses on neuroprotection.
Article
Kleeb Bua Daeng (KBD) formula has long been used in Thailand as a traditional herbal medicine for promoting brain health. Our recent reports illustrated that KBD demonstrates multiple modes of action against several targets in the pathological cascade of Alzheimer’s disease (AD). The main purpose of the present study was to determine the protective effect and mechanism of KBD in amyloid beta (Aβ)-induced AD rats and its toxicity profiles. Pretreatment with the KBD formula for 14 days significantly improved the short- and long-term memory performance of Aβ-induced AD rats as assessed by the Morris Water Maze (MWM) and object-recognition tests. KBD treatment increased the activities of the antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase; reduced the malondialdehyde content, and; decreased the acetylcholinesterase activity in the rat brain. An acute toxicity test revealed that the maximum dose of 2000 mg/kg did not cause any mortality or symptoms of toxicity. An oral, subchronic toxicity assessment of KBD at doses of 125, 250, and 500 mg/kg body weight/day for 90 days showed no adverse effects on behavior, mortality, hematology, or serum biochemistry. Our investigations indicate that KBD is a nontoxic traditional medicine with good potential for the prevention and treatment of AD.
Article
In addition to beta-amyloid (Aβ) plaques and neurofibrillary tangles, Alzheimer's disease (AD) is typically triggered or accompanied by abnormal inflammation, oxidative stress and astrocyte activation. Safflower (Carthamus tinctorius L.) leaf, featuring functional ingredients, is a commonly consumed leafy vegetable. Whether and how dietary safflower leaf powder (SLP) ameliorates cognitive function in an AD mouse model has remained minimally explored. Therefore, we orally administered SLP to APP/PS1 transgenic mice to explore the neuroprotective effects of SLP in preventing AD progression. We found that SLP markedly improved cognitive impairment in APP/PS1 mice, as indicated by the water maze test. We further demonstrated that SLP treatment ameliorated inflammation, oxidative stress and excessive astrocyte activation. Further investigation indicated that SLP decreased the Aβ burden in APP/PS1 mice by mediating excessive astrocyte activation. Our study suggests that safflower leaf is possibly a promising, cognitively beneficial food for preventing and alleviating AD-related dementia.
Article
Background: Diabetes is one of the most challenging health problems in 21st century. It is a group of endocrine-metabolic disorder characterized by high glucose level (hyperglycemia) due to insufficient insulin secretion/action or both. It causes multi-organ failure viz hepatorenal damage, adult-onset blindness, lower-limb amputations, heart diseases and stroke, high blood pressure and nerve damage. Moreover, diabetic patients are having higher risk of cardiovascular complications including atherosclerosis, hypertension, lipoprotein abnormalities and cerebrovascular disease. Study design: Considering the potencies of currently available drugs for the treatment of diabetes and associated complications, present study was focussed to explore the role of plant bioactive components as alternative and easily accessible therapeutic remedies. Hypothesis/Purpose: This study the pooled status of diabetes, available treatments, attitude and traditional herbal polyphenols regarding diabetes. Results: This study was aimed to summarize the natural polyphenols having anti-diabetic, anti-inflammatory, anti-apoptotic and anti-cancerous activities. Polyphenols can decrease other metabolic diseases such as insulin resistance, hyperglycemia, hyperlipidemic, and obesity and Type-2 diabetes. Conclusion: Polyphenols are promising alternatives that can decrease the severity of diabetes and promote the other protective roles by decreasing the adverse effects of diabetes on other metabolic organs and their functions.
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The major constituent of air pollution is petrol exhaust a complex mixture of particles, gases and chemicals. The aim of the current research was to evaluate whether ultrafine petrol exhaust nanoparticles (PENPs), the particle component of exhaust from petrol engines can induce neurotoxicity in rats. We administered rats with repeated doses of PENPs (90 μg/rat and 180 μg/rat for 6 days (every second day) intratracheally (i.t.). This was followed by the evaluation of several neurotoxicity parameters in various sections of rat brain. PENP exposure caused surge in levels of inflammatory mediators such as reactive oxygen species (ROS) and neurodegenerative disorder indicators like amyloid beta 42 (Aβ42) levels in rat brain. Each section of the brain responded differently upon PENP exposure. Prior treatment with quercetin (60 mg/kg b.wt) inhibited elevation in the aforementioned parameters. Hence, PENP exposure was closely linked to neurotoxicity and the neuroprotective capacity of quercetin was also proved.
Article
Alzheimer's disease (AD), an extensive age‐associated neurodegenerative disorder. In spite of wide‐ranging progress in understanding the AD pathology for the past 50 years, clinical trials based on the hypothesis of amyloid‐beta (Aβ) have reserved worsening particularly at late‐stage human trials. Consequently, very few old drugs are presently used for AD with inadequate clinical consequences and various side effects. We focus on widespread pharmacological and beneficial principles for existing as well as future drugs. Multi‐targeting approaches by means of general antioxidant and anti‐inflammatory mechanisms allied with particular receptor and/or enzyme‐mediated actions in neuroprotection and neurodegeneration. The plant kingdom comprises a vast range of species with an incredible diversity of bioactive metabolites with diverse chemical scaffolds. In recent times, an increasing body of facts recommended the use of phytochemicals to decelerate AD's onset and progression. The definitive goal of AD investigation is to avert the onset of neurodegeneration; thereby it allows successful aging devoid of cognitive decline. At this point, we discussed the neurological protective role of natural products and naturally derived therapeutic agents for AD from various natural polyphenolic compounds and medicinal plants. In conclusion, medicinal plants act as a chief source of different bioactive constituents. This article is protected by copyright. All rights reserved
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Developing therapies for neurodegenerative diseases are challenging because of the presence of blood–brain barrier and Alzheimer being one of the commonest and uprising neurodegenerative disorders possess the need for developing novel therapies. Alzheimer’s is attributed to be the sixth leading cause of death in the USA and the number of cases is estimated to be increased from 58 million in 2021 to 88 million by 2050. Natural drugs have benefits of being cost-effective, widely available, fewer side effects, and immuno-booster can be useful in managing Alzheimer. Flavonoids can slow the neuronal degeneration as they have shown activity in central nervous system and are able to cross the blood–brain barrier. These can be easily extracted from fruits, vegetable, and plants. In Alzheimer disease, flavonoids scavenges the reactive oxygen species and reduces the production of amyloid beta protein. Agents from sub-classes of flavonoids such as flavanones, flavanols, flavones, flavonols, anthocyanins, and isoflavones having pharmacological action in treating Alzheimer disease are discussed in this review.
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Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.
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Alzheimer’s disease (AD) is one of the most devastating neurological disorders causing memory loss and impairment of cognitive functions. It is distinguished by the presence of extracellular amyloid beta peptides, intracellular neurofibrillary tangles, and substantial loss in the cortex and hippocampus region of the brain. AD is incurable and has significant social and economic impacts. The disease, therefore, essentially requires successful diagnostics and effective therapeutic approaches. It has been demonstrated that conventional approaches often fail to achieve excellent pharmacokinetic and pharmacodynamic properties at the target site and thus produce low therapeutic efficacy and high toxicity. Recent advances in the pharmaceutical domain have shown the development of nano-systems to overcome the limitations associated with conventional therapy. In addition, emergence of nanotechnology serves as a potential tool in understanding complex mechanisms as well as treatment strategies of AD. These nanosystems are site-specific and offer desired pharmacokinetic properties such as solubility, bioavailability, absorption, permeability across the blood-brain barrier, and better therapeutic effects. Nowadays, a plethora of nano-carriers including solid lipid carriers, liposomes, emulsions, and carbon nanotubes have been designed to attain greater therapeutic effect in AD. Furthermore, nanotechnology also contributes to the early diagnosis of AD. The current chapter encompasses latest developments in nanotechnology-based diagnosis and therapeutic strategies for AD.
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CDK5 is a member of the cyclin-dependent kinase family with diverse functions in both the developing and mature nervous system. The inappropriate activation of CDK5 due to the proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles and chronic neurodegeneration. At 18 months of age 3xTg-AD mice were sacrificed after 1 year (long term) or 3 weeks (short term) of CDK5 knockdown. In long-term animals CDK5 knockdown prevented insoluble Tau formation in the hippocampi and prevented spatial memory impairment. In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice. Neither long-term nor short-term CDK5 knock-down had an effect on old littermates. These findings further validate CDK5 as a target for Alzheimer's disease both as a preventive measure and after the onset of symptoms.
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Excessive accumulation of β-amyloid peptide (Aβ) is one of the major mechanisms responsible for neuronal death in Alzheimer's disease. Flavonoids, primarily antioxidants, are a group of polyphenolic compounds synthesized in plant cells. The present study aimed to identify flavonoid compounds that could inhibit Aβ-induced neuronal death by examining the effects of various flavonoids on the neurotoxicity of Aβ fragment 25-35 (Aβ25-35) in mouse cortical cultures. Aβ25-35 induced concentration- and exposure-time-dependent neuronal death. Neuronal death induced by 20 µM Aβ25-35 was significantly inhibited by treatment with either Trolox or ascorbic acid. Among 10 flavonoid compounds tested [apigenin, baicalein, catechin, epicatechin, epigallocatechin gallate (EGCG), kaempferol, luteolin, myricetin, quercetin, and rutin], all except apigenin showed strong 1,1-diphenyl-2-pycrylhydrazyl (DPPH) scavenging activity under cell-free conditions. The flavonoid compounds except apigenin at a concentration of 30 µM also significantly inhibited neuronal death induced by 20 µM Aβ25-35 at the end of 24 hours of exposure. Epicatechin, EGCG, luteolin, and myricetin showed more potent and persistent neuroprotective action than did the other compounds. These results demonstrated that oxidative stress was involved in Aβ-induced neuronal death, and antioxidative flavonoid compounds, especially epicatechin, EGCG, luteolin, and myricetin, could inhibit neuronal death. These findings suggest that these four compounds may be developed as neuroprotective agents against Alzheimer's disease.
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The entorhinal cortex has been implicated in the early stages of Alzheimer's disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer's disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.
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The purpose of the present investigation was to evaluate cadmium (Cd)-induced neurotoxicity in hippocampal tissues and beneficial effect of quercetin (QE) against neuronal damage. A total of 30 male rats were divided into 3 groups: control, Cd-treated, and Cd + QE-treated groups. After the treatment, the animals were killed and hippocampal tissues were removed for biochemical and histopathological investigation. Cd significantly increased tissue malondialdehyde (MDA) and protein carbonyl (PC) levels and also decreased superoxide dismutase (SOD) and catalase (CAT) enzyme activities in hippocampal tissue compared with the control. Administration of QE with Cd significantly decreased the levels of MDA and PC and significantly elevated the levels of antioxidant enzymes in hippocampal tissue. In the Cd-treated group, the neurons of both tissues became extensively dark and degenerated with pyknotic nuclei. The morphology of neurons in Cd + QE group was well protected, but not as neurons of the control group. The caspase-3 immunopositivity was increased in degenerating neurons of the Cd-treated group. Treatment of QE markedly reduced the immunoreactivity of degenerating neurons. The results of the present study show that QE therapy causes morphologic improvement in neurodegeneration of hippocampus after Cd exposure in rats.
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Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFTs) and extracellular neuritic plaques (NPs) surrounded by activated astrocytes and microglia. NFTs consist of paired helical filaments of truncated tau protein that is abnormally hyperphosphorylated. The main component in the NP is the amyloid-β peptide (Aβ), a small fragment of 40-42 amino acids with a molecular weight of 4 kD. It has been proposed that the amyloid aggregates and microglia activation are able to favor the neurodegenerative process observed in AD patients. However, the role of inflammation in AD is controversial, because in early stages the inflammation could have a beneficial role in the pathology, since it has been thought that the microglia and astrocytes activated could be involved in Aβ clearance. Nevertheless the chronic activation of the microglia has been related with an increase of Aβ and possibly with tau phosphorylation. Studies in AD brains have shown an upregulation of complement molecules, pro-inflammatory cytokines, acute phase reactants and other inflammatory mediators that could contribute with the neurodegenerative process. Clinical trials and animal models with non-steroidal anti-inflammatory drugs (NSAIDs) indicate that these drugs may decrease the risk of developing AD and apparently reduce Aβ deposition. Finally, further studies are needed to determine whether treatment with anti-inflammatory strategies, may decrease the neurodegenerative process that affects these patients.
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The neuropathological correlates of Alzheimer's disease (AD) include amyloid-β (Aβ) plaques and neurofibrillary tangles. To study the interaction between Aβ and tau and their effect on synaptic function, we derived a triple-transgenic model (3×Tg-AD) harboring PS1M146V, APPSwe, and tauP301L transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1M146V knockin mice, generating mice with the same genetic background. 3×Tg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Aβ. These studies suggest a novel pathogenic role for intraneuronal Aβ with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Aβ, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
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Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes in APP/PS1 mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with the immune/inflammatory calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway, shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2-VIVIT, APP/PS1 mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies.
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Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O- glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ 1-40 and Aβ1-42 that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD diseasemodifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.
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Biomarkers for Alzheimer's disease (AD) based on non-invasive methods are highly desirable for diagnosis, disease progression, and monitoring therapeutics. We aimed to study the use of hippocampal volume, entorhinal cortex (ERC) thickness, and whole brain volume (WBV) as predictors of cognitive change in patients with AD. 120 AD subjects, 106 mild cognitive impairment (MCI), and 99 non demented controls (NDC) from the multi-center pan-European AddNeuroMed study underwent MRI scanning at baseline and clinical evaluations at quarterly follow-up up to 1 year. The rate of cognitive decline was estimated using cognitive outcomes, Mini-Mental State Examination (MMSE) and Alzheimer disease assessment scale-cognitive (ADAS-cog) by fitting a random intercept and slope model. AD subjects had smaller ERC thickness and hippocampal and WBV volumes compared to MCI and NDC subjects. Within the AD group, ERC > WBV was significantly associated with baseline cognition (MMSE, ADAS-cog) and disease severity (Clinical dementia rating). Baseline ERC thickness was associated with both longitudinal MMSE and ADAS-cog score changes and WBV with ADAS-cog decline. These data indicates AD subjects with thinner ERC had lower baseline cognitive scores, higher disease severity, and predicted greater subsequent cognitive decline at one year follow up. ERC is a region known to be affected early in the disease. Therefore, the rate of atrophy in this structure is expected to be higher since neurodegeneration begins earlier. Focusing on structural analyses that predict decline can identify those individuals at greatest risk for future cognitive loss. This may have potential for increasing the efficacy of early intervention.
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Many studies have demonstrated that the flavonoid quercetin protects against cardiovascular disease (CVD) and related risk factors. Atherosclerosis, the underlying cause of CVD, is also attenuated by oral quercetin administration in animal models. Although macrophages are key players during fatty streak formation and plaque progression and aggravation, little is known about the effects of quercetin on atherogenic macrophages. Here, we report that primary bone marrow-derived macrophages internalized less oxidized low-density lipoprotein (oxLDL) and accumulated less intracellular cholesterol in the presence of quercetin. This reduction of foam cell formation correlated with reduced surface expression of the oxLDL receptor CD36. Quercetin also targeted the lipopolysaccharide-dependent, oxLDL-independent pathway of lipid droplet formation in macrophages. In oxLDL-stimulated macrophages, quercetin inhibited reactive oxygen species production and interleukin (IL)-6 secretion. In a system that evaluated cholesterol crystal-induced IL-1β secretion via nucleotide-binding domain and leucine-rich repeat containing protein 3 inflammasome activation, quercetin also exhibited an inhibitory effect. Dyslipidemic apolipoprotein E-deficient mice chronically treated with intraperitoneal quercetin injections had smaller atheromatous lesions, reduced lipid deposition, and less macrophage and T cell inflammatory infiltrate in the aortic roots than vehicle-treated animals. Serum levels of total cholesterol and the lipid peroxidation product malondialdehyde were also reduced in these mice. Our results demonstrate that quercetin interferes with both key proatherogenic activities of macrophages, namely foam cell formation and pro-oxidant/proinflammatory responses, and these effects may explain the atheroprotective properties of this common flavonoid.
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Microglia have long been noted to be present and activated in Alzheimer brain. Demonstrations that these microglia are associated with the specific lesions of Alzheimer disease-Aβ plaques and neurofibrillary tangles-and that these microglia overexpress the potent proinflammatory cytokine interleukin-1 led to the recognition of a potential pathogenic role for these cells in initiation and progression of disease. Activated, cytokine-overexpressing microglia are near-universal components of Aβ plaques at early (diffuse) and mid (neuritic) stages of progression in Alzheimer brain, and only decline in end-stage, dense core plaques. They correlate with plaque distribution across cerebral cortical cytoarchitectonic layers and across brain regions. They also show close associations with tangle-bearing neurons in Alzheimer brain. Microglial activation is a consistent feature in conditions that confer increased risk for Alzheimer disease or that are associated with accelerated appearance of Alzheimer-type neuropathological changes. These include normal ageing, head injury, diabetes, heart disease, and chronic intractable epilepsy. The neuropathological demonstration of microglial activation in Alzheimer brain and in Alzheimer-related conditions opened the field of basic and applied investigations centered on the idea of a pathogenically important neuroinflammatory process in Alzheimer disease.
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This was a prospective, randomized, between-subjects experimental study to investigate the anxiolytic effects of naringenin, a component of mentha aquatica, and its potential interaction with the benzodiazepine binding site on the γ-aminobutyric acid (GABAA) receptor in the rat. Fifty-five rats were assigned to one of 5 groups with 11 rats per group: control, naringenin, midazolam, midazolam with naringenin, and flumazenil with naringenin. The elevated plus maze measured the behavioral components of anxiety and motor movements. Our data suggest that naringenin does not produce anxiolysis by modulation of the GABAA receptor; however, the findings indicate that naringenin decreases motor movements (P < .05).
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The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.
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This study was designed to evaluate the effect of quercetin, a natural flavonoid, on behavioral alterations, brain oxidative stress, and immune dysregulation caused by a chemotherapeutic agent, Adriamycin (ADR; 7 mg/kg of body weight). Different subsets of male Wistar rats were used to determine the benefit of quercetin on ADR-related depression-like and anxiety-like behaviors in the forced swim test, open field, and elevated plus maze, respectively. Quercetin (60 mg/kg of body weight) was administered 24, 5, and 1 h before the test session of forced swim test (FST) or at the same time points before the elevated plus maze/open field (EPM/OF) tests. Other subsets of rats were sacrificed after quercetin injections to assess the plasma corticosterone level, the brain oxidative status, and the immune cell count. Our results indicate that quercetin alleviated the anxio-depressive-like behavior, attenuated the brain oxidative stress, and suppressed the corticosterone excess that appeared following ADR treatment. The ADR-induced immune disturbance was slightly diminished after quercetin administration, especially for the lymphocyte count. This study suggests that quercetin can mitigate the neurobehavioral and immunological impairments that manifest in ADR-treated rats. Therefore, the combination of quercetin treatment with the chemotherapeutic regimen seems to be beneficial against chemotherapy-related complications.
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Amyloid-β (Aβ)-induced mitochondrial dysfunction has been recognized as a prominent, early event in Alzheimer’s disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Quercetin, a bioflavanoid, has been reported to have potent neuro-protective effects, but its preventive effects on Aβ-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. Three-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group, two quercetin (either 20 or 40 mg kg−1 day−1) groups, or an Aricept (2 mg kg−1 day−1) group. After 16 weeks of treatment, we observed beneficial effects of quercetin (40 mg kg−1 day−1), including lessening learning and memory deficits, reducing scattered senile plaques, and ameliorating mitochondrial dysfunction, as evidenced by restoration of mitochondrial membrane potential, reactive oxygen species and ATP levels in mitochondria isolated from the hippocampus compared to control. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated (40 mg kg−1 day−1) group. These findings suggest that a reduction in plaque burden and mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms by which quercetin improves cognitive functioning in the APPswe/PS1dE9 transgenic mouse model of AD.
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Biological activities of flavonoids in vivo are ultimately dependent on the systemic bioavailability of the aglycones as well as their metabolites. In the present study, a physiologically based kinetic (PBK) model was developed to predict plasma concentrations of the flavonoid quercetin and its metabolites and to tentatively identify the regiospecificity of the major circulating metabolites. The model was developed based on in vitro metabolic parameters and by fitting kinetic parameters to literature available in vivo data. Both exposure to quercetin aglycone and to quercetin-4′-O-glucoside, for which in vivo data were available, were simulated. The predicted plasma concentrations of different metabolites adequately matched literature reported plasma concentrations of these metabolites in rats exposed to 4′-O-glucoside. The bioavailability of aglycone was predicted to be very low ranging from 0.004% to 0.1% at different oral doses of quercetin or quercetin-4′-O-glucoside. Glucuronidation was a crucial pathway that limited the bioavailability of the aglycone, with 95 to 99% of the dose being converted to monoglucuronides within 1.5 h to 2.5 h at different dose levels ranging from 0.1 to 50 mg/kg bw quercetin or quercetin-4′-O-glucoside. The fast metabolic conversion to monoglucuronides allowed these metabolites to further conjugate to di- and tri-conjugates. The regiospecificity of major circulating metabolites was observed to be dose-dependent. As we still lack in vivo kinetic data for many flavonoids, the developed model has a great potential to be used as a platform to build PBK models for other flavonoids as well as to predict the kinetics of flavonoids in humans.
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Among Spinal Cord Injury (SCI) intervention the administration of high-dose high-potency steroidal drugs such as methylprednisolone or dexamethasone is used to reduce the inflammation associated with primary injury and prevention of the subsequent secondary injury. The administration of steroids has several side-effects that jeopardize their use and therefore safer chemical neuro-entities are required. Natural compounds such as curcumin (anti-oxidant) and quercetin (anti-inflammatory) have been investigated as alternative neuroactive, but are not as potent as the steroids. Hence, they are required in very high doses which may lead to significant toxicity causing an increase in cellular levels of reactive oxygen species, active iron chelation, inhibiting the activity of the cytochrome P450 enzymes such as glutathione-S-transferase and UDP-glucuronosyltransferase. A reduction in the dose of these neuroactives is possible with the administration of a ‘chemically-variant’ permutation with additive or synergistic therapeutic benefits. Therefore, we hypothesize that curcumin and quercetin, both natural polyphenolic flavonoids, can “additively and synergistically” improve the physiological outcome after traumatic SCI when used in combination and termed ‘Cur(Que)min’ – thereby decreasing the dose levels and hence reducing the inherent high dose-cytotoxicity of the individual neuroactives. This hypothesis provides the first-account of a curcumin-quercetin combination for SCI intervention theorizing the possible biomolecular-mechanism that may provide the scientific community with a novel neuroprotective and neurotherapeutic treatment option for SCI.
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Huntington's disease (HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3-nitropropionic acid (3-NP)-induced HD in rats where both drugs were administered simultaneously. Performance of rats on beam balancing, elevated plus maze and gait traits were investigated following 3-NP and/or quercetin treatments for 4 days. Striatal biogenic amine levels and monoamine oxidase activity were assayed. Striatal sections were examined for Cd11B and glial fibrillary acidic protein immunoreactivity, and for evidences of neuronal lesion. Quercetin significantly attenuated 3-NP-induced anxiety, motor coordination deficits, and gait despair. While the dopaminergic hyper-metabolism was unaffected, quercetin provided a significant reduction of 3-NP mediated increase in serotonin metabolism. Quercetin failed to affect 3-NP-induced striatal neuronal lesion, but decreased microglial proliferation, and increased astrocyte numbers in the lesion core. These results taken together suggest that quercetin could be of potential use not only for correcting movement disturbances and anxiety in HD, but also for addressing inflammatory damages.
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Increased consumption of fruits and vegetables can represent an easy strategy to significantly reduce the incidence of cancer. From this observation, derived mostly from epidemiological data, the new field of chemoprevention has emerged in the primary and secondary prevention of cancer. Chemoprevention is defined as the use of natural or synthetic compounds able to stop, reverse, or delay the process of tumorigenesis in its early stages. A large number of phytochemicals are potentially capable of simultaneously inhibiting and modulating several key factors regulating cell proliferation in cancer cells. Quercetin is a flavonoid possessing potential chemopreventive properties. It is a functionally pleiotropic molecule, possessing multiple intracellular targets, affecting different cell signaling processes usually altered in cancer cells, with limited toxicity on normal cells. Simultaneously targeting multiple pathways may help to kill malignant cells and slow down the onset of drug resistance. Among the different substrates triggered by quercetin, we have reviewed the ability of the molecule to inhibit protein kinases involved in deregulated cell growth in cancer cells.
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