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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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... 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]. ...
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.
... 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. ...
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.
... The ability of quercetin to inhibit xanthine oxidase and lipid peroxidation or its oxygen-scavenging activity exerts its neuroprotective activity [18]. Further, quercetin administration in 3xTg-AD mice has shown reversal of paired helical filaments (PTH), βamyloid (βA) 1-40, and βA 1-42 levels due to inhibition of phosphorylation of AT-8 tau in the brain [19]. Moreover, quercetin has been reported to regulate the Akt/PKB and ERK1/2 signaling pathway by impeding the activity of PI3K, resulting in its neurotropic effect [20]. ...
... It has been reported that the administration of AlCl3 is responsible for oxidative stress, which leads to the peroxidation of lipid membranes and cell apoptosis. Further, the dysfunction of neuronal cells and progressive death of neurons are also associated with oxidative stress [19,56]. ...
Recent evidences indicate that there is a substantial increase in worldwide cases of dementia. Alzheimer's disease is the leading cause of dementia and may contribute to 60–70% of cases. Quercetin is a unique bioflavonoid that has numerous therapeutic benefits such as anti-allergy, anti-ulcer, anti-inflammatory, anti-hypertensive, anti-cancer, immuno-modulatory, anti-infective, antioxidant, acetylcholinesterase inhibitory activity, neuroprotective effects, etc. In the present study, we evaluated the neuroprotective effect of orally administered quercetin with memantine in albino Wistar rats after inducing neurotoxicity through AlCl3 (100 mg/kg, p.o.). Chronic administration of AlCl3 resulted in poor retention of memory and significant oxidative damage. Various behavioral parameters, such as locomotor activity, Morris water maze, elevated plus maze, and passive avoidance test, were assessed on days 21 and 42 of the study. The animals were euthanatized following the completion of the last behavioral assessment. Various oxidative stress parameters were assessed to know the extent of oxidative damage to brain tissue. Quercetin with memantine has shown significant improvement in behavioral studies, inhibition of AChE activity, and reduction in oxidative stress parameters. Histopathological studies assessed for cortex and hippocampus using hematoxylin and eosin (H&E), and Congo red stain demonstrated a reduction in amyloid-β plaque formation after treatment of quercetin with memantine. Immunohistochemistry showed that quercetin with memantine treatment also improved the expression of brain-derived neurotrophic factor (BDNF) and inhibited amyloid-β plaque formation. The present study results demonstrated protective effects of treatment of quercetin with memantine in the neurotoxicity linked to aluminum chloride in albino Wistar rats .
... Compared to galantamine, quercetin showed slightly lower inhibitory activity and could not completely inhibit AChE. Furthermore, it was considered a potential bioactivity compound that could prevent both β-amyloidosis and tau hyperphosphorylation [16]. Quercetin demonstrated a considerably lower IC50 value than taxifolin (54.01 ± 1.58 µM, saturated bond between C2 and C3) [30], indicating that the double bond at positions C2 and C3 of the C-ring in phenylchromone played an important role in inhibiting the activity of AChE [31,32]. ...
... Furthermore, the PAS site possibly has a critical effect in accelerating the deposition and aggregation of β-amyloid peptides, indicating that the interaction between quercetin and PAS might reduce nerve injury caused by aggregation of Aβ-amyloid protein [47]. The result was consistent with that of Sabogal-Guaqueta, who demonstrated that quercetin significantly reduced extracellular Aβ-amyloid deposition in cerebral brain regions in a 3xTg-AD mouse model [16]. ...
This study investigated the inhibitory mechanism of quercetin in acetylcholinesterase (AChE) and its neuroprotective effects on β-amyloid25–35-induced oxidative stress injury in PC12 cells. Quercetin inhibited AChE in a reversible mixed manner with an IC50 of 4.59 ± 0.27 µM. The binding constant of quercetin with AChE at 25 °C was (5.52 ± 0.05) × 104 L mol−1. Hydrogen bonding and van der Waals forces were the main interactions in forming the stable quercetin–AChE complex. Computational docking revealed that quercetin was dominant at the peripheral aromatic site in AChE and induced enzymatic allosterism; meanwhile, it extended deep into the active center of AChE and destabilized the hydrogen bond network, which caused the constriction of the gorge entrance and prevented the substrate from entering the enzyme, thus resulting in the inhibition of AChE. Molecular dynamics (MD) simulation emphasized the stability of the quercetin–AChE complex and corroborated the previous findings. Interestingly, a combination of galantamine hydrobromide and quercetin exhibited the synergistic inhibition effect by binding to different active sites of AChE. In a β-amyloid25–35-induced oxidative stress injury model in PC12 cells, quercetin exerted neuroprotective effects by increasing the glutathione level and reducing the malondialdehyde content and reactive oxygen species levels. These findings may provide novel insights into the development and application of quercetin in the dietary treatment of Alzheimer’s disease.
... Studies showed that quercetin could modulate Nrf-2 translocation from cytoplasm to nucleus, protect mitochondrial dysfunction [116]. Besides, Quercetin was identified to inhibit Aβ plaque aggregation and neurofibrillary tangles formation [116,117]. ...
... Quercetin was proven to improve cognitive functioning in the APPswe/PS1dE9 transgenic AD model mouse by reducing plaque mitochondrial dysfunction through the activation of AMPK [116]. Quercetin was identified to reverse histological hallmarks of AD and protect cognitive and emotional function in aged triple transgenic AD model (3xTg-AD) mice [117]. Rutin (C 27 H 30 O 16 ), 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chrome n-3-yl-6-O-(6-deoxy-α-L-mannopyrano-syl)-β-D-glucopyranoside, is a glycone of quercetin with a flavonol structure. ...
Background
Millions of people suffer from Alzheimer's disease (AD) and Parkinson's disease (PD) worldwide. Due to their complex pathology, no effective pharmacological treatment has been found to date, despite extensive research. Developing new, effective therapeutic agents to cure these disease remains a major challenge. Although the cause of AD and PD remains illusive, numerous studies indicates that oxidative stress and neuro-inflammation lead to neurodegeneration in the central nervous system and play vital role in AD and PD morbidity and progression. Flavonoids, which are found widely in nature, exhibit anti-oxidative, anti-inflammatory, anti-mutative, anti-microbial, and neuroprotective properties, so have potential to treat these two kinds of diseases.
Methods
In this review, we focus on the anti-oxidative and neuroprotective action of flavonoids in attenuating Alzheimer's and Parkinson's disease, and how they might be harnessed in the development of new pharmacological agents to treat these two diseases.
Result
Some flavonoid compounds, like hesperidin, naringin, naringenin, tangeretin, nobiletin, silibinin, Epigallocatechin-3-gallate, displayed to be effective in both AD and PD.
Conclusion
Considerable studies have demonstrated the anti-AD and anti-PD effects of flavonoids through various in vitro and in vivo models. However, more rigorous studies are needed to be done for flavonoids to develop into effective drugs and apply them to clinical practice.
... Tandon et al.,(2012) A quercetina (3,3',4',5,7-penta-hidroxiflavona) é um dos principais flavonoides que fez parte da dieta humana, encontrada também em vegetais e frutas como, cebolas, maçãs e vinho tinto (Babaei, et al., 2018;Sabogal-Guáqueta, et al., 2015). É uma molécula com propriedade neuroprotetora, capaz de atravessar a barreira hematoencefálica e que pode aumentar a resistência neuronal por possuir atividade antioxidante (Vargas-Restrepo, et al., 2018;Moreno et al., 2017). ...
... É uma molécula com propriedade neuroprotetora, capaz de atravessar a barreira hematoencefálica e que pode aumentar a resistência neuronal por possuir atividade antioxidante (Vargas-Restrepo, et al., 2018;Moreno et al., 2017). Além disso, a quercetina possui efeito ansiolítico e melhora a cognição, modulando vias de sinalização e diminuindo a inflamação (Sabogal-Guáqueta et al., 2015). ...
A Doença de Alzheimer (DA) representa a principal causa de demência em todo o mundo. Exemplos de abordagens promissoras na investigação de produtos contra a DA é a avaliação in vitro da inibição da enzima acetilcolinesterase e da proteção contra o stress oxidativo induzido em células neuronais por H2O2, já utilizadas em extratos de P. guajava. Este trabalho tem o objetivo de avaliar in vivo a eficácia do extrato da folha de P. guajava na reversão do déficit de memória de trabalho induzida por escopolamina. Para tanto foram utilizados 33 camundongos Swiss, machos, albinos (35-45g). Animais controle (Ctr) receberam salina, o déficit de memória foi induzido por escopolamina 5 mg/kg (Esc). O extrato etanólico da folha de P. guajava (EFPG) foi diluído em etanol 5% em salina e administrado em duas diferentes concentrações (EFPG 1 e 10 mg/kg). A administração de escopolamina promoveu o déficit na memória de trabalho (alternações espontâneas: Ctr: 69,2 ± 4,9; Esc: 51,8 ± 5,0). Na dose de 10 mg/kg do EEPG, observou-se um bloqueio parcial do déficit de memória (Esc + EEPG 10: 62,6 ± 3,1). Não foram observadas alterações estatisticamente significativas entre os grupos quando se avaliou o número de entradas nos braços durante o teste (Eventos: Ctr: 22,9±2,7; Esc: 28,1±2,9; Esc + EEPG 1: 25,2±3,1; Esc + EEPG 10: 23,6±2,6). Como para o extrato da folha de P. guajava foi relatada atividade anticolinesterásica in vitro, o presente trabalho contribui para adicionar evidências do seu potencial terapêutico para o tratamento da Doença de Alzheimer.
... 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. ...
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.
... Its antioxidant activity scavenges free radicals and reduces the formation of phenoxyl radicals; it is widely used in medicine and dietary supplementation as a phytochemical remedy. Quercetin has shown protection against oxidative damage in various in vitro and in vivo models [83]. Quercetin and rutin not only suppressed A formation but also disaggregated A fibrils in AD and prevented scopolamine-induced amnesia in animal model [84]. ...
... The oral bioavailability is improved by encapsulating quercetin in nano-sized vectors, which enhance its antioxidant and anti-inflammatory action. Quercetin is reported for various nano-formulations, like solid lipid nanoparticles [107], lipid-coated nanocapsules and PLGA encapsulated ( Table 1 and Fig. 1) [75,83,[129][130][131][132][133][134][135][136]. Cur-PEG-PLA-NPs were used in Tg2576 AD model of mice for neurodegenerative disease treatments and were shown to easily cross the BBB; significant in vivo and in vitro mechanisms were observed. ...
Neurodegenerative diseases are a heterogeneous group of disorders among aging populations worldwide characterized by the progressive degeneration of the structure and function of brain cells and the nervous system. Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases (NDs). Classic pathological features of AD are the accumulation of the amyloid betaprotein and aggregates of hyperphosphorylated tau protein around the brain cells. Dopaminergic neuronal death in the midbrain and accumulation of β- synuclein in the neurons are the hallmark of Parkinson’s disease. The pathogenesis is multifactorial, and both neurodegenerative disorders have complex etiology. Oxidative stress closely linked with mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity, and neuro-inflammation, is anticipated to trigger neuronal death. Ample evidence has implicated that oxidative stress and inflammation contribute to the pathology of neurodegeneration in AD and PD. Currently, acetylcholinesterase inhibitors are the main treatment option for AD, while LDOPA is the gold standard therapy for PD. Along with the main therapy, many endogenous antioxidants, like vitamin E, selenium, etc., are also given to the patients to combat oxidative stress. Current treatment for these NDs is limited due to the blood–brain barrier (BBB) that hinders drug targeting towards neurons. In this review, we emphasize adjunct treatment with anti-inflammatory agents that act at the site of the disease and can halt the disease progression by attenuating the effect of ROS triggering neuro-inflammatory response. Polyphenols, either as purified compounds or extracts from various natural plant sources, have been well studied and documented for anti-inflammatory effects, but their use for ND is limited due to their physicochemical attributes. Nanoparticle-mediated drug delivery system exhibits immense potential to overcome these hurdles in drug delivery to the CNS, enabling nanoparticle-based therapies to directly target the inflammation and release bioactive compounds with anti-inflammatory properties to the site of action.
... Knocking down of TRKB counteracted the neurite outgrowth enhancing effect of the test flavones against Aβ toxicity, further elaborating the neuroprotective action of quercetin and apigenin against Aβ toxicity by enhancing TRKB signaling. Meanwhile, quercetin protects cognitive and emotional function in old 3×Tg-AD mice (Sabogal-Guaqueta et al., 2015), and improves the decays of learning and memory induced by Aβ (Li et al., 2017). Apigenin influences APP processing and reduces Aβ accumulation through down-regulation of β-secretase (Zhao et al., 2013). ...
Alzheimer's disease (AD) is a neurodegenerative disease with progressive memory loss and the cognitive decline. AD is mainly caused by abnormal accumulation of misfolded amyloid β (Aβ), which leads to neurodegeneration via a number of possible mechanisms such as down-regulation of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TRKB) signaling pathway. 7,8-Dihydroxyflavone (7,8-DHF), a TRKB agonist, has demonstrated potential to enhance BDNF-TRKB pathway in various neurodegenerative diseases. To expand the capacity of flavones as TRKB agonists, two natural flavones quercetin and apigenin, were evaluated. With tryptophan fluorescence quenching assay, we illustrated the direct interaction between quercetin/ apigenin and TRKB extracellular domain. Employing Aβ folding reporter SH-SY5Y cells, we showed that quercetin and apigenin reduced Aβ-aggregation, oxidative stress, caspase-1 and acetylcholinesterase activities, as well as improved the neurite outgrowth. Treatments with quercetin and apigenin increased TRKB Tyr516 and Tyr817 and downstream cAMP-response-element binding protein (CREB) Ser133 to activate transcription of BDNF and BCL2 apoptosis regulator (BCL2), as well as reduced the expression of pro-apoptotic BCL2 associated X protein (BAX). Knockdown of TRKB counteracted the improvement of neurite outgrowth by quercetin and apigenin. Our results demonstrate that quercetin and apigenin are to work likely as a direct agonist on TRKB for their neuroprotective action, strengthening the therapeutic potential of quercetin and apigenin in treating AD.
... It was stated that quercetin nanoparticles could be used to prevent or delay the onset of AD [146]. In transgenic AD model mice, quercetin reduced Aβ-mediated cytotoxicity, tauopathy, and histopathological symptoms, and improved cognitive and emotional impairments without adverse effects [147]. Quercetin has beneficial properties against mechanisms of AD pathology, as shown in various in vitro and in vivo models. ...
Neurodegenerative diseases occur due to progressive and sometimes irreversible loss of function and death of nerve cells. A great deal of effort is being made to understand the pathogenesis of neurodegenerative diseases. In particular, the prevalence of Alzheimer's disease (AD) is quite high, and only symptomatic therapy is available due to the absence of radical treatment. The aim of this review is to try to elucidate the general pathogenesis of AD, to provide information about the limit points of symptomatic treatment approaches, and to emphasize the potential neurologic effects of phytocompounds as new tools as therapeutic agents for disease prevention, retardation, and therapy. This survey also covers the notable properties of herbal compounds such as their effects on the inhibition of an enzyme called acetylcholinesterase, which has significant value in the treatment of AD. It has been proven that phytopharmaceuticals have long-term effects that could protect nervous system health, eliminate inflammatory responses, improve cognitive damage, provide anti-aging effects in the natural aging process, and alleviate dementia sequelae. Herbal-based therapeutic agents can afford many advantages and can be used as potentially as new-generation therapeutics or complementary agents with high compliance, fewer adverse effects, and lower cost in comparison to the traditional pharmaceutical agents in the fight against AD.
... It inhibits the formation of Aβ 1-42 fibrils and oxidative stress in cell-based models [90,91]. Quercetin reduces Aβ1-40 and Aβ1-42 formation and improves cognitive functions in the AD mouse model [92]. Reduced acetylcholine receptors and increased acetylcholinesterase activity in AD cause hyperphosphorylation of Tau protein, reduced secretion of soluble amyloid precursor protein (APP) and increased synthesis of Aβ. ...
Healthy diet is vital to cellular health. The human body succumbs to numerous diseases which afflict severe economic and psychological burdens on the patient and family. Oxidative stress is a possible crucial regulator of various pathologies, including type 2 diabetes and neurodegenerative diseases. It generates reactive oxygen species (ROS) that trigger the dysregulation of essential cellular functions, ultimately affecting cellular health and homeostasis. However, lower levels of ROS can be advantageous and are implicated in a variety of signaling pathways. Due to this dichotomy, the terms oxidative “eustress,” which refers to a good oxidative event, and “distress,” which can be hazardous, have developed. ROS affects multiple signaling pathways, leading to compromised insulin secretion, insulin resistance, and β-cell dysfunction in diabetes. ROS is also associated with increased mitochondrial dysfunction and neuroinflammation, aggravating neurodegenerative conditions in the body, particularly with age. Treatment includes drugs/therapies often associated with dependence, side effects including non-selectivity, and possible toxicity, particularly in the long run. It is imperative to explore alternative medicines as an adjunct therapy, utilizing natural remedies/resources to avoid all the possible harms. Antioxidants are vital components of our body that fight disease by reducing oxidative stress or nullifying the excess toxic free radicals produced under various pathological conditions. In this review, we focus on the antioxidant effects of components of dietary foods such as tea, coffee, wine, oils, and honey and the role and mechanism of action of these antioxidants in alleviating type 2 diabetes and neurodegenerative disorders. We aim to provide information about possible alternatives to drug treatments used alone or combined to reduce drug intake and encourage the consumption of natural ingredients at doses adequate to promote health and combat pathologies while reducing unwanted risks and side effects.
... Sabogal-Guáqueta et al. performed a study to evaluate the in vivo neuroprotective effect of quercetin treatment (25 mg/kg, every 48 h for three months) in aged triple transgenic mice of the AD model (3xTg-AD). The results demonstrated that quercetin improves learning and memory function by decreasing Aβ1-40, Aβ1-42, and BACE1 levels and the paired helical filament (PHF) as well as reducing microglial activation [113]. The 10 mg/kg dose of quercetin administered to rats injected with Aβ1-40 intrahippocampally was found to improve learning and memory and short-term spatial recognition memory in a Y-maze test. ...
Alzheimer’s disease remains one of the most widespread neurodegenerative reasons for dementia worldwide and is associated with considerable mortality and morbidity. Therefore, it has been considered a priority for research. Indeed, several risk factors are involved in the complexity of the therapeutic ways of this pathology, including age, traumatic brain injury, genetics, exposure to aluminum, infections, diabetes, vascular diseases, hypertension, dyslipidemia, and obesity. The pathophysiology of Alzheimer’s disease is mostly associated with hyperphosphorylated protein in the neuronal cytoplasm and extracellular plaques of the insoluble β-amyloid peptide. Therefore, the management of this pathology needs the screening of drugs targeting different pathological levels, such as acetylcholinesterase (AchE), amyloid β formation, and lipoxygenase inhibitors. Among the pharmacological strategies used for the management of Alzheimer’s disease, natural drugs are considered a promising therapeutic strategy. Indeed, bioactive compounds isolated from different natural sources exhibit important anti-Alzheimer effects by their effectiveness in promoting neuroplasticity and protecting against neurodegeneration as well as neuroinflammation and oxidative stress in the brain. These effects involve different sub-cellular, cellular, and/or molecular mechanisms, such as the inhibition of acetylcholinesterase (AchE), the modulation of signaling pathways, and the inhibition of oxidative stress. Moreover, some nanoparticles were recently used as phytochemical delivery systems to improve the effects of phytochemical compounds against Alzheimer’s disease. Therefore, the present work aims to provide a comprehensive overview of the key advances concerning nano-drug delivery applications of phytochemicals for Alzheimer’s disease management.
... Similarly, chronic administration of the flavone baicalein decreases Aβ production . Quercetin (3,5,7,3′,4′-pentahydroxyflavone) is a dietary flavonol widely distributed in plants, fruits and vegetables, and it is also effective at modulating contents of soluble and insoluble Aβ in the brain (Sabogal-Guaqueta et al., 2015;Moreno et al., 2017). Altogether, these results show that select polyphenols can modulate α-secretase or BACE activities and reduce Aβ production both in vitro and in vivo, however, there has been very few research on mechanisms of action and how select polyphenols promote non-amyloidogenic or inhibit amyloidogenic processing of APP. ...
Alzheimer′s disease (AD) is an irreversible progressive neurodegenerative disease affecting approximately 50 million people worldwide. It is estimated to reach 152 million by the year 2050. AD is the fifth leading cause of death among Americans age 65 and older. In spite of the significant burden the disease imposes upon patients, their families, our society, and our healthcare system, there is currently no cure for AD. The existing approved therapies only temporarily alleviate some of the disease’s symptoms, but are unable to modulate the onset and/or progression of the disease. Our failure in developing a cure for AD is attributable, in part, to the multifactorial complexity underlying AD pathophysiology. Nonetheless, the lack of successful pharmacological approaches has led to the consideration of alternative strategies that may help delay the onset and progression of AD. There is increasing recognition that certain dietary and nutrition factors may play important roles in protecting against select key AD pathologies. Consistent with this, select nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory, and neurotrophic properties and as such, could serve as lead candidates for further novel AD therapeutic developments. Here we summarize some of the more promising dietary phytochemicals, particularly polyphenols that have been shown to positively modulate some of the important AD pathogenesis aspects, such as reducing β-amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation, and synapse loss. We also discuss the recent development of potential contribution of gut microbiome in dietary polyphenol function.
... In addition, previous studies have demonstrated that QCN exhibits diverse biological activities, including antioxidant [23], anti-inflammatory [24], and anticancer [25,26] effects. Moreover, the neuroprotective effect of QCN has been reported in a number of animal models, such as neurodegeneration [27][28][29], cerebral ischemia [30], traumatic brain injury [31,32], and spinal cord injury (SCI) Conclusions: Taken together, these findings have for the first time unequivocally indicated that QCN has promising potential for further development into a novel therapeutic in conjunction with reimplantation surgery for the treatment of BPA. [33][34][35]. ...
Highlights • Quercetin (QCN) promotes motoneuron survival and accelerates axonal regeneration after brachial plexus root avulsion/re-implantation in rats. • QCN improves motor function recovery of the forelimb. • QCN exhibits neuroprotective effects via inhibiting neuroinflammation and upregulating the neurotrophins. • QCN alleviates the avulsion-induced oxidative damage in rats. • QCN inhibits the avulsion-induced neuronal apoptosis in rats. • QCN modulates Nrf2/HO-1 and neurotrophin/Akt/MAPK signaling pathways.
... Contrary to these results, another study revealed that quercetin reduced paired helical filament (PHF) and β-amyloid (βA) levels by lowering BACE1mediated cleavage of APP (into CTFβ) on triple transgenic AD mice. Consequently, this improved performance on learning and spatial memory based on the elevated plus maze test (Sabogal-Guáqueta et al., 2015). In silico studies with crystal structure analysis of the Sirt6 and Sirt2 complexes, it was reported that quercetin activated Sirt6-dependent deacetylation by binding to the acyl channel Sirt6 (You et al., 2019). ...
Dietary compounds from the foods we eat on a daily basis offer several benefits; they help prevent disease and preserve health. The epigenetic advantages of the vegetables we eat every day are one of the benefits that have not been well-reported. Epigenetic pathways involving histone modification, DNA methylation, and alterations caused by miRNAs are extensively engaged in signal transmission, cell development, and death in various disease states, including brain cells. Through this narrative review collected from multiple studies available on reputable online databases until March 2022 shows the epigenetic advantages of various vegetables' content such as gallic acid, quercetin, kaempferol, apigenin, luteolin, resveratrol, genistein, sulforaphane, and diallyl disulfide in neurodegenerative conditions are summarized. However, in-depth investigations are still required to clarify these epigenetic mechanisms before these compounds are ready to be used in the future, as several studies still provide contradictory results
... Fisetin exhibited a neuroprotective effect through suppression of amyloid load, β-secretase level modulation, and inhibition of tau hyperphosphorylation. It has been reported that the flavonol quercetin alleviates cognitive dysfunction caused by AD pathology in a triple transgenic AD mouse model [121]. The neuroprotective effects of quercetin are mediated through its ability to minimize the effects of Aβ-amyloidosis and tauopathy. ...
Neurotoxicity occurs in Alzheimer’s disease due to the formation of Amyloid-β peptide aggregates and damage caused by oxidative stress. Upon aggregation of amyloid-β peptides, oxidative stress is generated; however, oxidative stress can also promote excess amyloid-β peptide production and aggregate formation. Currently available therapeutic options are little effective against Alzheimer’s disease, and they cannot stop the progression of the disease. As a new therapeutic alternative rather than inhibiting amyloid-β peptide production, inhibiting amyloid-β peptide aggregation along with oxidative stress management may be more effective considering that these processes are not typically associated with normal physiology. In addition to antiamyloidogenic properties, flavonoids exhibit antioxidant properties as well. The structural features of flavonoids that are needed for these two activities are similar. Even oxidized flavonoids are more likely to inhibit the aggregation of Amyloid-β peptides. Thus, the discovery of flavonoids with superior antioxidant activity could lead to the identification of better aggregation inhibitors. Despite flavonoids having the potential to be used as drugs, there are no medications that can be used to treat Alzheimer’s disease. This review describes how the structural features of different flavonoids affect their antiamyloidogenic and antioxidant activities, which may help develop future therapeutics for Alzheimer’s disease.
Graphical abstract
... Additionally, grape juice has a positive effect on the maintenance of protection and improves the health of the brain's circulatory system [99]. The study by Sabogal M. et al. observed that quercetin reverses the histopathological features of Alzheimer's disease and alleviates cognitive and emotional impairment in mice with the triple transgenic Alzheimer's disease model [102]. Additionally, of note is the prospective environmental study conducted as part of the Rush Memory and Aging Project. ...
Alzheimer’s disease is a progressive brain disease that is becoming a major health problem in today’s world due to the aging population. Despite it being widely known that diet has a significant impact on the prevention and progression of Alzheimer’s disease, the literature data are still scarce and controversial. The application of the principles of rational nutrition for the elderly is suggested for Alzheimer’s disease. The diet should be rich in neuroprotective nutrients, i.e., antioxidants, B vitamins, and polyunsaturated fatty acids. Some studies suggest that diets such as the Mediterranean diet, the DASH (Dietary Approaches to Stop Hypertension) diet, and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet have a beneficial effect on the risk of developing Alzheimer’s disease.
... Evidence-Based Complementary and Alternative Medicine ameliorate Alzheimer's disease pathology (such as β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala) and recover cognitive deficits in triple transgenic Alzheimer's disease model mice [52,53]. Another study has shown that quercetin can ameliorate hippocampus-dependent learning and memory deficits in mice fed with high fat diet through attenuating oxidative stress by activating antioxidant signaling system [54]. ...
Convolvulus pluricaulis (CP), a Medhya Rasayana (nootropic) herb, is a major ingredient in Ayurvedic and Traditional Chinese formulae indicated for neurological conditions, namely, dementia, anxiety, depression, insanity, and epilepsy. Experimental evidence suggests various neuroactive potentials of CP such as memory-enhancing, neuroprotective, and antiepileptic. However, precise mechanisms underlying the neuropharmacological effects of CP remain unclear. The study, therefore, aimed at deciphering the molecular basis of neuroprotective effects of CP phytochemicals against the pathology of dementia disorders such as Alzheimer’s (AD) and Parkinson’s (PD) disease. The study exploited bioinformatics tools and resources, such as Cytoscape, DAVID (Database for annotation, visualization, and integrated discovery), NetworkAnalyst, and KEGG (Kyoto Encyclopedia of Genes and Genomes) database to investigate the interaction between CP compounds and molecular targets. An in silico analysis was also employed to screen druglike compounds and validate some selective interactions. ADME (absorption, distribution, metabolism, and excretion) analysis predicted a total of five druglike phytochemicals from CP constituents, namely, scopoletin, 4-hydroxycinnamic acid, kaempferol, quercetin, and ayapanin. In network analysis, these compounds were found to interact with some molecular targets such as prostaglandin G/H synthase 1 and 2 (PTGS1 and PTGS2), endothelial nitric oxide synthase (NOS3), insulin receptor (INSR), heme oxygenase 1 (HMOX1), acetylcholinesterase (ACHE), peroxisome proliferator-activated receptor-gamma (PPARG), and monoamine oxidase A and B (MAOA and MAOB) that are associated with neuronal growth, survival, and activity. Docking simulation further confirmed interaction patterns and binding affinity of selected CP compounds with those molecular targets. Notably, scopoletin showed the highest binding affinity with PTGS1, NOS3, PPARG, ACHE, MAOA, MAOB, and TRKB, quercetin with PTGS2, 4-hydroxycinnamic acid with INSR, and ayapanin with HMOX1. The findings indicate that scopoletin, kaempferol, quercetin, 4-hydroxycinnamic acid, and ayapanin are the main active constituents of CP which might account for its memory enhancement and neuroprotective effects and that target proteins such as PTGS1, PTGS2, NOS3, PPARG, ACHE, MAOA, MAOB, INSR, HMOX1, and TRKB could be druggable targets against dementia.
... It was noted that quercetin glucosides, a kind of flavonoid, exert therapeutic effects on animal models of neurodegeneration or neurotoxicity by inhibiting the fibrillar formation of Aβ protein, interfering with cellular lysis and inflammatory cascades (Aliev et al., 2008;Belo et al., 2013;Davis et al., 2009). Also, quercetin glucoside has the ability to reduce lipid peroxidation and ultimately protect the oxidative damage of neurons, thereby improving learning, memory, and cognitive functions via activating AMPK activity and decreasing mitochondrial dysfunction in animal models (Sabogal-Guaqueta et al., 2015;Singh et al., 2016;Wang et al., 2014). Furthermore, antioxidant activity containing various natural compounds including quercetin glucosides can restore brain AChE activity in metal-exposed experimental animals (Abdalla et al., 2013;Gonçalves et al., 2010;Schmatz et al., 2009;Gutierres et al., 2012). ...
Arsenic (As) poisoning has caused an environmental catastrophe in Bangladesh as millions of people are exposed to As-contaminated drinking water. Chronic As-exposure causes depression, memory impairment, and liver injury in experimental animals. This study was carried out to assess the protective effect of mulberry leaves juice (Mul) against As-induced neurobehavioral and hepatic dysfunctions in Swiss albino mice. As-exposed mice spent significantly reduced time in open arms and increased time spent in closed arms in the elevated plus maze (EPM) test, whereas they took significantly longer time to find the hidden platform in the Morris water maze (MWM) test and spent significantly less time in the desired quadrant when compared to the control mice. A significant reduction in serum BChE activity, an indicator of As-induced neurotoxicity-associated behavioral changes, was noted in As-exposed mice compared to control mice. Supplementation of Mul to As-exposed mice significantly increased serum BChE activity, increased the time spent in open arms and reduced time latency to find the hidden platform, and stayed more time in the target quadrant in EPM and MWM tests, respectively, compared to As-exposed-only mice. Also, a significantly reduced activity of BChE, AChE, SOD, and GSH in brain, and elevated ALP, AST, and ALT activities in serum were noted in As-exposed mice when compared to control mice. Mul supplementation significantly restored the activity of these enzymes and also recovered As-induced alterations in hepatic tissue in As-exposed mice. In conclusion, this study suggested that mulberry leaves juice attenuates As-induced neurobehavio-ral and hepatic dysfunction in mice. K E Y W O R D S anxiety, arsenic exposure, learning and memory, oxidative stress
... Quercetin found in the petals of N. nucifera, exerts a potential neuroprotective effect [71]. Quercetin administration protected against cognitive impairment in AD mice, reversing β-amyloidosis in the hippocampus and the amygdala [72]. However, these neuroprotective effects of quercetin are mainly associated with its antioxidant properties [73]. ...
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.
... 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). ...
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.
... 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]. ...
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. ...
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.
... Similarly, other plants such as Picrorhiza kurroa Royle and Centella asiatica were utilized owing to their antioxidant, anti-inflammatory as well as neuroprotective properties in ND (Krupashree et al. 2014;Lee et al. 2007;Pointel et al. 1987;Veerendra Kumar and Gupta 2002). Moreover, one of the extensively studied polyphenols, quercetin, was shown to significantly reduce oxidative stress thus inhibiting cytotoxicity and apoptosis (Ansari et al. 2009) and improve cognitive and emotional functions as well as inhibit proinflammatory mediators in neurodegenerative animal models (de Andrade Teles et al. 2018;Sabogal-Guáqueta et al. 2015). ...
t Traumatic brain injury (TBI) is one of the key causes of deaths and
disabilities worldwide. TBI progresses in two phases. The primary phase of injury is the direct result of the physical damage caused by the external force applied to the brain while the secondary injury takes place minutes to days after the primary injury. The secondary phase of TBI is marked by a series of pathological events that start following the initial mechanical impact. The mechanisms underlying TBI pathogenesis in the secondary phase are intricate and include metabolic alterations, excitotoxicity, oxidative stress, and neuroinflammation, among others; all culminating in neuronal cell damage and death. Currently, there is no FDA-licensed drug that
targets TBI. Hence, the search for novel therapeutic agents that can target one or more of the mechanisms underlying the pathology of the secondary phase of TBI is warranted. Such novel therapeutic agents are expected to ameliorate the adverse consequences of TBI
... 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. ...
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. ...
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.
... 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. ...
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.
... 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. ...
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.
Previous reports revealed that peel extracts of Ficus carica (fig) have a wide range of pharmacological and biological activities. The current study aimed to determine the phytochemical components of the ethanol extracts of Peggy Red fig (PRF) and Green fig (GF) peels by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, along with its antioxidant properties and neuroprotective effect in Caenorhabditis elegans. LC-MS/MS analysis confirmed 50 compounds in the extract, which revealed the presence of phenols, flavonoids, and anthocyanins, and exhibited in vitro antioxidant activity. PRF and GF peel had 163.25 (mg gallic acid equivalent [mg GAE]) g-1, 125.32 (mg GAE) g-1 of total phenolic content, 62.52 (mg rutin equivalent [mg RE]) g-1, and 43.36 (mg RE) g-1 flavonoids content, respectively. In all antioxidant assays, the extract of PRF peel showed higher antioxidant activity than the GF peel, and the extract of PRF peel could effectively reduce the aggregation of amyloid-beta (Aβ), decrease the paralysis of the body, and increase the antioxidant enzyme activities to reduce the toxicity of Aβ1-42 in Alzheimer's disease (AD) transgenic C. elegans CL4176. Therefore, PRF peel extract may have potential applications as a new source for drug development against AD.
Objective:
This study aimed to examine the effects of quercetin glycoside-containing beverages on cognitive function and cerebral blood flow (CBF) in adult men and women aged between 60 and 75 years.
Patients and methods:
Eighty healthy men and women with no cognitive impairment and aware of ageing-related forgetfulness underwent a placebo-controlled, randomized, double-blind, and parallel-group trial. They regularly consumed 500 mL of beverage containing 110 mg of quercetin glycoside as isoquercitrin for 40 weeks. Cognitive function assessment by Cognitrax was the endpoint of the study. The participants were assessed for CBF, health-related quality of life, as well as physical, biological, and hematological parameters, and lateral index.
Results:
Cognitrax demonstrated that the reaction time significantly improved in the quercetin glycoside intake group. The CBF measurement suggested that quercetin glycoside intake could likely suppress the decrease in cerebral blood volume, CBF, and cerebral activity owing to stress alleviation and inhibition of the accumulation of amyloid β (Aβ), a waste product in the brain, although there were no significant differences between the groups.
Conclusions:
Quercetin glycoside intake as a beverage could improve reaction time and may potentially inhibit the decrease in CBF and suppress Aβ accumulation.
Bioactive ingredients from natural products have always been an important resource for the discovery of drugs for Alzheimer's disease (AD). Senile plaques, which are formed with amyloid-beta (Aβ) peptides and excess metal ions, are found in AD brains and have been suggested to play an important role in AD pathogenesis. Here, we attempted to design an effective and smart screening method based on cheminformatics approaches to find new ingredients against AD from Vaccinium myrtillus (bilberry) and verified the bioactivity of expected ingredients through experiments. This method integrated advanced artificial intelligence models and target prediction methods to realize the stepwise analysis and filtering of all ingredients. Finally, we obtained the expected new compound malvidin-3-O-galactoside (Ma-3-gal-Cl). The in vitro experiments showed that Ma-3-gal-Cl could reduce the OH· generation and intracellular ROS from the Aβ/Cu ²⁺ /AA mixture and maintain the mitochondrial membrane potential of SH-SY5Y cells. Molecular docking and Western blot results indicated that Ma-3-gal-Cl could reduce the amount of activated caspase-3 via binding with unactivated caspase-3 and reduce the expression of phosphorylated p38 via binding with mitogen-activated protein kinase kinases-6 (MKK6). Moreover, Ma-3-gal-Cl could inhibit the Aβ aggregation via binding with Aβ monomer and fibers. Thus, Ma-3-gal-Cl showed significant effects on protecting SH-SY5Y cells from Aβ/Cu ²⁺ /AA induced damage via antioxidation effect and inhibition effect to the Aβ aggregation.
Neurodegenerative diseases are the most widely affected disease condition in an aging population. The treatment available reduces the elevated manifestations but is ineffective due to the drug’s poor bioavailability, plasma stability, and permeability across the blood-brain barrier (BBB). Until now, no therapeutic compound has been able to stop the progression of neurodegenerative disease. Even the available therapeutic moiety manages it with possible adverse effects up to the later stage. Hence, phytobioactive compounds of plant origin offer effective treatment strategies against neurodegenerative diseases. The only difficulty of these phytobioactive compounds is permeability across the BBB. Engineered nanocarriers such as liposomes provide high lipid permeability across BBB. Liposomes have unique physicochemical properties that are widely investigated for their application in diagnosing and treating neurodegenerative diseases. The surface modification on liposomes by peptides, antibodies, and RNA aptamers offers receptor targeting. These brain-targeted approaches by liposomes improve the efficacy of phytoconstituents. Additional surface modification methods are utilized on liposomes, which increases the brain-targeted delivery of phytobioactive compounds. The marketing strategy of the liposomal delivery system is in its peak mode, where it has the potential to modify the existing therapy. This review will summarize the brain target liposomal delivery of phytobioactive compounds as a novel disease-modifying agent for treating neurodegenerative diseases.
Ficus religiosa (Bo tree or sacred fig) and Ficus benghalensis (Indian banyan) are of immense spiritual and therapeutic importance. Various parts of these trees have been investigated for their antioxidant, antimicrobial, anticonvulsant, antidiabetic, anti-inflammatory, analgesic, hepatopro-tective, dermoprotective, and nephroprotective properties. Previous reviews of Ficus mostly discussed traditional usages, photochemistry, and pharmacological activities, though comprehensive reviews of the neuroprotective potential of these Ficus species extracts and/or their important phy-tocompounds are lacking. The interesting phytocompounds from these trees include many ben-galenosides, carotenoids, flavonoids (leucopelargonidin-3-O-β-d-glucopyranoside, leucopelargo-nidin-3-O-α-l-rhamnopyranoside, lupeol, cetyl behenate, and α-amyrin acetate), flavonols
Quercetin is a naturally occurring bioactive flavonoid abundant in many plants and fruits. Quercetin and its derivatives have shown an array of pharmacological activities in preclinical tests against various illnesses and ailments. Owing to its protective role against oxidative stress and neuroinflammation, quercetin is a possible therapeutic choice for the treatment of neurological disorders. Quercetin and its derivatives can modulate a variety of signal transductions, including neuroreceptor, neuroinflammatory receptor, and redox signaling events. The research on quercetin and its derivatives in neurology-related illnesses mainly focused on the targets, such as redox stress, neuroinflammation, and signaling pathways; however, the function of quercetin and its derivatives on specific molecular targets, such as nuclear receptors and proinflammatory mediators are yet to be explored. Findings showed that various molecular targets of quercetin and its derivatives have therapeutic potential against psychological and neurodegenerative disorders.
Alzheimer's disease (AD) is the leading cause of disabilities in old age and a rapidly growing condition in the elderly population. AD brings significant burden and has a devastating impact on public health, society and the global economy. Thus, developing new therapeutics to combat AD is imperative. Human glutaminyl cyclase (hQC), which catalyzes the formation of neurotoxic pyroglutamate (pE)-modified β-amyloid (Aβ) peptides, is linked to the amyloidogenic process that leads to the initiation of AD. Hence, hQC is an essential target for developing anti-AD therapeutics. Here, we systematically screened and identified hQC inhibitors from natural products by pharmacophore-driven inhibitor screening coupled with biochemical and biophysical examinations. We employed receptor-ligand pharmacophore generation to build pharmacophore models and Phar-MERGE and Phar-SEN for inhibitor screening through ligand-pharmacophore mapping. About 11 and 24 hits identified from the Natural Product and Traditional Chinese Medicine databases, respectively, showed diverse hQC inhibitory abilities. Importantly, the inhibitors TCM1 (Azaleatin; IC50 = 1.1 μM) and TCM2 (Quercetin; IC50 = 4.3 μM) found in foods and plants exhibited strong inhibitory potency against hQC. Furthermore, the binding affinity and molecular interactions were analyzed by surface plasmon resonance (SPR) and molecular modeling/simulations to explore the possible modes of action of Azaleatin and Quercetin. Our study successfully screened and characterized the foundational biochemical and biophysical properties of Azaleatin and Quercetin toward targeting hQC, unveiling their bioactive potential in the treatment of AD.
In recent years, experimental evidence suggested a possible role of the gut microbiota in the onset and development of several neurodegenerative disorders, such as AD and PD, MS and pain. Flavonoids, including anthocyanins, EGCG, the flavonol quercetin, and isoflavones, are plant polyphenolic secondary metabolites that have shown therapeutic potential for the treatment of various pathological conditions, including neurodegenerative diseases. This is due to their antioxidant and anti-inflammatory properties, despite their low bioavailability which often limits their use in clinical practice. In more recent years it has been demonstrated that flavonoids are metabolized by specific bacterial strains in the gut to produce their active metabolites. On the other way round, both naturally-occurring flavonoids and their metabolites promote or limit the proliferation of specific bacterial strains, thus profoundly affecting the composition of the gut microbiota which in turn modifies its ability to further metabolize flavonoids. Thus, understanding the best way of acting on this virtuous circle is of utmost importance to develop innovative approaches to many brain disorders. In this review, we summarize some of the most recent advances in preclinical and clinical research on the neuroinflammatory and neuroprotective effects of flavonoids on AD, PD, MS and pain, with a specific focus on their mechanisms of action including possible interactions with the gut microbiota, to emphasize the potential exploitation of dietary flavonoids as adjuvants in the treatment of these pathological conditions.
Kleeb Bua Daeng formula is a popular traditional remedy sold by the Chao Phya Abhaibhubejhr Hospital, Thailand. This formula contains Piper nigrum L., Nelumbo nucifera Gaertn. and Centella asiatica L. components. A reliable and accurate analytical method for the determination of five major active compounds in this formula was developed and validated. High performance liquid chromatography with a diode-array detector was used to quantify piperine, quercitin, kaempferol, asiaticoside and madecassoside in Kleeb Bua Daeng formula. The separation was carried out using a hypersil C18 column with detection at wavelengths 210, 280 and 370 nm. Gradient chromatographic conditions using a mixture of 0.05% phosphoric acid and acetonitrile allowed for complete resolution of the 5 active compounds. The validation outcomes for accuracy, precision, linearity, limit of detection, limit of quantitation and robustness demonstrated that this HPLC method was accurate and reliable for the simultaneous determination of active compounds in this formula. Hence, this developed and validated HPLC fingerprint method is appropriate for quality control of Kleeb Bua Daeng formula and could be applied to modified Kleeb Bua Daeng formulations.
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.KeywordsAlzheimer’s diseasePolyphenolsRosmarinic acidResveratrolGreen tea polyphenolEGCGCurcuminQuercetin
Ethnopharmacological relevance
Alzheimer's disease (AD) is a multicausal neurodegenerative disease clinically characterized by generalized dementia. The pathogenic process of AD not only is progressive and complex but also involves multiple factors and mechanisms, including β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. As the first-line treatment for AD, cholinesterase inhibitors can, to a certain extent, relieve AD symptoms and delay AD progression. Nonetheless, the current treatment strategies for AD are far from meeting clinical expectations, and more options for AD treatment should be applied in clinical practice.
Aim of the review
The aim of this review was to investigate published reports of C. tinctorius L. and its active constituents in AD treatment through a literature review.
Materials and methods
Information was retrieved from scientific databases including Web of Science, ScienceDirect, Scopus, Google Scholar, Chemical Abstracts Services and books, PubMed, dissertations and technical reports. Keywords used for the search engines were “Honghua” or “Carthamus tinctorius L.” or “safflower” in conjunction with “(native weeds OR alien invasive)”AND “Chinese herbal medicine”.
Results
A total of 47 literatures about C. tinctorius L. and its active constituents in AD treatment through signaling pathways, immune cells, and disease-related mediators and systematically elucidates potential mechanisms from the point of anti-Aβ aggregation, suppressing tau protein hyperphosphorylation, increasing cholinergic neurotransmitters levels, inhibiting oxidative stress, anti-neuroinflammation, ameliorating synaptic plasticity, and anti-apoptosis.
Conclusions
Chinese herbal medicine (CHM) is a treasure endowed by nature to mankind. Emerging studies have confirmed that CHM and its active constituents play a positive role in AD treatment. Carthamus tinctorius L., the most commonly used CHM, can be used with medicine and food, with the effect of activating blood circulation and eliminating blood stasis. In the paper, we have concluded that the existing therapeutic mechanisms of C. tinctorius L. and summarized the potential mechanisms of C. tinctorius L. and its active constituents in AD treatment through a literature review.
The ongoing decline of bee populations and its impact on food security demands integrating multiple strategies. Sublethal impairments associated with exposure to insecticides, affecting the individual and the colony levels, have led to insecticide moratoria and bans. However, legislation alone is not sufficient and remains a temporary solution to an evolving market of insecticides. Here, we ask whether bees can be prophylactically protected against sublethal cognitive effects of two major neurotoxic insecticides, imidacloprid and fipronil, with different mechanisms of action. We evaluated the protective effect of the prophylactic administration of the flavonoid rutin, a secondary plant metabolite, present in nectar and pollen, and known for its neuroprotective properties. Following controlled or ad libitum administration of rutin, foragers of the North American bumble bee B. impatiens received oral administration of the insecticides at sublethal realistic dosages. Learning acquisition, memory retention and decision speed were evaluated using olfactory absolute conditioning of the proboscis extension response. We show that the insecticides primarily impair acquisition but not retention or speed of conditioned response. We further show that the administration of the flavonoid rutin successfully protects the bees against impairments produced by acute and chronic administration of insecticides. Our results suggest a new avenue for the protection of bees against sublethal cognitive effects of insecticides.
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.
Alzheimer's disease (AD) is a severe progressive neurodegenerative condition that shows misfolding and aggregation of proteins contributing to a decline in cognitive function involving multiple behavioral, neuropsychological, and cognitive domains. Multiple epi (genetic) changes and environmental agents have been shown to play an active role in ER stress induction. Neurodegeneration due to endoplasmic reticulum (ER) stress is considered one of the major underlying causes of AD. ER stress may affect essential cellular functions related to biosynthesis, assembly, folding, and post-translational modification of proteins leading to neuronal inflammation to promote AD pathology. Treatment with phytochemicals has been shown to delay the onset and disease progression and improve the well-being of patients by targeting multiple signaling pathways in AD. Phytochemical's protective effect against neuronal damage in AD pathology may be associated with the reversal of ER stress and unfolding protein response by enhancing the antioxidant and anti-inflammatory properties of the neuronal cells. Hence, pharmacological interventions using phytochemicals can be a potential strategy to reverse ER stress and improve AD management. Towards this, the present review discusses the role of phytochemicals in preventing ER stress in the pathology of AD.
Proteostasis refers to the dynamic regulation of protein homeostasis which is mediated by a network of molecular machines responsible for both protein synthesis and degradation. With age and various diseases, proteostasis can be disrupted, leading to the formation of intracellular protein aggregates (Labbadia and Morimoto 2015). Under normal conditions, aggregated proteins are broken down through the ubiquitin-proteasomal system or through activation of the autophagy pathway. In pathological conditions however, these protein degradation pathways can be dysregulated. Protein misfolding is a hallmark of many neurodegenerative disorders and is associated with numerous disease processes in autophagy (Watanabe et al. 2020; Limanaqi et al. 2020).
Stroke is a sudden neurological disorder that occurs due to impaired blood flow to an area of the brain. Stroke can be caused by the blockage or rupture of a blood vessel in the brain, called ischemic stroke and hemorrhagic stroke, respectively. Stroke is more common in men than women. Atrial fibrillation, hypertension, kidney disease, high cholesterol and lipids, genetic predisposition, inactivity, poor nutrition, diabetes mellitus, family history and smoking are factors that increase the risk of stroke. Restoring blood flow by repositioning blocked arteries using thrombolytic agents or endovascular therapy are the most effective treatments for stroke. However, restoring circulation after thrombolysis can cause fatal edema or intracranial hemorrhage, and worsen brain damage in a process known as ischemia–reperfusion injury. Therefore, there is a pressing need to find and develop more effective treatments for stroke. In the past, the first choice of treatment was based on natural compounds. Natural compounds are able to reduce the symptoms and reduce various diseases including stroke that attract the attention of the pharmaceutical industry. Nowadays, as a result of the numerous studies carried out in the field of herbal medicine, many useful and valuable effects of plants have been identified. The death-associated protein kinase (DAPK) family is one of the vital families of serine/threonine kinases involved in the regulation of some biological functions in human cells. DAPK1 is the most studied kinase within the DAPKs family as it is involved in neuronal and recovery processes. Dysregulation of DAPK1 in the brain is involved in the developing neurological diseases such as stroke. Natural products can function in a variety of ways, including reducing cerebral edema, reducing brain endothelial cell death, and inhibiting TNFα and interleukin-1β (IL-1β) through regulating the DAPK1 signal against stroke. Due to the role of DAPK1 in neurological disorders, the aim of this article was to investigate the role of DAPK1 in stroke and its modulation by natural compounds.
Graphical Abstract
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.
Aging is inevitable. Along with reduced ability to maintain the homeostasis of various biological processes, aging gradually deteriorates overall health. Extensive research on the aging brain has identified cellular senescence as a critical risk factor of neurodegeneration and cognitive decline. Associations of cellular senescence with neurodegenerative diseases like Alzheimer’s disease, Down syndrome, Parkinson’s disease, and multiple sclerosis are evident in an extensive body of literature generated over decades of research on aging. Cellular senescence triggers neurodegeneration via a complex interplay of mechanisms including neuroinflammation, mitochondrial dysfunction, oxidative stress burden, deranged protein homeostasis, and compromised nuclear and blood-brain-barrier integrity. Thus, cellular senescence can serve as a primary therapeutic target for various neurodegenerative diseases. This review summarizes the concept of cellular senescence, its role in the aging brain, and how it mediates neurodegeneration in several neurodegenerative disorders. Further, we have also highlighted senolytic therapeutics discovered and employed to ameliorate cellular senescence-associated degenerative diseases. This review can aid in providing directions for repurposing senolytic compounds and finding more therapeutic strategies targeting cellular senescence for the management and treatment of neurodegenerative diseases.
The accumulation of β-amyloid (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer’s disease (AD). The lack of estrogen is one of the risk factors for AD. Quercetin is a phytoestrogen with a chemical structure similar to that of estrogen. However, the mechanism by which quercetin prevents AD is unclear. PC12 cells were cultured with Aβ 25–35 for 24 h. Then the cells were further treated with 17β-estradiol, genistein, and quercetin for another 24 h, respectively. Next, ICI182780 and U0126 were used to study the mechanisms of estrogen-like neuroprotection. Methyl thiazolyl tetrazolium (MTT) assay was performed to detect cell survival. The protein expression was analyzed by immunofluorescence and western blot. The survival of PC12 cells induced by Aβ 25–35 was increased by quercetin. The levels of estrogen receptor α (ERα) and p-extracellular signal-regulated kinase (ERK)1/2 were improved by quercetin, but not those of ERβ. On the contrary, Bcl-2/Bax was increased and the expression of Caspase-3 was decreased. When the cell was pretreated with ICI182780, the p-ERK1/2 and Bcl-2/Bax ratio was decreased, but Caspase-3 expression was increased. In addition, pretreatment with U0126 would reduce Bcl-2/Bax ratio and increase Caspase-3 protein expression. Conclusively, quercetin plays a neuroprotective role through the ER pathway and the mitogen-activated protein kinase (MAPK) pathway. The MAPK signaling pathways could also be activated by quercetin via the mediation of ERα.
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.
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.
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.
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.
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.
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.
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.
Recent studies suggest that moderate red wine consumption reduces the incidence of Alzhei- mer's disease (AD) clinical dementia. Using Tg2576 mice, which model AD-type amyloid beta-protein (A) neuropathology, we tested whether moderate consump- tion of the red wine Cabernet Sauvignon modulates AD-type neuropathology and cognitive deterioration. The wine used in the study was generated using Caber- net Sauvignon grapes from Fresno, California, and was delivered to Tg2576 in a final concentration of 6% ethanol. We found that Cabernet Sauvignon signifi- cantly attenuated AD-type deterioration of spatial mem- ory function and A neuropathology in Tg2576 mice relative to control Tg2576 mice that were treated with either a comparable amount of ethanol or water alone. Chemical analysis showed the Cabernet Sauvignon used in this study contains a very low content of resveratrol (0.2 mg/L), 10-fold lower than the minimal effective concentration shown to promote A clearance in vitro. Our studies suggest Cabernet Sauvignon exerts a ben- eficial effect by promoting nonamyloidogenic process- ing of amyloid precursor protein, which ultimately prevents the generation of A peptides. This study supports epidemiological evidence indicating that moder- ate wine consumption, within the range recommended by the FDA dietary guidelines of one drink per day for women and two for men, may help reduce the relative risk for AD clinical dementia.—Wang, J., Ho, L., Zhao, Z., Seror, I., Humala, N., Dickstein, D. L., Meenakshi- sundaram, T., Percival, S. S., Talcott, S. T., Pasinetti, G. M. Moderate consumption of Cabernet Sauvignon attenuates A neuropathology in a mouse model of Alzheimer's disease. FASEB J. 20, 2313-2320 (2006)
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.
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.
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.
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.
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.
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).
Genetic and pharmacological studies have demonstrated that α2- and α4-containing GABA(A) receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA(A) receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2'-methoxy-6-methylflavone (3-OH-2'MeO6MF) potentiates GABA-induced currents at recombinant α1/2β2, α1/2/4/6β1-3γ2L but not α3/5β1-3γ2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC(50) values between 38 and 106 μM) and occurred in a flumazenil-insensitive manner. 3-OH-2'MeO6MF displayed preference for β2/3- over β1-containing receptors with the highest efficacy observed at α2β2/3γ2L, displaying a 4-11-fold increase in efficacy over α2β1γ2L and α1/4/6-containing subtypes. In contrast, 3-OH-2'MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic α4β2/3δ receptors expressed in oocytes. The affinity of 3-OH-2'MeO6MF for α4β2/3δ receptors (EC(50) values between 1.4 and 2.5 μM) was 10-fold higher than at α4β1δ GABA(A) receptors. 3-OH-2'MeO6MF acted as a full agonist at α4β2/3δ (105% of the maximal GABA response) but as a partial agonist at α4β1δ (61% of the maximum GABA response) receptors. In mice, 3-OH-2'MeO6MF (1-100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2'MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the α2β2/3γ2L and direct activation of α4β2/3δ GABA(A) receptor subtypes.
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.
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.
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.
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.
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.
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.
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.