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The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease

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The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease

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Abstract

One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer’s disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics’ pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence.

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... Consequently, activated microglia produce NFkB, leading the synthesis of proinflammatory mediators that finally signal on neuronal receptors, with reactivation of proteins kinases responsible for tau hyperphosphorylation. In a search of nutraceutical bioactive principles, we can find compounds with tau antiaggregant activity, as well as compounds with antioxidative and anti-inflammatory activities [3][4][5]. ...
... Functional foods are those that are considered beneficial for health and that go beyond simple nutrition: some in their natural form, such as fish or vegetables; others are preparations such as preprobiotics that are important in protecting the organism against chronic diseases and/or pathological disorders [12]. Many bioactive compounds are present in food but at low concentrations, such as flavonoid and anthocyanins in fruits and vegetables, but if used in a concentrate preparation these can be nutraceutical products that strongly contribute to the integral health of individuals [5,13,14]. Smart "drugs" quickly boost cognition. For those seeking a natural approach, four plant extracts improve brain processing speed, memory, learning, and mental concentration: blueberries, rosemary, curcuma, and garlic. ...
... The chemical structure of quercetin consists of three ring structures and five hydroxyl groups. It can cross the blood brain barrier, which is an important feature in the neurodegenerative disease's context [5,19]. Quercetin has multiple properties that are beneficial for human health including anti-inflammatory and antioxidant capacities [19]. ...
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Alzheimer’s disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean shilajit. Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD.
... Alzheimer's categorised as a foremost subtype of dementia disease is a devastating neurodegenerative disease. This is characterised by gradual loss of memory resulting into decrease in behavioural functions such as memory, thinking and language skills (Calfio et al., 2020). Parkinson's disease is the next most common neurodegenerative disorder among men than women on the increase among people of 60 years and above. ...
... Quercetin also protects neuronal cells from neurotoxicity induced by oxidative stress (Li et al., 2020). The in vitro studies have shown that quercetin increases cell survival in neurotoxic conditions and plays a good role in vascular dementia by decreasing the size of ischaemic lesions (Calfio et al., 2020). Banana, Musa paradisica L. (Musaseae) has a prospective for nutraceutical and pharmaceutical value based on its abundance in polyphenolic content especially flavonoids and phenol domicile in their peels and flesh (Oyeyinka & Afolayan, 2020). ...
Article
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A changing lifestyle in food consumption due to the frequent taking of junk drinks based on the fast‐food and ready‐to‐eat concept has brought about overloaded oxidative stress, thus weakening the body's defense mechanism to scavenge free oxygen radicals by destroying antioxidants. Oxidative stress occurs as a result of an imbalance between pro and antioxidant levels in favour of pro‐oxidants resulting in the pathogenesis of neurodegenerative diseases. Though researches on the probable cure for neurodegenerative diseases are on‐going, fruits have been found to play an important dietetic role in preventing neurodegenerative diseases and other physiological disorders. Most fruits have their own valuable, unique active ingredients, having tremendous nutraceutical potentials and therapeutic implications. Therefore, people are required to make rational choices on the correct type of food for consumption to engender proper growth and development. The role of fruits or fruit juice in ameliorating neurodegenerative diseases has created a reawakening in nutrition and human health research.
... Few disadvantages with resveratrol are low bioavailability, high metabolism and poor lipophilicity. It can be formulated by liposomal-encapsulation to overcome these disadvantages [144,[154][155][156]. ...
... It scavenges the free radicals and reduces neuroinflammation, oxidative stress and autophagy and thus, acts as a neuroprotective agent. It enhances the mitochondrial restoration via various signaling pathways by blocking the expression of iNOS, COX-2 and other enzymes which leads to the generation of pro-inflammatory mediators [144,[154][155][156]. ...
... Another recent study has shown that nutraceuticals such as luteolin can enhance memory in AD patients. 74 AD and TBI-induced beta-amyloid (Aβ) level, phospho tau (p-tau), glycogen synthase-3 (GSK-3), and inflammatory cytokine/chemokine levels were reduced by peripheral administration of luteolin in mice. 75 Luteolin reduced TBI-induced elevation of IL-1β, neuronal death, brain edema, BBB disorders, and activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-ARE and protected the brain from secondary brain injury in mice. ...
Article
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Neuroinflammation leads to neurodegeneration, cognitive defects, and neurodegenerative disorders. Neurotrauma/traumatic brain injury (TBI) can cause activation of glial cells, neurons, and neuroimmune cells in the brain to release neuroinflammatory mediators. Neurotrauma leads to immediate primary brain damage (direct damage), neuroinflammatory responses, neuroinflammation, and late secondary brain damage (indirect) through neuroinflammatory mechanism. Secondary brain damage leads to chronic inflammation and the onset and progression of neurodegenerative diseases. Currently, there are no effective and specific therapeutic options to treat these brain damages or neurodegenerative diseases. Flavone luteolin is an important natural polyphenol present in several plants that show anti-inflammatory, antioxidant, anticancer, cytoprotective, and macrophage polarization effects. In this short review article, we have reviewed the neuroprotective effects of luteolin in neurotrauma and neurodegenerative disorders and pathways involved in this mechanism. We have collected data for this study from publications in the PubMed using the keywords luteolin and mast cells, neuroinflammation, neurodegenerative diseases, and TBI. Recent reports suggest that luteolin suppresses systemic and neuroinflammatory responses in Coronavirus disease 2019 (COVID-19). Studies have shown that luteolin exhibits neuroprotective effects through various mechanisms, including suppressing immune cell activation, such as mast cells, and inflammatory mediators released from these cells. In addition, luteolin can suppress neuroinflammatory response, activation of microglia and astrocytes, oxidative stress, neuroinflammation, and the severity of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and TBI pathogenesis. In conclusion, luteolin can improve cognitive decline and enhance neuroprotection in neurodegenerative diseases, TBI, and stroke.
... Quercetin is a natural bioactive flavonoid with significant pharmacological effects that has been lately widely studied for its antioxidant biological properties connected to its antioxidant activity (Albarracin et al., 2012;Song X. et al., 2020), and with benefits to counteract the neurodegenerative processes. Recently, it was shown that quercetin is able to inhibit tau hyperphosphorylation by reducing the formation of insoluble neurofibrillary tangles associated with AD (Calfio et al., 2020). In another study, plasma sEVs were chosen as therapeutic cargo carriers, improving the solubility and the brain targeting of quercetin in an animal model of AD (Qi et al., 2020). ...
Article
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Small extracellular vesicles (sEVs) have ∼30–200 nm diameter size and may act as carriers of different cargoes, depending on the cell of origin or on the physiological/pathological condition. As endogenous nanovesicles, sEVs are important in intercellular communication and have many of the desirable features of an ideal drug delivery system. sEVs are naturally biocompatible, with superior targeting capability, safety profile, nanometric size, and can be loaded with both lipophilic and hydrophilic agents. Because of their biochemical and physical properties, sEVs are considered a promising strategy over other delivery vehicles in the central nervous system (CNS) since they freely cross the blood-brain barrier and they can be directed to specific nerve cells, potentiating a more precise targeting of their cargo. In addition, sEVs remain stable in the peripheral circulation, making them attractive nanocarrier systems to promote neuroregeneration. This review focuses on the recent progress in methods for manufacturing, isolating, and engineering sEVs that can be used as a therapeutic strategy to overcome neurodegeneration associated with pathologies of the CNS, with particular emphasis on Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis diseases, as well as on brain tumors.
... As far as brain aging and neurodegeneration, these processes have been the target of many therapeutic attempts that made use of nutraceutical approaches and/or diet modifications, as well as, more recently, interventions aimed at interfering with the gut-brain connection and the activities of the microbiota [101][102][103][104]. The jury is out on their efficacy [105]. ...
Article
Brain aging and aging-related neurodegenerative disorders are posing a significant challenge for health systems worldwide. To date, most of the therapeutic efforts aimed at counteracting dementia-related behavioral and cognitive impairment have been focused on addressing putative determinants of the disease, such as b-amyloid or tau. In contrast, relatively little attention has been paid to pharmacological interventions aimed at restoring or promoting the synaptic plasticity of the aging brain. The review will explore and discuss the most recent molecular, structural/functional, and behavioral evidence that supports the use of non-pharmacological approaches as well as cognitive-enhancing drugs to counteract brain aging and early-stage dementia.
... On the other hand, curcumin (12), a yellow pigment isolated from the rhizome of curcuma longa (turmeric), extensively used in traditional medicine for thousands of years, has been widely studied because of its uncountable therapeutic properties [39], from cancer [40,41] and arthritis [42] to neurodegenerative diseases [43] like Parkinson [44] and Alzheimer [45], as well as pain [46]. Its biological activity is mainly attributed to its particular chemical structure, having the advantage of low toxicity. ...
Article
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The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.
... Recently, many natural products were placed under investigation in pre-clinical and clinical trials in the treatment of AD [21], confirming the relevance of natural compounds. Several studies report that nutraceuticals and phytochemicals can have a crucial role in cell survival, neuron function, synaptic plasticity, and memory formation, thus contributing to prevention of neurodegenerative diseases onset [22][23][24]. Furthermore, in addition to other functions such as antioxidant activity and anti-inflammatory activity, several of these compounds are able to modulate the expression or proteolytic activity of MMPs. ...
Article
Full-text available
Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer’s disease.
... Furthermore, EGCG enhanced neuronal survival via activation of brain-derived neurotrophic factor (BDNF) and glial cell linederived neurotrophic factor (GDNF), inhibited caspase activity that promotes disease, reduces Aβ accumulation via inhibition of the enzymes involved in APP processing, and hinders BACE1 activation [118][119][120][121]. Inhibition of amyloid-beta fibril formation was observed following catechin and epicatechin administration. Delphinidin is an anthocyanidin that was suggested according to its potential in inhibition of tau hyperphosphorylation and activation of GSK-3β induced by Aβ in PC12 cells [122]. ...
Article
Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disease accompanying memory deficits. The available pharmaceutical care has some limitations mostly entailing side effects, shelf-life, and patient’s compliance. The momentous implications of nutraceuticals in AD have attracted scientists. Several preclinical studies for the investigation of nutraceuticals have been conducted. Areas covered: This review focuses on the potential use of a nutraceuticals-based therapeutic approach to treat and prevent AD. Increasing knowledge of AD pathogenesis has led to the discovery of new therapeutic targets including pathophysiological mechanisms and various cascades. Hence the present contribution will attend to the most popular and effective nutraceuticals with proposed brief mechanisms entailing antioxidant, anti-inflammatory, autophagy regulation, mitochondrial homeostasis, and more. Therefore, even though the effectiveness of nutraceuticals cannot be dismissed, it is indispensable to do further high-quality randomized clinical trials. Expert opinion: According to the potential of nutraceuticals to combat AD as multi-target directed drugs, there is critical importance to assess them as feasible lead compounds for drug discovery and development. To the best of the authors’ knowledge, modification of blood-brain barrier permeability, bioavailability, and features of randomized clinical trials should be considered in prospective studies.
... The nutraceutical NT-020, which is a proprietary blend of blueberries, green tea, vitamin D3, and carnosine, has been shown to reduce inflammation in elderly rats and prevent age-related cognitive decline and enhance neurogenesis [484][485][486][487][488]. Treating aged rats with NT-020 increases neurogenesis and serum from these animals' rescued aged hippocampal neural stem/precursor cells (NPCs) and bone-marrow derived mesenchymal stem cells (MSCs) from age-related reduction in cell proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2′-deoxyuridine (BrdU) assays and serum from aged rats treated with NT-020 was not different from serum. ...
Article
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Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.
... Nutritional formulations represent non-pharmacological therapeutic alternatives for several disorders, and a growing body of evidence suggests that combinations of nutraceutical compounds may be more effective to minimize brain damage in AD than the use of single nutrients [23][24][25]. Studies using natural dietary or nutraceutical supplementation with neuroimmune modulators have been shown to ameliorate symptoms and improve patient life quality [26,27]. For example, phosphatidylserine (PS) was shown to reduce hippocampal inflammation and improve memory in AD [28,29]. ...
Article
Background: Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by progressive cognitive decline. Considerable evidence supports an important role of amyloid-β oligomers (AβOs) in the pathogenesis of AD, including the induction of aberrant glial activation and memory impairment. Objective: We have investigated the protective actions of a nutritional formulation, denoted AZ formulation, on glial activation and memory deficits induced by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Methods: Two-month-old male mice were treated orally with AZ formulation or isocaloric placebo for 30 consecutive days. Microglial and astrocytic activation were analyzed by immunohistochemistry in the hippocampus 10 days after i.c.v. infusion of AβOs (n = 5 mice per experimental condition). Memory loss was assessed by the novel object recognition (NOR) test (n = 6-10 mice per experimental condition). Results: Oral treatment with the AZ formulation prevented hippocampal microglial and astrocytic activation induced by i.c.v. infusion of AβOs. The AZ formulation further protected mice from AβO-induced memory impairment. Conclusion: Results suggest that administration of the AZ formulation may comprise a promising preventative and non-pharmacological strategy to reduce brain inflammation and attenuate memory impairment in AD.
... Aerobic exercises could be advantageous in terms of normal tasks but could maybe promote health [3] . Antipsychotics have been prescribed to treat behavioural difficulties or hallucinations caused by dementia, although they are not normally advised but they do provide little improvement but also raise the risk of premature mortality [4] . As per WHO report, globally, there were approximately 30 million people living with Alzheimer's disease in 2015, whereas with a projected 50 million people suffering from dementia by 2020. ...
... Following catechin and epicatechin treatment, amyloid-beta fibril production was inhibited. Delphinidin is an anthocyanidin that has been recommended for its ability to reduce tau hyperphosphorylation and GSK-3β activation produced by Aβ in PC12 cells (Calfio et al., 2020). ...
Article
Full-text available
Alzheimer's disease (AD) is a neurological illness that causes memory loss over time. Currently, available pharmaceutical medicines and products are limited, and they have side effects at a higher price. Researchers and scientists have observed significant effects of nutraceuticals. Various preclinical and clinical studies were investigated for the Anti‐Alzheimer's activity of nutraceuticals. The increasing ability of the pathogenesis of AD has led to the analysis of novel therapeutic targets, including the pathophysiological mechanisms and distinct cascades. So, current improvement will show the most adequate and prominent nutraceuticals and suggested concise mechanisms involving autophagy regulation, anti‐inflammatory, antioxidant, mitochondrial homeostasis, and others. The effects of nutraceuticals cannot be ignored; it is important to investigate high‐quality clinical trials. Given the potential of nutraceuticals to battle AD as multi‐targeted therapies, it's vital to evaluate them as viable lead compounds for drug discovery and development. To the best of the authors ‘knowledge, modification of blood–brain barrier permeability, bioavailability, and aspects of randomized clinical trials should be considered in prospective investigations. Practical applications Advancements in molecular diagnostic and fundamentals have implemented particular usefulness for drug evaluation. An excess of experimental knowledge occurs regarding the effect of nutraceuticals on AD. There are various preclinical and clinical studies that have been done on nutraceuticals. In addition, various substitute inhibit and enhance some pathophysiological levels associated with AD. Nutraceuticals are easily available and have fewer side effects with cost‐effective advantages. However, further investigations and clinical trials are required to encourage its effect on disease.
... Aerobic exercises could be advantageous in terms of normal tasks but could maybe promote health [3] . Antipsychotics have been prescribed to treat behavioural difficulties or hallucinations caused by dementia, although they are not normally advised but they do provide little improvement but also raise the risk of premature mortality [4] . As per WHO report, globally, there were approximately 30 million people living with Alzheimer's disease in 2015, whereas with a projected 50 million people suffering from dementia by 2020. ...
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Alzheimer's disease is a catastrophic form of cognition that impairs a patient's capacity to think critically and hold a conversation. This is also termed as senile dementia, and is the most neurodegenerative disease. It mostly affects persons over the age of 65 year, however there have been found middle age people (age within 30-60 year) also experienced Alzheimer's complication. Medicinal herbs have been demonstrated to be important in improving the functionality of nervous system in a number of scientific studies. Phytochemicals from the Spatholobus genus plant were tested as folk remedies to the acetylcholinesterase enzyme (1ACJ) which triggers Alzheimer's disease in this study. We discovered that Medicarpin (interaction energy-9.9 Kcal/mol) is the best of the four molecules examined from S. suberectus for interacting with protein 1ACJ. We reported that Prestegane B has a higher binding potential to the target protein 1ACJ, i.e.,-10.2 Kcal/mol with two hydrogen bonds in contact, than the other five molecules studied from S. sinensis. In this investigation, 12 phytocompounds from S. suberectus were examined. Maackiain had the strongest affinity with the target protein 1ACJ, with a-10.3 Kcal/mol. When compared to the experimental medications Donepezil and Tacrine, all of these compounds had a higher binding affinity. In furthermore, in silico drug likeness and ADMET analyses of the phytochemicals demonstrated significant therapeutic advantages. As a conclusion, the present investigation would serve as a springboard for much more exploration to assess the phytocompounds' effectiveness against Alzheimer's disease complications.
... For example, the common flowering quince (FQ) has been used traditionally to treat migraine, neuralgia, depression, tremors, and dyskinesia (Zhao et al., 2008). Over the recent years, researchers have been exploring various phytochemicals like Berberine (BBR), Curcumin, Ginsenoside, Puerarin, etc., with potential application toward the management of neurodegenerative disorders and symptoms (Price et al., 2012;Lin et al., 2018;Corpas et al., 2019;Nair et al., 2019;Wang et al., 2019;Calfio et al., 2020;Balakrishnan et al., 2021). For example, phytochemical like Resveratrol (a bioactive component of red wine) (Price et al., 2012;Lin et al., 2018;Corpas et al., 2019;Nair et al., 2019) and Melatonin have shown reported benefit, both in vitro and vivo conditions, toward improving the mitochondrial function believed to be one primary cause for diseases like AD and PD. ...
Article
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The study of human movement and biomechanics forms an integral part of various clinical assessments and provides valuable information toward diagnosing neurodegenerative disorders where the motor symptoms predominate. Conventional gait and postural balance analysis techniques like force platforms, motion cameras, etc., are complex, expensive equipment requiring specialist operators, thereby posing a significant challenge toward translation to the clinics. The current manuscript presents an overview and relevant literature summarizing the umbrella of factors associated with neurodegenerative disorder management: from the pathogenesis and motor symptoms of commonly occurring disorders to current alternate practices toward its quantification and mitigation. This article reviews recent advances in technologies and methodologies for managing important neurodegenerative gait and balance disorders, emphasizing assessment and rehabilitation/assistance. The review predominantly focuses on the application of inertial sensors toward various facets of gait analysis, including event detection, spatiotemporal gait parameter measurement, estimation of joint kinematics, and postural balance analysis. In addition, the use of other sensing principles such as foot-force interaction measurement, electromyography techniques, electrogoniometers, force-myography, ultrasonic, piezoelectric, and microphone sensors has also been explored. The review also examined the commercially available wearable gait analysis systems. Additionally, a summary of recent progress in therapeutic approaches, viz., wearables, virtual reality (VR), and phytochemical compounds, has also been presented, explicitly targeting the neuro-motor and functional impairments associated with these disorders. Efforts toward therapeutic and functional rehabilitation through VR, wearables, and different phytochemical compounds are presented using recent examples of research across the commonly occurring neurodegenerative conditions [viz., Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS)]. Studies exploring the potential role of Phyto compounds in mitigating commonly associated neurodegenerative pathologies such as mitochondrial dysfunction, α-synuclein accumulation, imbalance of free radicals, etc., are also discussed in breadth. Parameters such as joint angles, plantar pressure, and muscle force can be measured using portable and wearable sensors like accelerometers, gyroscopes, footswitches, force sensors, etc. Kinetic foot insoles and inertial measurement tools are widely explored for studying kinematic and kinetic parameters associated with gait. With advanced correlation algorithms and extensive RCTs, such measurement techniques can be an effective clinical and home-based monitoring and rehabilitation tool for neuro-impaired gait. As evident from the present literature, although the vast majority of works reported are not clinically and extensively validated to derive a firm conclusion about the effectiveness of such techniques, wearable sensors present a promising impact toward dealing with neurodegenerative motor disorders.
... The use of natural products or nutraceutical chemicals has emerged as a potential preventative therapy approach, as most medications focusing on specific targets have failed to establish a medical cure. Nutraceutical substances have the benefit of a multitarget strategy, tagging several biochemical locations in the human brain, as compared to the single-target action of most AD medications [49]. In the last decade, more than 200 potential therapeutic candidates have failed during clinical trials, indicating that the illness and its causes are likely to be complicated. ...
Article
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Alzheimer's disease (AD) is a progressive neurological condition. The rising prevalence of AD necessitates the rapid development of efficient therapy options. Despite substantial study, only a few medications are capable of delaying the disease. Several substances with pharmacological activity, derived from plants, have been shown to have positive benefits for the treatment of AD by targeting various enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, and monoamine oxidases (MAOs), which are discussed as potential targets. Medicinal plants have already contributed a number of lead molecules to medicine development, with many of them currently undergoing clinical trials. A variety of medicinal plants have been shown to diminish the degenerative symptoms associated with AD, either in their raw form or as isolated compounds. The aim of this review was to provide a brief summary of AD and its current therapies, followed by a discussion of the natural compounds examined as therapeutic agents and the processes underlying the positive effects, particularly the management of AD.
... Natural products are a rich source of phytochemicals, such as polyphenols, which serve as a pool of antioxidants for the maintenance of steady health. According to emerging evidence, phytochemicals promote learning, memory, and other general cognitive abilities (Bakoyiannis et al., 2019;Calfio et al., 2020;Yadav, 2021). ...
Article
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Neurodegenerative disorders (NDs) are a cluster of progressive, severe, and disabling disorders that affect millions of people worldwide and are on the surge. These disorders are characterized by the gradual loss of a selectively vulnerable group of neurons. Due to the complex pathophysiological mechanisms behind neurodegeneration and despite enormous efforts and understanding of the occurrence and progression of NDs, there is still a lack of an effective treatment for such diseases. Therefore, the development of a new therapeutic strategy for NDs is an unmet clinical need. Various natural compounds extracted from medicinal plants or fruits have shown promising activities in treating different types of NDs by targeting multiple signaling pathways. Among natural entities, flavonoids have incited a rise in public and scientific interest in recent years because of their purported health‐promoting effects. Dietary supplementation of flavonoids has been shown to mitigate the severity of NDs such as Parkinson's disease (PD), Alzheimer's disease (AD), and dementia by their antioxidant effects. Naringenin is a citrus flavonoid that is known to possess numerous biological activities like antioxidant, anti‐proliferative, and anti‐inflammatory activities. Therefore, naringenin has emerged as a potential therapeutic agent that exerts preventive and curative effects on several neurological disorders. Increasing evidence has attained special attention on the variety of therapeutic targets along with complex signaling pathways of naringenin, which suggest its possible therapeutic applications in several NDs. Derived from the results of several pre‐clinical research and considering the therapeutic effects of this compound, this review focuses on the potential role of naringenin as a pharmacological agent for the treatment and management of Alzheimer's and Parkinson's disease. The overall neuroprotective effects and different possible underlying mechanisms related to naringenin are discussed. In the light of substantial evidence for naringenin's neuroprotective efficacy in several experimental paradigms, this review suggests that this molecule should be investigated further as a viable candidate for the management of Alzheimer's and Parkinson's disease, with an emphasis on mechanistic and clinical trials to determine its efficacy. Practical applications Naringenin is a flavanone, aglycone of Naringin, predominantly found in citrus fruits with a variety of pharmacological actions. Naringenin has been shown to exhibit remarkable therapeutic efficacy and has emerged as a potential therapeutic agent for the management of a variety of diseases such as various heart, liver, and metabolic disorders. Similarly, it has shown efficacy in neurodegenerative illnesses. Therefore, this review enables us to better understand the neuroprotective effects and different possible underlying mechanisms of naringenin. Also, this review provides a new indication to manage the symptoms of NDs like AD and PD. Furthermore, naringenin will be useful in the field of medicine as a new active ingredient for the treatment of neurodegenerative disorders like AD and PD.
... Shilajit activated peritoneal macrophages and splenocytes in tumor bearing murine during different tumor growth stages (Rahmani Barouji et al., 2020a). Shilajit is also attributed to a number of beneficial effects against neurological disorders including Alzheimer's disease (Bhattarai et al., 2016;Calfio et al., 2020;Carrasco-Gallardo et al., 2012a, 2012b. Importantly, shilajit has been shown to prevent liver damage in highfat diet-induced non-alcoholic fatty liver disease and induce apoptosis in hepatic cancer cells k (Ghezelbash et al., 2020;Pant et al., 2016). ...
Article
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Osteosarcoma is a primary malignant cancer of the bone identified by the direct formation of osteoid tissue or immature bone by cancer cells. The liver and kidneys represent two major secondary organs to which osteosarcoma metastasizes. In this study, we assessed Shilajit, a phytomineral diffusion traditionally used in Ayurvedic medicine, for its possible protective effects against metastasis induced liver and kidney damages in an osteosarcoma rat model. Osteosarcoma rats displayed typical dysregulation of serum levels of hepatic and renal functional markers (p<0.05) including aspartate aminotransferase (AST)* and alanine aminotransferase (ALT), alkaline phosphatase (ALP), total proteins, albumin, bilirubin, creatinine, urea, and uric acid. Changes in functional markers were also positively correlated with marked histopathological alterations in liver and kidney tissues. Whereas, Shilajit's treatment of osteosarcoma rates in combination with CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy drug cocktail significantly (p<0.05) reversed the studied functional markers to their near-normal levels. Co-treatment of shilajit and drug cocktails also markedly alleviated histopathological changes in liver and kidney tissues. Correlation co-efficient analysis of hepatic and renal functional markers revealed a significant inter-association among these markers. Collectively, present data indicate that shilajit may potentiate the effects of chemotherapy drugs and mitigate the metastasis-induced liver and kidney damage in osteosarcoma. Thus, the findings of this study substantiate the beneficial health effects of shilajit and promote its regular consumption.
Article
Objectives Huangpu Tongqiao Capsule (HPTQC) is a traditional Chinese medicine (TCM) that has been used to treat Alzheimer's disease (AD). This study was to explore the pharmacological action and molecular mechanism of HPTQC in the treatment of AD. Methods The possible targets of HTPQC were predicted by the molecular docking technique. Intraperitoneal injection of D-galactose and bilateral injection of Aβ25-35 in hippocampus induced AD rat model. Morris water maze was used to observe learning and memory function. The primary hippocampal neurons were induced by Aβ25-35. Moreover, the apoptosis rate of hippocampal nerve cells was detected through AnnexinV/PI double standard staining. The mRNA and protein levels of GRP78, CHOP, Caspase 12, Caspase 9, and Caspase 3 were detected by PCR and western blot. Results The prediction results suggest that HPTQC may act on GRP78. HPTQC significantly improved the learning and memory function, and decreased neuronal apoptosis in vivo and in vitro. In addition, HPTQC could decrease the mRNA and protein expression levels of GRP78, CHOP, Caspase12, Caspase9, and Caspase3, and the effect trend was consistent with the specific inhibitor of GRP78. Conclusions HPTQC has a neuroprotective effect against AD by inhibiting the apoptosis pathway mediated by endoplasmic reticulum stress.
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Alzheimer's disease (AD) is a progressive neurodegenerative disease, which has brought a huge burden to the world. The current therapeutic approach of one-molecule-one-target strategy fails to address the issues of AD because of multiple pathological features of AD. Traditionally, the herb of Angelica sinensis (AS) comes from the root of an umbrella plant Angelica sinensis (Oliv.) Diels. As a typical medicine-food herb, studies have shown that AS can alleviate AD and AD-complications by multiple targets through the various foundations of pharmaceutical material and dietary supply basis. Therefore, this review summarizes the pharmacological effects of AS for the treatment of AD and AD-complications for the first time. AS contains many effective components, such as ligustilide, z-ligustilide, n-butylidenephthalide, α-pinene, p-cymene, myrcene, ferulic acid, vanillic acid and coniferyl ferulate. It is found that AS, AS-active compounds and AS-compound recipes mainly treat AD through neuroprotective, anti-inflammation, and anti-oxidant effects, improving mitochondrial dysfunction, anti-neuronal apoptosis, regulating autophagy, regulating intestinal flora and enhancing the central cholinergic system, which shows the multi-component and multi-target effect of AS. The role of dietary supplement components in AS for AD intervention is summarized, including vitamin B12, folic acid, arginine, and oleic acid, which can improve the symptoms of AD. Besides, this review focuses on the safety and toxicity evaluation of AS, which provides a basis for its application. This review will provide further support for the research on AD and the application of medicine-food herb AS in a healthy lifestyle in the future.
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Alzheimer’s disease is a neurological disorder that progressively affects the brain cells. It is sometimes accompanied with dementia and commonly seen in elderly people. It ultimately leads to impaired cognitive functions and loss of memory. Widely used drugs such as donepezil and galantamine successfully abate mild to moderate symptoms of the disease though they have profound side effects. Natural products have been a source of medicine for over thousands of years. Plant secondary metabolites such as alkaloids, flavonoids, terpenoids, etc. are major sources of such medicines. In recent times, the use of natural products to treat various diseases has gained a lot of popularity. Extensive research is being undertaken to identify and isolate various natural products that can be used to not only reduce the disease symptoms but also as a permanent cure. The review article aims to summarize the effects of various natural products and their neuroprotective mechanisms that can be helpful to cure Alzheimer’s disease.
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The Alzheimer’s disease pathology is associated with accumulation of intracellular neurofibrillary tangles and extracellular senile plaques. The formation of initial nucleus triggers conformational changes in Tau and leads to its deposition. Hence, there is a need to eliminate these toxic proteins for proper functioning of neuronal cells. In this aspect, we screened the effect of basic limonoids such as gedunin, epoxyazadiradione, azadirone and azadiradione on inhibiting Tau aggregation as well as disintegration of induced Tau aggregates. It was observed that these basic limonoids effectively prevented aggregates formation by Tau and also exhibited the property of destabilizing matured Tau aggregates. The molecular docking analysis suggests that the basic limonoids interact with hexapeptide regions of aggregated Tau. Although these limonoids caused the conformational changes in Tau to β-sheet structure, the cytological studies indicate that basic limonoids rescued cell death. The dual role of limonoids in Tau aggregation inhibition and disintegration of matured aggregates suggests them to be potent molecules in overcoming Tau pathology. Further, their origin from a medicinally important plant neem, which known to possess remarkable biological activities was also found to play protective role in HEK293T cells. Basic limonoids were non-toxic to HEK293T cells and also aided in activation of HSF1 by inducing its accumulation in nucleus. Western blotting and immunofluorescence studies showed that HSF1 in downstream increased the transcription of Hsp70 thus, aggravating cytosolic Hsp70 levels that can channel clearance of aberrant Tau. All these results mark basic limonoids as potential therapeutic natural products.
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This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.
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Alzheimer's disease (AD) is a type of incurable neurodegenerative disease that is characterized by the accumulation of amyloid-b (Ab; plaques) and tau hyperphosphorylation as neurofibrillary tangles (NFTs) in the brain followed by neuronal death, cognitive decline, and memory loss. The high prevalence of AD in the developed world has become a major public health challenge associated with social and economic burdens on individuals and society. Due to there being limited options for early diagnosis and determining the exact pathophysiology of AD, finding effective therapeutic strategies has become a great challenge. Several possible risk factors associated with AD pathology have been identified; however, their roles are still inconclusive. Recent clinical trials of the drugs targeting Ab and tau have failed to find a cure for the AD pathology. Therefore, effective preventive strategies should be followed to reduce the exponential increase in the prevalence of cognitive decline and dementia, especially AD. Although the search for new therapeutic targets is a great challenge for the scientific community, the roles of lifestyle interventions and nutraceuticals in the prevention of many metabolic and neurodegenerative diseases are highly appreciated in the literature. In this article, we summarize the molecular mechanisms involved in AD pathology and the possible ameliorative action of lifestyle and nutritional interventions including diet, exercise, Calorie restriction (CR), and various bioactive compounds on cognitive decline and dementia. This article will provide insights into the role of non-pharmacologic interventions in the modulation of AD pathology, which may offer the benefit of improving quality of life by reducing cognitive decline and incident AD.
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Overstimulation of glutamate receptors leads to development of excitotoxicity, which is implicated as final destructive pathway in neurodegenerative diseases. Development of alternative therapeutic strategies effective against glutamate-induced excitotoxicity is much in demand. Herbal drug development is emerging as a major research area for the treatment of various debilitating diseases due to multimodal action and least side effects of herbal products. The current study was aimed to investigate neuroprotective potential of butanol extract of Tinospora cordifolia (B-TCE) against glutamate-induced excitotoxicity using primary hippocampal neurons as in vitro and Wistar strain albino rats as in vivo model systems. Molecular and behavioral parameters were studied to elucidate the underlying mechanism of beneficial effects of B-TCE. B-TCE treatment was also effective in prevention of anxiety, cognition, and motor-coordination deficits induced by glutamate. B-TCE pre-treatment protected the hippocampal neurons from glutamate-induced neurodegeneration and impaired plasticity. At molecular level, B-TCE was observed to attenuate overactivation of glutamate receptors. B-TCE promoted upregulation of ERK and AKT pathways of synaptic plasticity and cell survival in the hippocampus region of brain. This study provides first evidence of neuroprotective potential of B-TCE against glutamate-induced excitotoxicity in hippocampus region and suggests that B-TCE may act as a potential candidate for neuroprotective therapeutic approaches. A single compound ‘tinosporicide’ was further isolated from B-TCE, which was found to be effective at 800× lower concentration against glutamate-induced neurodegeneration under in vitro conditions.
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Background Alzheimer’s disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubule-associated protein tau. Increasing evidences demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has been previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging; The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay; The uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the mouse brains were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reduced the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.
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Alzheimer's disease (AD) is linked to an extensive neuron loss via accumulation of amyloid-beta (A β ) as senile plaques associated with reactive astrocytes and microglial activation in the brain. The objective of this study was to assess the therapeutic effect of WS-5 ethanol extract in vitro and in vivo against A β -induced AD in mice and to identify the extract’s active constituents. In the present study, WS-5 exerted a significant inhibitory effect on acetylcholinesterase (AChE). Analysis by transmission electron microscopy (TEM) revealed that WS-5 prevented A β oligomerization via inhibition of A β1-42 aggregation. Evaluation of antioxidant activities using 1, 1-diphenyl-2-picrylhydrazyl (DPPH) demonstrated that WS-5 possessed a high antioxidant activity, which was confirmed by measuring the total antioxidant status (TAS). Furthermore, the anti-inflammatory properties of WS-5 were examined using lipopolysaccharide-stimulated BV-2 microglial cells. WS-5 significantly inhibited the lipopolysaccharide–induced production of nitric oxide and two proinflammatory cytokines, TNF- α and IL-6. The memory impairment in mice with A β -induced AD was studied using the Morris water maze and passive avoidance test. Immunohistochemistry was performed to monitor pathological changes in the hippocampus and cortex region of the mouse brain. The animal study showed that WS-5 (250 mg/kg) treatment improved learning and suppressed memory impairment as well as reduced A β plaque accumulation in A β -induced AD. HPLC analysis identified the extract’s active compounds that exert anti-AChE activity. In summary, our findings suggest that WS-5 could be applied as a natural product therapy with a focus on neuroinflammation-related neurodegenerative disorders.
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Introduction: Medicinal herbs have several components with different pharmacological effects. It has been described that Melissa officinalis is able to improve memory in different models of learning. Nevertheless, its influence has not been studied in animal models of AD. Here, we studied the potential therapeutic effect of M. officinalis in intracerebroventricular (i.c.v) amyloid-β (Aβ) model of Alzheimer's disease (AD). Methods: Male Wistar rats weighing 260-330 g received the hydro-alcoholic extract of M. officinalis (50, 100, 200, 400 mg/kg; P.O), chronically for 30 consecutive days. The control group received solvent of the drug. Memory retrieval was assessed, using the passive avoidance task. Three groups of the rats received Aβ (1-42; 10 μg/rat bilaterally; i.c.v). One group received DMSO 1% (2 μL/rat; i.c.v). Twenty days later memory retrieval was assessed. The Aβ-treated rats, received M. officinalis (50, 100 mg/kg; P.O) or saline (1 mL/kg; P.O), chronically for 30 consecutive days. The DMSO 1%-treated rats received saline (1 mL/kg; P.O). Results: The hydro-alcoholic extract of M. officinalis (50, 100, 200, 400 mg/kg; P.O) did not have a significant effect on step-through latency (STL). Aβ impaired memory retrieval by decreasing STL and increasing the time spent in the dark compartment (TDC). M. officinalis (50, 100 mg/kg; P.O) improved memory retrieval in AD rats by increasing STL and decreasing TDC, significantly. Conclusion: The outcomes of the study show that M. officinalis has a therapeutic effect in the Aβ model of AD. It seems that the extracts of M. officinalis can be suggested as a powerful therapeutic herb for AD patients.
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Polyphenols such as Epigallocatechin-3 gallate (EGCG) are currently bearer of hope to prevent or at least to slow down the deleterious effect of Tauopathies such as Alzheimer disease. One of the main effects of these neurodegenerative pathologies is the hyperphosphorylation and consequent aggregation of the Tau protein that leads to the irremediable neuronal cells death. In the present paper, we show how EGCG can play a crucial role to prevent Tau aggregation: (i) in binding Tau in its phosphorylation region with an affinity of the same order of magnitude than kinases (0.5 mM), hindering their access to the protein and (ii) in modifying the 3D-structure of Tau whose preferential conformation changes in the presence of EGCG. For this purpose, two peptides were synthesized, one of 20 residues long issued from the first Proline-rich region of Tau (171Ile-190Lys), the second of 50 residues long (171Ile-220Thr) corresponding to more than 50% of the Tau Proline rich domaine. The total attribution of all the 1H, 13C and 15N resonances of the two peptides has been achieved thanks to a "divide and conquer" strategy leading to their 3D structure preference and their affinity towards EGCG.
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The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid- (A)-induced toxicity in Alzheimer’s disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on A and curcumin has revealed that curcumin prevents A aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and A in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin’s bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
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The formation of paired helical filaments (PHF), which are composed of hyperphosphorylated Tau protein dissociating from microtubules, is one of the pathological hallmarks of Alzheimer’s disease (AD) and other tauopathies. The most important phosphatase that is capable of dephosphorylating Tau at AD specific phospho-sites is protein phosphatase 2 A (PP2A). Here we show that resveratrol, a polyphenol, significantly induces PP2A activity and reduces Tau phosphorylation at PP2A-dependent epitopes. The increase in PP2A activity is caused by decreased expression of the MID1 ubiquitin ligase that mediates ubiquitin-specific modification and degradation of the catalytic subunit of PP2A when bound to microtubules. Interestingly, we further show that MID1 expression is elevated in AD tissue. Our data suggest a key role of MID1 in the pathology of AD and related tauopathies. Together with previous studies showing that resveratrol reduces β-amyloid toxicity they also give evidence of a promising role for resveratrol in the prophylaxis and therapy of AD.
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Alzheimer’s disease is a common tauopathy where fibril formation and aggregates are the hallmark of the disease. Efforts targeting amyloid-b plaques have succeeded to remove plaques but failed in clinical trials to improve cognition; thus, the current therapeutic strategy is at preventing tau aggregation. Here, we demonstrated that four phenolic diterpenoids and rosmarinic acid inhibit fibrillization. Since, rosmarinic acid was the most active compound, we observe morphological changes in atomic force microscopy images after treatment. Hence, rosmarinic acid leads to a decrease in amide regions I and III, indicating that rosmarinic acid prevents b-sheet assembly. Molecular docking study inside the steric zipper model of the hexapeptide 306VQIVYK311 involved in fibrillization and b sheet formation, suggests that rosmarinic acid binds to the steric zipper with similar chemical interactions with respect to those observed for orange G, a known pharmacofore for amyloid.
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The aggregation of the microtubule-associated protein tau is a seminal event in many neurodegenerative diseases, including Alzheimer's disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activities. We have previously screened Aspergillus nidulans secondary metabolites for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol. One aggregation inhibitor identified was asperbenzaldehyde, an intermediate in azaphilone biosynthesis. We therefore tested 11 azaphilone derivatives to determine their tau assembly inhibition properties in vitro. All compounds tested inhibited tau filament assembly to some extent, while four of the 11 compounds had the advantageous property of disassembling preformed tau aggregates in a dose-dependent fashion. The addition of these compounds to the tau aggregates reduced both the total length and numbers of tau polymers. The most potent compounds were tested in in vitro reactions to determine whether they interfere with tau's normal function of stabilizing microtubules (MTs). We found that they did not completely inhibit MT assembly in the presence of tau. These derivatives are very promising lead compounds for tau aggregation inhibitors and, more excitingly, for compounds that can disassemble pre-existing tau filaments. They also represent a new class of anti-tau aggregation compounds with a novel structural scaffold.
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Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin inhibits the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant. In conclusion, curcumin has the potential to be more efficacious than current treatments. However, its usefulness as a therapeutic agent may be hindered by its low bioavailability. If the challenge of low bioavailability is overcome, curcumin-based medications for AD may be in the horizon.
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The presence of β-amyloid (Aβ) containing plaques in the brain is a hallmark of Alzheimer×s disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Early diagnosis is of great importance for optimal treatment and for monitoring disease progression in the brain. Highly specific and sensitive biomarkers are thus greatly needed to assess therapeutic efficacy, not only clinically, but also in terms of clearance of histopathological lesions and decelerated neurodegeneration. The objective of the present study was to give more insight into the binding of curcumin analogues, curcuminoids, to Aβ containing plaques in postmortem tissue from AD patients. In vitro autoradiography was utilized to explore affinity and displacement of the curcuminoids; curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and dimethoxycurcumin (DIMC). We found that BDMC had the highest affinity for Aβ containing plaques in cortical AD brain tissue in comparison to other curcuminoids. Subsequently, [(3)H]BDMC showed significantly higher specific binding in cortical AD brain tissue compared to control subjects. These findings suggest that curcumin analogues, especially BDMC, may serve as a potential radioligands for Aβ plaque neuroimaging.
Chapter
Curcumin is an active polyphenol from the rhizome of Curcuma longa (turmeric) that has been used in traditional medicine for centuries and widely investigated in the last decades. The numerous activities reported for curcumin are related with its peculiar structure and modulation of multiple molecular and biochemical targets. Many of them impact in the recently proposed hallmarks of aging. Curcumin is viewed nowadays as a potential phytochemical useful for aging interventions as shown by its actions on healthspan and longevity in different model organisms. This polyphenol is also increasingly associated with health promoting effects by its potential in the prevention and treatment of aging-related diseases, such as cancer, diabetes, cardiovascular, and neurodegenerative diseases. To solve the low bioavailability of curcumin, new formulations are being developed to envisage its use in functional foods and for pharmacological applications to promote healthy aging. This will be the step forward for this golden nutraceutical.
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Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive cognitive impairment and multiple distinct neuropathological features. Currently, there are no available therapies to delay or block the disease progression. Thus, the disease-modifying therapies are urgent for this devastating disorder by simultaneously targeting multiple distinct pathological processes. Morin, a natural bioflavonoid, have been shown to be strongly neuroprotective in vitro and in vivo. In this study, we first investigated the disease-modifying effects of chronic morin administration on the neuropathological and cognitive impairments in APPswe/PS1dE9 double transgenic mice. Our results showed that chronic morin administration prevented spatial learning and memory deficits in the APPswe/PS1dE9 mice. Morin treatment in the APPswe/PS1dE9 mice markedly reduced cerebral Aβ production and Aβ plaque burden via promoting non-amyloidogenic APP processing pathway by increasing ADAM10 expression, inhibiting amyloidogenic APP processing pathway by decreased BACE1 and PS1 expression, and facilitating Aβ degradation by enhancing Aβ-degrading enzyme expression. In addition, we also found that morin treatment in the APPswe/PS1dE9 mice markedly decreased tau hyperphosphorylation via its inhibitory effect on CDK5 signal pathway. Furthermore, morin treatment in the APPswe/PS1dE9 mice markedly reduced the activated glial cells and increased the expression of synaptic markers. Collectively, our findings demonstrate that chronic morin treatment restores cognitive functions and reverses multiple distinct neuropathological AD-like hallmarks in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective actions and neurobiological mechanisms of morin against AD, suggesting that morin is a potently promising disease-modifying agent for treatment of AD.
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Virtually none of the hypotheses on Alzheimer's disease (AD) pathogenesis address the earliest events that trigger the molecular alterations that precede cerebral degeneration and account for the diversity of risk factors that converge on a well-defined disease phenotype. We propose that long-term activation of the innate immune system by an individual array of risk factors constitutes a unifying mechanism leading to the triggering of an inflammatory cascade that converges in cytoskeletal alterations (tau aggregation, paired helical filament formation) as a previously hypothesized final common pathway in AD. The key pathogenic phenomena consist in the long-term, maladaptive activation of innate immunity-triggering receptors-such as the toll-like and advanced glycation end-products receptors, and others located in the microglial membrane-by seemingly heterogeneous risk factors such as hyperlipidemia, hyperglycemia, oxidative stress, head injury, amyloid oligomers, etc. Our hypothesis provides a unifying mechanism that explains both the diversity of risk factors acting over long periods of time and the individual response to such insults. This formulation is amenable to both empirical testing and implementation into therapeutic strategies that may lead to effective prevention of AD as well as other disorders in which impaired regulation of the innate immunity is the unifying cause of the condition.
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Multi-target approach has gained increasing acceptance as useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β), by attacking both beta-amyloid and tau protein cascades, has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6 and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.
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Ethnopharmacological relevance: Depression is a serious psychological disorder that causes extreme economic loss and social problems. However, the conventional medications typically cause side effects that result in patients opting to out of therapy. Lemon balm (Melissa officinalis L., MO) is an old and particularly reliable medicinal herb for relieving feelings of melancholy, depression and anxiety. The present study aims to investigate the antidepressant-like activity of water extract of MO (WMO) by evaluating its influence on the behaviors and the relevant neurotransmitters of rats performed to forced swimming test. Materials and methods: Two phases of the experiment were conducted. In the acute model, rats were administered ultrapure water (control), fluoxetine, WMO, or the indicated active compound (rosmarinic acid, RA) three times in one day. In the sub-acute model, rats were respectively administered ultrapure water (control), fluoxetine, or three dosages of WMO once a day for 10 days. Locomotor activity and depression-like behavior were examined using the open field test and the forced swimming test, respectively. The levels of relevant neurotransmitters and their metabolites in the frontal cortex, amygdala, hippocampus, and striatum were analyzed by high performance liquid chromatography. Results: In the acute model, WMO and RA significantly reduced depressive-like behavior but the type of related neurotransmitter could not be determined. The results indicated that the effect of WMO administration on the reduction of immobility time was associated with an increase in swimming time of the rats, indicative of serotonergic neurotransmission modulation. Chromatography data validated that the activity of WMO was associated with a reduction in the serotonin turnover rate. Conclusion: The present study shows the serotonergic antidepressant-like activity of WMO. Hence, WMO may offer a serotonergic antidepressant activity to prevent depression and to assist in conventional therapies.