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The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease
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.
... Alzheimer's disease (AD) is regarded as a neurodegenerative disease with a progressive loss of the basal forebrain with the characteristics of loss of memory, dementia, and impairment in memory. [3,4] Aging is the most common factor of AD. Alois Alzheimer, a German psychiatrist, was the first to notice this disease in 1906. ...
... Auguste, a patient with growing cognitive impairment, was diagnosed by Dr. Alzheimer. [4,5] Auguste's brain was investigated using histology after his death, and Dr. Alzheimer discovered many military clusters of brain tissue in the cortex. [5,6] These military clusters are neurofibril deposits, which are well-known nowadays. ...
... In AD, the formation of the oligomeric Aβ plaques is associated with dementia and memory loss. [4,9,36,37] Curcumin was found to be beneficial in lowering Aβ plaque development in a murine model. It inhibited the BACE-1 enzyme, which transforms APP to Ab through APP cleavage. ...
Various chemical compounds with natural dietary origins have been shown to protect against age-related disorders, such as neurodegenerative diseases such as Alzheimer’s disease (AD). Such substances are known as nutraceuticals, and they differ structurally, function at distinct biochemical and metabolic levels, and have various neuroprotective characteristics. In this review, we analyzed the evidence from explanatory studies on the effects of selected nutritional supplements on age-related cognitive decline and dementia in humans, randomized clinical trials, and clinical trials. We provide findings from research on vitamins, flavonoids, and other natural compounds that have been researched in AD and may be useful for maintaining excellent cognitive function. In dementia-related therapy, nutraceuticals are not a choice due to a severe absence of high-quality research studies. Despite this, the significant potential for their neuroprotective effects discourages future research.
... 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]. ...
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.
... Recently, Debashis Dutta et al. demonstrated that, by specifically targeting the TLR2/NF-κB pathway, it is possible to reduce the a-synuclein spreading in vitro and in vivo, finally contributing to the treatment of neurodegenerative diseases such as Parkinson's disease (PD) [117]. Clinical studies highlight the preventive effects of correct and healthy nutrition in the field of neurodegenerative diseases and especially AD or atherosclerosis [118,119]. Many nutraceutical bioactive principles have antiplatelet activity as well as anti-inflammatory activities [118]. ...
... Clinical studies highlight the preventive effects of correct and healthy nutrition in the field of neurodegenerative diseases and especially AD or atherosclerosis [118,119]. Many nutraceutical bioactive principles have antiplatelet activity as well as anti-inflammatory activities [118]. ...
Flavonoids are polyphenolic phytochemical compounds found in many plants, fruits, vegetables, and leaves. They have a multitude of medicinal applications due to their anti-inflammatory, antioxidative, antiviral, and anticarcinogenic properties. Furthermore, they also have neuroprotective and cardioprotective effects. Their biological properties depend on the chemical structure of flavonoids, their mechanism of action, and their bioavailability. The beneficial effects of flavonoids have been proven for a variety of diseases. In the last few years, it is demonstrated that the effects of flavonoids are mediated by inhibiting the NF-κB (Nuclear Factor-κB) pathway. In this review, we have summarized the effects of some flavonoids on the most common diseases, such as cancer, cardiovascular, and human neurodegenerative diseases. Here, we collected all recent studies describing the protective and prevention role of flavonoids derived from plants by specifically focusing their action on the NF-κB signaling pathway.
... Recently, Debashis Dutta et al. demonstrated that, by specifically targeting the TLR2/NF-κB pathway, it is possible to reduce the -synuclein spreading in vitro and in vivo, finally contributing to the treatment of neurodegenerative diseases such as Parkinson's disease (PD) [124]. Clinical studies highlight the preventive effects of correct and healthy nutrition in the field of neurodegenerative diseases and especially AD or atherosclerosis [125,126]. Many nutraceutical bioactive principles have anti-platelet activity as well as anti-inflammatory activities [125]. ...
... Clinical studies highlight the preventive effects of correct and healthy nutrition in the field of neurodegenerative diseases and especially AD or atherosclerosis [125,126]. Many nutraceutical bioactive principles have anti-platelet activity as well as anti-inflammatory activities [125]. ...
Flavonoids are polyphenolic phytochemical compounds found in many plants, fruits, vegetables, and leaves. They have a multitude of medicinal applications due to their anti-inflammatory, anti-oxidative, anti-viral, and anti-carcinogenic properties. Furthermore, they also have neuroprotective and cardioprotective effects. Their biological properties depend on the chemical structure of flavonoids, their mechanism of action, and their bioavailability. The flavonoid’s beneficial effects have been proven for a variety of diseases. In the last few years, it is demonstrated that flavonoids’ effects are mediated by inhibiting the NF-κB (Nuclear Factor-κB) pathway. In this review, we have summarized the effects of some flavonoids on the most common diseases such as cancer, cardiovascular, and neurodegenerative human diseases. In particular, here we collected all recent studies describing plant-derived flavonoids’ protective and prevention role, by specifically focusing their action on the NF-κB signaling pathway.
... 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]. ...
... The histopathology of Alzheimer's disease is characterized by the accumulation of intracellular hyperphosphorylated tau proteins and extracellular aggregation of neuritic plaques, both promoting synaptic loss and neuronal death in the cerebral cortex and hippocampus of the brain [17,30]. Concerning the biological study of Alzheimer's brain, two major proteins have been detected: 1) Senil plaques, synthesized by deposition of the amyloid peptide of 39-42 amino acid residues, formed by the proteolytic excision of amyloid precursor protein (APP) by enzymes, in the extracellular space and 2) neurofibrillary tangles (NFT), formed by progressive aggregation of the hyperphosphorylated tau protein inside neurons [3,19]. ...
... They have been shown to be beneficial in the prevention and treatment of diseases, as well as in improving longevity and normalizing body functions. ( Calfio C, 2020). One of the significant advantages of nutraceuticals is their cost-effectiveness compared to synthetic drugs. ...
The ApoE4 allele is a well-studied genetic risk factor for Alzheimer's disease, a condition with increasing prevalence and no cure. Precision nutrition, which targets metabolic pathways affected by ApoE4, offers a potential tool for disease prevention. However, long-term human studies on effective nutritional protocols for preventing Alzheimer's in ApoE4 carriers are lacking, partly because the precise mechanisms underlying the increased dementia risk in carriers are not fully understood. Fortunately, recent research has shed light on these mechanisms, opening up opportunities for potential risk reduction through lifestyle and nutrition interventions. In this research paper we discuss about the chawanprash phytocompounds and it is found that Terchebin is the effective phytocompund though docking and simulation methods and thereby indicating the potent Nutraceutical against various Neurological manifestations that is caused due to SARS Cov2 and AD. In this review, we explore recent findings on how ApoE4 impacts various cellular processes, including microglia and other inflammatory pathways.
... 35 In addition, different prevention strategies have been proposed based on changing people's lifestyles, mainly diet. The diet changes involve using supplements, functional foods, natural extracts, and nutraceuticals to modify the inflammatory and neurodegeneration mechanisms of AD. 36 A food-based intervention is an attractive strategy for preventing and ameliorating AD. ...
Nowadays, nutraceuticals are being incorporated into functional foods or used as supplements with nonpharmacological approaches in the prevention and management of several illnesses, including age-related conditions and chronic neurodegenerative diseases. Nutraceuticals are apt for preventing and treating such disorders because of their nontoxic, non-habit-forming, and efficient bioactivities for promoting neurological well-being due to their ability to influence cellular processes such as neurogenesis, synaptogenesis, synaptic transmission, neuro-inflammation, oxidative stress, cell death modulation, and neuronal survival. The capacity of nutraceuticals to modify all of these processes reveals the potential to develop food-based strategies to aid brain development and enhance brain function, prevent and ameliorate neurodegeneration, and possibly reverse the cognitive impairment observed in Alzheimer’s disease, the most predominant form of dementia in the elderly. The current review summarizes the experimental evidence of the neuroprotective capacity of nutraceuticals against Alzheimer’s disease, describing their mechanisms of action and the in vitro and in vivo models applied to evaluate their neuroprotective potential.
... Therefore, inhibition of the β-sheet plays an important role in inhibiting Aβ aggregation. A number of studies have been conducted to find methods that can inhibit Aβ aggregation based on pathological findings caused by its aggregation [90,91]. Small molecule natural products have been found to be effective in inhibiting the aggregation of Aβ oligomers, protofibrils, and fibrosis, thus significantly reducing the harmful toxicity caused by Aβ deposition. ...
Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.
... In this context, it is relevant that flavonoids could have anti-inflammatory [34, [203][204][205][206][207][208][209] and neuroprotective effects [210], as well as reduce cognitive dysfunction [211][212][213][214][215], especially brain fog [216][217][218]. In particular, luteolin inhibited both microglia [219][220][221] and mast cells [222,223]. ...
Mast cells have existed for millions of years in species that never suffer from allergic reactions. Hence, in addition to allergies, mast cells can play a critical role in homeostasis and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may utilize different modes that involve the cytoskeleton, but our understanding of the molecular mechanisms regulating secretion is still not well understood. The Ezrin/Radixin/Moesin (ERM) family of proteins is involved in linking cell surface-initiated signaling to the actin cytoskeleton. However, how ERMs may regulate secretion from mast cells is still poorly understood. ERMs contain two functional domains connected through a long α-helix region, the N-terminal FERM (band 4.1 protein-ERM) domain and the C-terminal ERM association domain (C-ERMAD). The FERM domain and the C-ERMAD can bind to each other in a head-to-tail manner, leading to a closed/inactive conformation. Typically, phosphorylation on the C-terminus Thr has been associated with the activation of ERMs, including secretion from macrophages and platelets. It has previously been shown that the ability of the so-called mast cell “stabilizer” disodium cromoglycate (cromolyn) to inhibit secretion from rat mast cells closely paralleled the phosphorylation of a 78 kDa protein, which was subsequently shown to be moesin, a member of ERMs. Interestingly, the phosphorylation of moesin during the inhibition of mast cell secretion was on the N-terminal Ser56/74 and Thr66 residues. This phosphorylation pattern could lock moesin in its inactive state and render it inaccessible to binding to the Soluble NSF attachment protein receptors (SNAREs) and synaptosomal-associated proteins (SNAPs) critical for exocytosis. Using confocal microscopic imaging, we showed moesin was found to colocalize with actin and cluster around secretory granules during inhibition of secretion. In conclusion, the phosphorylation pattern and localization of moesin may be important in the regulation of mast cell secretion and could be targeted for the development of effective inhibitors of secretion of allergic and inflammatory mediators from mast cells.
... Further, the powder of A. costus has been reported to have a significant effect against blisters, skin to cure boils, and leprosy (Nadda et al., 2020). Ayurveda medicines significantly affect acetylcholinesterase expression, oxidation products, β-amyloid senile plaques, inflammatory pathways, specific brain receptors involved in Alzheimer's disease (AD) (Calfio et al., 2020). The main goal of TCM was to get balanced nutrition providing all the nutrients to achieve balance and harmony within the body . ...
Herbal-based traditional medicines have a long history of therapeutic application throughout the world. Ayurveda and Chinese herbs have been traditionally used as indigenous complementary and alternative medicine to treat various types of diseases since ancient times effectively. These medicines demonstrated fewer toxic effects, prolonged survival rates, and enhanced quality of life. Further, the use of Ayurvedic and Chinese medicine in combination with chemotherapy and radiotherapy enhances these therapies' efficacy. Cancer is a complex disease and the leading cause of death worldwide. The existing anti-cancer therapies do not address the challenges arising from tumor heterogeneity, such as developing drug resistance and the side effects of these therapies. In this context, different preclinical and clinical experiments show different modes of actions of Ayurveda and Chinese herbs in various cancers, such as induction of apoptosis, modulation of tumor suppressor genes and oncogenes, interaction with the tumor microenvironment, inhibition of metastasis, and cancer stem cells proliferation. Interestingly, these medicines have less or no toxic effect on normal cells. This chapter will illustrate the efficacy of Ayurvedic and Chinese herbal medicine in combating different cancers, either alone or in combination with other therapies.
... Epigallocatechin-3-gallate (EGCG) is the most abundant and essential catechin in green tea extract, with antioxidative, antiinflammatory, and neuroprotective benefits [98][99][100] . Substantial evidence supports that EGCG could be a new therapeutic agent for AD [101 , 102] . ...
Alzheimer's disease (AD) is a progressive neurodegenerative disease in which senile plaques, neurofibrillary tangles, insulin resistance, oxidative stress, chronic neuroinflammation, and abnormal neurotransmission are the potential mechanisms involved in its onset and development. Although it is still an intractable disorder, diet intervention has been developed as an innovative strategy for AD prevention. Some bioactive compounds and micronutrients from food, including soy isoflavones, rutin, vitamin B1, etc., have exhibited numerous neuronal health-promoting effects in both in vivo and in vitro studies. It is well known that their antiapoptotic, antioxidative, and anti-inflammatory properties prevent the neuronal or glial cells from injury or death, minimize oxidative damage, inhibit the production of proinflammatory cytokines by modulating typical signaling pathways of MAPK, NF-kβ, and TLR, and further reduce Aβ genesis and tau hyperphosphorylation. However, parts of the dietary components trigger AD-related proteins productions and inflammasome as well as inflammatory gene upregulation. This review summarized the neuroprotective or nerve damage-promoting role and underlying molecular mechanisms of flavonoids, vitamins, and fatty acids via the data from library databases, PubMed, and journal websites, which provides a comprehensive analysis of the prevention potential of these dietary components against AD.
... Inhibition of brain inflammation could instead be accomplished with the use of some natural flavonoids [79,[307][308][309][310][311][312]. In particular, the flavone luteolin inhibits both Cells 2023, 12, 688 9 of 24 microglia [149,313,314] and mast cells [315,316], as well as related inflammatory processes [147,311]. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as “Long-COVID,” characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain. However, the precise role of the neuroinflammatory response that contributes to the disease severity of COVID-19 and long COVID pathogenesis is not clearly understood. Here, we review the reports that the SARS-CoV-2 spike protein can cause blood–brain barrier (BBB) dysfunction and damage neurons either directly, or via activation of brain mast cells and microglia and the release of various neuroinflammatory molecules. Moreover, we provide recent evidence that the novel flavanol eriodictyol is particularly suited for development as an effective treatment alone or together with oleuropein and sulforaphane (ViralProtek®), all of which have potent anti-viral and anti-inflammatory actions.
... Herbal medicines have been extensively explored in recent years regarding their biological activities and potential therapeutic benefits for neurodegenerative disorders (Mohd Sairazi and Sirajudeen, 2020) (Mecocci et al., 2014;Makkar et al., 2020). Emerging evidence has shown that some herbal medicines and their bioactive components used in combination can illustrate synergistic and multi-target effects (Liebner et al., 2018;Choi et al., 2011;Lin, 2011;Calfio et al., 2020). Yang et al. (2021b) demonstrated that a herbal combination of Aconitum carmichaelii Debx. ...
Introduction: Neuroinflammation is an important pathological event contributing to the onset and progression of neurodegenerative diseases. The hyperactivation of microglia triggers the release of excessive proinflammatory mediators that lead to the leaky blood-brain barrier and impaired neuronal survival. Andrographolide (AN), baicalein (BA) and 6-shogaol (6-SG) possess anti-neuroinflammatory properties through diverse mechanisms of action. The present study aims to investigate the effects of the pair-combinations of these bioactive compounds in attenuating neuroinflammation.
Methods: A tri-culture model with microglial N11 cells, microvascular endothelial MVEC(B3) cells, and neuroblastoma N2A cells was established in a transwell system. AN, BA and 6-SG used alone (25 µM) or in pair-wised combinations (12.5 + 12.5 µM) were subjected to the tri-culture system. Upon the stimulation of lipopolysaccharides (LPS) at 1 μg/mL, tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) levels were determined by ELISA assays. Immunofluorescence staining was applied to investigate the nuclear translocation of nuclear factor kappa B p65 (NF-κB p65) on N11 cells, expressions of protein zonula occludens-1 (ZO-1) on MVEC cells and phosphorylated tau (p-tau) on N2A cells, respectively. The endothelial barrier permeability of MVEC cells was assessed by the Evans blue dye, and the resistance from the endothelial barrier was measured by transepithelial/endothelial electrical resistance (TEER) value. Neuronal survival of N2A cells was determined by Alamar blue and MTT assays.
Results: Combinations of AN-SG and BA-SG synergistically lowered the TNF and IL-6 levels in LPS-induced N11 cells. Remarkably, the combined anti-neuroinflammatory effects of AN-SG and BA-SG remained significantly greater compared to their individual components at the same concentration level. The molecular mechanism of the attenuated neuroinflammation was likely to be mediated by downregulation of NF-κB p65 translocation ( p < 0.0001 vs. LPS stimulation) in N11 cells. In the MVEC cells, both AN-SG and BA-SG restored TEER values, ZO-1 expression and reduced permeability. Furthermore, AN-SG and BA-SG significantly improved neuronal survival and reduced expressions of p-tau on N2A cells.
Discussion: The AN-SG and BA-SG combinations showed greater anti-neuroinflammatory potential than those used alone in mono- and tri-cultured N11 cells, thereby further protecting endothelial tight junction and neuronal survival. Taken together, AN-SG and BA-SG may provide improved anti-neuroinflammatory and neuroprotective activities.
... Based on biological plausibility and pre-clinical evidence of potential benefit [10][11][12], several dietary supplements have been formally studied in PD clinical trials, such as coenzyme Q10 [13][14][15], creatine [16,17], glutathione [18][19][20], N-acetyl cysteine (NAC) [21] and nicotinamide [22]. The results have been mixed in randomized clinical trials, suggesting either true non-efficacy of nutraceuticals or that our pre-clinical models, traditional outcome measures, and/or study designs are flawed. ...
Background:
It is estimated that half of the individuals with Parkinson's disease (PD) use some form of over-the-counter vitamin, herbal supplement or nutraceutical. The goal of this study was to survey individuals with PD about their use of the nutraceuticals and evaluate the association of the nutraceutical with the severity of symptoms.
Methods:
Participants with self-reported idiopathic PD within the 2021 cohort (n = 1084) were included in a cross-sectional study to assess association of nutraceuticals with symptom severity via linear regression analysis. PD severity was measured using the patient-reported outcomes in PD, and supplement use reflected self-reported consistent use over the previous six months. All regression analyses adjusted for age, gender, income and years since diagnosis. The use of the term progression refers to PRO-PD scores adjusted for years since diagnosis.
Results:
The most frequently used supplements were vitamin D (71%), B12 (44%), vitamin C (38%) and fish oil (38%). None of the supplements being used were associated with statistically significant worse outcomes. Nutraceuticals associated with improved outcomes were Ginkgo biloba (GB), NAD+ or its precursors, 5-methyltetrahydrofolate, glutathione, mucuna, CoQ10, low dose lithium, curcumin, homocysteine factors, DHEA, coconut oil, vitamin C, and omega-3 fatty acids (fish oil).
Conclusions:
These data suggest that in a real-world setting, some over-the-counter supplements are associated with fewer patient-reported symptoms. Supplements with significant associations with fewer symptoms have biological plausibility and future clinical trials should be explored.
... Moreover, the effects of both natural (genistein and delphinidin) and synthetic antioxidants, a nitroxide (4-amino-TEMPO, 4-AT), and nitroxide-containing redox nanoparticles (NPs) were examined. Delphinidin was found to interfere with the mechanisms of tau protein aggregation [17], inhibit tau hyperphosphorylation [18], and inhibit spatial memory impairment and AD hallmarks in Meynert lesioned rats in an animal model of AD [19]. Genistein has been reported to inhibit dopaminergic neuronal death [20] and was suggested to have potential for the delay and treatment of AD [21,22]. ...
Abnormally phosphorylated tau protein is the principal component of neurofibrillary tangles, accumulating in the brain in many neurodegenerative diseases, including Alzheimer’s disease. The aim of this study was to examine whether overexpression of tau protein leads to changes in the redox status of human neuroblastoma SH-SY5Y cells. The level of reactive oxygen species (ROS) was elevated in tau-overexpressing cells (TAU cells) as compared with cells transfected with the empty vector (EP cells). The level of glutathione was increased in TAU cells, apparently due to overproduction as an adaptation to oxidative stress. The TAU cells had elevated mitochondrial mass. They were more sensitive to 6-hydroxydopamine, delphinidin, 4-amino-TEMPO, and nitroxide-containing nanoparticles (NPs) compared to EP controls. These results indicate that overexpression of the tau protein imposes oxidative stress on the cells. The nitroxide 4-amino-TEMPO and nitroxide-containing nanoparticles (NPs) mitigated oxidative stress in TAU cells, decreasing the level of ROS. Nitroxide-containing nanoparticles lowered the level of lipid peroxidation in both TAU and EP cells, suggesting that nitroxides and NPs may mitigate tau-protein-induced oxidative stress.
... Recently, some preclinical research into PSCs has been conducted, which will aid in creating innovative therapeutics for CP. In addition, natural chemicals derived from medicinal plants have great potential as antifibrotic drugs for the treatment of CP and deserve more in-depth studies in vivo and in vitro (Calfio et al., 2020). ...
Chronic pancreatitis (CP) is a precancerous illness linked to pancreatic ductal adenocarcinoma (PDAC), although the evolutionary mechanism is uncertain. CP is distinguished by severe fibrosis caused by the activation of pancreatic stellate cells (PSCs). The current clinical therapeutic protocol for CP lacks specific therapeutic medicines for the prevention and suppression of inflammation and fibrosis aggravating in CP. More research on specifically targeting PSCs would help facilitate the development of novel therapies for pancreatic fibrosis. Notably, using natural compounds from medicinal plants as new antifibrotic agents has become a focus of recent research and is widely employed as an alternative and complementary approach. Our goal was to shed light on the role of PSCs in the development of CP and provide a focused update on the new potential therapeutic strategies against PSCs in CP models. Future studies can refer to these possible strategies for drug design, bioavailability, pharmacokinetics, and other issues to obtain better clinical outcomes for treating CP.
... 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). ...
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.
... 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). ...
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.
... However, the exact etiology and prognosis of AD are not completely clear, and effective treatment drugs and preventive measures are still lacking. Symptomatic treatment of AD with a single target can delay the progression of the disease, but cannot fundamentally treat AD (Calfio et al., 2020). Clinical studies have shown that traditional Chinese medicine (TCM) can improve patients' neuropsychological scale score, TCM symptom score and quality of life, delay Ab deposition, and tau lesions, and regulate the metabolism of the cholinergic neurotransmitters, etc. . ...
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.
... 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). ...
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.
... 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. ...
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.
... 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. ...
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.
... 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). ...
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.
... 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. ...
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.
... 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. ...
Background:
Alzheimer's disease (AD) is a leading killer of Americans, imparting a tremendous societal toll. Relationships between immune function and inflammation with cognition are well-established in AD, but the Th1/Th2 ratio of immune function is unknown. Describing the Th1/Th2 ratio and its relationship with cognition may shed light on the disease's clinical context. How the Th1/Th2 ratio responds to dietary supplementation is another unknown question in this population.
Objective:
The objectives of the study were to: 1) characterize the Th1/Th2 ratio according to IL-2/IL-10, IFN-γ/IL-10, IL-2/IL-4, IFN-γ/IL-4, IL-2/TNF-α, and IFN-γ/TNF-α in subjects with moderate-to-severe AD and in comparison to healthy adults; 2) investigate the effect of an aloe polymannose multinutrient complex (APMC) dietary supplement on the Th1/Th2 ratios over 12 months; and 3) compare the changes in the Th1/Th2 ratios with the changes in cognition from baseline to 12 months.
Methods:
Subjects consumed 2.5 g of the APMC four times per day for 12 months, and they were assessed on cognition and cytokines at baseline and 12 months.
Results:
The Th1/Th2 ratios in AD patients were significantly higher than the healthy controls, and five of the six ratios decreased from baseline to 12 months follow-up (other than IL-2/TNF-α). Several significant relationships were noted between the changes in Th1/Th2 ratios with cognitive assessments.
Conclusions:
Our results showed an overall rebalancing of the Th1/Th2 ratio in response to APMC, these changes were related to improved cognition in subjects with moderate-to-severe AD, and the APMC supplement was safely tolerated.
Different investigations lead to the urgent need to generate validated clinical protocols as a tool for medical doctors to orientate patients under risk for a preventive approach to control Alzheimer’s disease. Moreover, there is consensus that the summation of risk factors for the disease can be modified according to lifestyle, thus controlling at least 40% of cases. Another fraction of cases derives from candidate genes and epigenetic components as a relevant factor in AD pathogenesis. At this point, it appears to be of critical relevance the search for molecular biomarkers that may provide information on probable pathological events and alert about early detectable risks to prevent symptomatic events of the disease. These precocious detection markers will then allow early interventions of non-symptomatic subjects at risk. Here, we summarize the status and potential avenues of prevention and highlight the usefulness of biological and reliable markers for AD.
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder without a cure, despite the enormous number of investigations and therapeutic approaches. AD is a consequence of microglial responses to “damage signals”, such as aggregated tau oligomers, which trigger a neuro-inflammatory reaction, promoting the misfolding of cytoskeleton structure. Since AD is the most prevalent cause of dementia in the elderly (>60 years old), new treatments are essential to improve the well-being of affected subjects. The pharmaceutical industry has not developed new drugs with efficacy for controlling AD. In this context, major attention has been given to nutraceuticals and novel bioactive compounds, such as molecules from the Andean Shilajit (AnSh), obtained from the Andes of Chile. Primary cultures of rat hippocampal neurons and mouse neuroblastoma cells were evaluated to examine the functional and neuroprotective role of different AnSh fractions. Our findings show that AnSh fractions increase the number and length of neuronal processes at a differential dose. All fractions were viable in neurons. The AnSh fractions inhibit tau self-aggregation after 10 days of treatment. Finally, we identified two candidate molecules in M3 fractions assayed by UPLC/MS. Our research points to a novel AnSh-derived fraction that is helpful in AD. Intensive work toward elucidation of the molecular mechanisms is being carried out. AnSh is an alternative for AD treatment or as a coadjuvant for an effective treatment
Ethnopharmacological relevance
The important genus Inula contains more than 100 species and is widespread in the temperate regions of Asia, Africa, and Europe. Numerous Inula species have an ethnobotanical background and are used in Traditional Chinese Medicine (TCM).
Aim of the study
This review is a comprehensive study of the more practical therapeutic uses of Inula spp. and their phytochemical compounds in terms of their pharmacological activities, mainly neuroprotective effects. Traditional uses of the genus are described by focusing of TCM. Pharmaceutical, cosmeceutical, and ecological impacts, and their importance in food science, are elaborated upon as well. The pharmacokinetic profile, safety, and toxicity of this genus are also described.
Materials and methods
Literature in this review was searched in PubMed, Scopus, Web of Science, and Google Scholar using the keywords “Inula”, “neuro*”, “Alzheimer's disease”, “neuroinflammation”, “seizure”, “epilepsy”, “headache”, “nociception”, “pain”, “insomnia”, “neurotoxicity”, “depression”, “glioblastoma”, and “traumatic brain injury”.
Results
This study will provide insight into the neuropharmacological applications of Inula spp. by focusing on the attributed mechanisms of action. The genus Inula has promising protective effects against Alzheimer's disease, neuroinflammation, seizures, insomnia, headaches, neurotoxicity attributed to oxidative damage, depression, nociception, traumatic brain injury, neuromuscular dysfunction, glioblastoma, and primary amoebic meningoencephalitis by targeting various mechanisms and signaling pathways.
Conclusion
Due to the acceptable oral bioavailability, blood-brain barrier permeability, and low toxicity of Inula spp. they can be considered promising alternative neuroprotective agents. However more clinical studies are needed in this regard.
Tau aggregation is a hallmark of several neurodegenerative disorders, such as Alzheimer's disease (AD), frontotemporal dementia, and progressive supranuclear palsy. Hyperphosphorylated tau is believed to contribute to the degeneration of neurons and the development of these complex diseases. Therefore, one potential treatment for these illnesses is to prevent or counteract tau aggregation. In recent years, interest has been increasing in developing nature-derived tau aggregation inhibitors as a potential treatment for neurodegenerative disorders. Researchers have become increasingly interested in natural compounds with multifunctional features, such as flavonoids, alkaloids, resveratrol, and curcumin, since these molecules can interact simultaneously with the various targets of AD. Recent studies have demonstrated that several natural compounds can inhibit tau aggregation and promote the disassembly of pre-formed tau aggregates. Nature-derived tau aggregation inhibitors hold promise as a potential treatment for neurodegenerative disorders. However, it is important to note that more research is needed to fully understand the mechanisms by which these compounds exert their effects and their safety and efficacy in preclinical and clinical studies. Nature-derived inhibitors of tau aggregation are a promising new direction in the research of neurodegenerative complexities. This review focuses on the natural products that have proven to be a rich supply for inhibitors in tau aggregation and their uses in neurodegenerative complexities, including AD.
Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by progressive cognitive dysfunction and memory impairment. Recent studies have shown that regulating silent information regulator 1 (SIRT1) expression has a significant neuroprotective effect, and SIRT1 may become a new therapeutic target for AD. Natural molecules are an important source of drug development for use in AD therapy and may regulate a wide range of biological events by regulating SIRT1 as well as other SIRT1-mediated signaling pathways. This review aims to summarize the correlation between SIRT1 and AD and to identify in vivo and in vitro studies investigating the anti-AD properties of natural molecules as modulators of SIRT1 and SIRT1-mediated signaling pathways. A literature search was conducted for studies published between January 2000 and October 2022 using various literature databases, including Web of Science, PubMed, Google Scholar, Science Direct, and EMBASE. Natural molecules, such as resveratrol, quercetin, icariin, bisdemethoxycurcumin, dihydromyricetin, salidroside, patchouli, sesamin, rhein, ligustilide, tetramethoxyflavanone, 1-theanine, schisandrin, curcumin, betaine, pterostilbene, ampelopsin, schisanhenol, and eriodictyol, have the potential to modulate SIRT1 and SIRT1 signaling pathways, thereby combating AD. The natural molecules modulating SIRT1 discussed in this review provide a potentially novel multi-mechanistic therapeutic strategy for AD. However, future clinical trials need to be conducted to further investigate their beneficial properties and to determine the safety and efficacy of SIRT1 natural activators against AD.
Introducción: el declive cognitivo es un marcador de la aparición y avance de la enfermedad de Alzheimer (EA). Actualmente, la modificación de factores de riesgo, como la nutrición, son promisorios para el tratamiento de la EA. El objetivo fue Identificar el efecto de la suplementación de vitaminas del complejo B sobre el declive cognitivo en pacientes con daño cognitivo o EA. Materiales y métodos: Revisión sistemática y metaanálisis de la literatura en cinco buscadores (PROSPERO CRD42021247743). Se incluyeron experimentos controlados, en adultos de 60 o más años, con medición del estado cognitivo (ADAS-Cog, Clinical dementia ratin-CDR y/o Mini Mental State Examination-MMSE) y uso de suplementos de vitaminas del complejo B de manera individual o combinada con otras vitaminas o fármacos. La evaluación de la calidad se hizo con la herramienta RoB-2. La selección, extracción y evaluación se hizo por tres investigadores de manera independiente. El metaanálisis empleo la diferencia media y modelos de efectos aleatorios. Resultados: la búsqueda arrojo 247 referencias y finalmente se incluyeron 12 para el metaanálisis. No se encontraron sesgos de publicación. La calidad de los estudios es adecuada. El suplemento de vitamina B no mostró efecto sobre el declive cognitivo medido por ADAS-Cog (DM 0.01 IC95% -0.7 a 0.72), CDR (DM –0.06 IC95% -0.48 a 0.36) y MMSE (DM 0.3 IC95% -0.01 a 0.61). Conclusiones: el declive cognitivo es invariable ante la suplementación de vitaminas del complejo B en adultos con daño cognitivo o Enfermedad de Alzheimer. Futuras investigaciones deben enfocarse hacia estrategias multi intervención. Palabras claves: Enfermedad de Alzheimer; declive cognitivo; vitaminas del complejo B; metaanálisis. Financiación: Los autores/as declaran que no ha existido financiación para realizar este estudio. Registro: PROSPERO CRD42021247743
Extensive research has revealed numerous benefits of many nutrients in the diet that could optimize brain function, which is critically important for everyone, especially particularly in light of the many potential long-term negative neurobiological consequences that survivors of adverse childhood experiences and trauma may experience throughout their life course. The purpose of this chapter is to present a review of the literature on the state of the science on the impact of dietary nutrition on the brain including specific diets, vitamins, herbs, spices, nutraceuticals, and essential fatty acids. Additionally, the emerging research on the microbiota-gut-brain axis, neuro-immunity, prebiotics, and probiotics associated with brain function and specific conditions such as autism spectrum disorders, neuropsychiatric conditions and neurodegeneration are described. Pragmatics for an anti-inflammatory brain health diet include foods that could optimize brain function, foods that could be detrimental to brain function, timing of food choices throughout the day, caloric restriction and directions for future research and public health policy are addressed. Optimally soon, much more research evidence will be available about precision and personalized nutritional approaches to optimize dietary guidance and improve nutritional status. Precision and personalized nutrition should vary between individuals for those who already have particular illnesses or are at risk for certain conditions that may potentially be prevented or delayed with specific dietary interventions.
Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.
Humulus japonicus (HJ) is an herbal medicine, which has been reported as being antioxidative and anti-inflammatory. The present study aimed to investigate the effect of oral administration of HJ water extract (HJW) on cognitive function through the cholinergic system in Alzheimer's disease (AD) mouse models. Institute of Cancer Research mice injected with beta-amyloid (Aβ) (1-42) (i.c.v.) and APP/PS1 transgenic (TG) mice were orally administered with HJW at 500 mg/kg/day for 3 weeks. Aβ-injected mice and APP/PS1 TG mice showed cognitive dysfunction, which was evaluated by various behavioral tests. HJW treatment significantly attenuated memory impairments in Aβ-injected mice and APP/PS1 TG mice. Aβ injection decreased acetylcholine (ACh) concentrations and choline acetyltransferase (ChAT) activity, and increased acetylcholinesterase (AChE) activity. These cholinergic impairments were also found in APP/PS1 TG mice. HJW significantly attenuated cholinergic alterations in Aβ-injected mice and TG mice. In addition, HJW significantly decreased Aβ plaque deposition in the cerebral cortex and hippocampus of TG mice. Therefore, the present study demonstrated that HJW protected against AD-related memory impairments via enhancing the cholinergic system and inhibiting Aβ plaque deposition.
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.
Lipids a source of energy and can also be stored in body cells for proper cellular functions. Defects in lipid metabolism can lead to a wide range of metabolic disorders. A number of risk factors are generally responsible for the dysregulation of lipid metabolism and subsequently the development of metabolic diseases. In this chapter, the pathophysiology of several lipid-metabolism-related diseases has been discussed, and the therapeutic potential of different phytochemicals or plant-derived phytonutrients in managing these disorders are highlighted. There are several medicinal secondary metabolites, which could be highly significant to manage the lipid profile and prevent the development of serious outcomes of lipid-metabolism abnormalities such as hyperchylomicronemia, hypercholesterolemia, atherosclerosis, cancer, obesity, insulin sensitivity, and resistance. Many phytonutrients isolated from fruits, vegetables, and plant sources have presented their broad spectrum of medicinal activities to modulate metabolic processes and are also involved in lipid metabolism and the management of cholesterol levels in body. Bioactive compounds such as small molecular phytonutrients from natural sources have suggested prospective treatments against lipid-metabolism-related abnormalities and have been defined in this chapter. Considering diverse physiochemical properties and therapeutic value of phytonutrients, it is highly recommended to introduce more vegetables, and fruits in the dietary regimen to intake food containing fewer fats and high fibers so that it could significantly aid the management of lipid-metabolism-related diseases.
The elaboration of therapeutic protocols using natural compounds can help in improving the outcomes of many human conditions such as malignant disorders, neurodegenerative diseases, and systemic disorders. Recently, the attention of scientists was more focused on nutraceuticals as potential candidates that can be administered in the management strategy of various pathologies. This rise in nutraceutical applications is due to their relative safety and their pleiotropic effects. Several studies suggest the use of dietary regimens and food-derived substances for the prevention and treatment of many metabolic disorders that affect the central nervous system. The neuroprotective actions offered by these substances are mediated by their pertinent antiapoptotic, antiinflammatory, and antioxidative potentials. Some compounds may also intervene in the promotion of individuals’ health via the regulation of the process of autophagy and via the enhancement of the functionality of intracellular organelles such as mitochondria. Furthermore, healthy diet and the use of dietary supplements can directly influence the functions and the progeny of neural stem cells and the metabolism of microglial cells and can influence the polarization of macrophages in the nervous tissue resulting in better outcomes in some pathologic situations. In this chapter, we review the different roles and applications of nutraceuticals in the treatment of the major brain disorders that can affect human beings.
Metabolic diseases are devastating abnormalities that address human lives toward death if they are not correctly managed. Obesity and diabetes mellitus are the prime factors that induce insulin resistance to signaling pathways and increase the risk of cardiovascular diseases. Phytonutrients are the biologically active agents derived from natural sources such as vegetables, fruits, grains, cereals, and medicinal plants, and present the ability to boost the immune system of patients with metabolic disease and also enhance the conditions by the management of lipid profiles, insulin resistance and glucose homeostasis, and chemopreventive events in case of cancer disease. This chapter highlights some phytonutrients that may have issues with the gene and produce healthy and unhealthy interactions. However, the interaction between genetic and environmental factors such as intake of particular healthy and sufficient diet plans with a good lifestyle encourages the development and pathogenesis of diseases of polygenic dietary components. Phytonutrients are critical tools for the modulation of gene expressions involved in signaling pathways and phenotypes linked with metabolic diseases. It is also noted that human health is also affected by dietary nutrients having carcinogens and aflatoxin attached with them and influence the genetic variants. As the knowledge of carcinogen and anticarcinogen increases, nutritional science leads to promising therapeutics for cancer management by healthy diet plans. This chapter has depicted essential aspects of phytonutrients and their interactions with genes in metabolic disease prevention and treatments.
In spite of the advanced researches, preventive measures, and treatment options, cancer remains a growing ailment all over the world and its prevalence is estimated to increase in future. Cellular metabolic alterations have been documented as a hallmark of cancer. Metabolic regulation is an intricately coupled process whose deregulation leads to tumor progression as well as metastasis. In order to thrive in the living system, cancer cells adapt different metabolic pathways (bioenergetics and biosynthesis). They replenish their metabolic demands by switching from normal metabolism to cancer metabolism by the process of metabolic rewiring. Recent researches suggest that starving cancer cells by the use of nontoxic chemical entities can give promising results regarding cancer proliferation. Natural products, especially those of plant origin, offer different chemical scaffolds to target cancer via modulation of multiple cell signaling cascades. Phytonutrients, the secondary metabolites from the plants, constitute edible phytochemicals which are abundantly found in vegetables, whole grains, and fruits. The growing numbers of evidences suggest that phytonutrients exhibit anticancer as well as chemopreventive activities of these bioactive molecules against several cancers by targeting the various significant enzymes of glycolysis, the PPP pathway, TCA cycle, and serine metabolism. This book chapter presents an update for the scientific community about targeting the cancer metabolism by phytonutrients. The alterations in the cancer metabolism in the context of bioenergetics, biosynthesis, and mitochondrial functions have been discussed while presenting the impact of phytonutrients as modulators of potential metabolic effectors in the cancer metabolism.
Mitochondria are the main organelles responsible for generating cellular energy. The common symptom of mitochondrial disorders is extreme fatigue. The lowered mitochondrial activity owing to lack of chemical transmembrane capacity, changes in the electron transport chain’s function, the maintenance of the inner mitochondrial membrane’s electrical and decrease in essential metabolites transport to the mitochondria. The change in mitochondrial activity is brought about by the reduction of adenosine-5′-triphosphate (ATP) and oxidative phosphorylation. The mitochondrial activity needs regular replacement of natural phytochemicals and supplementations that help to maintain the energy level. The efficacy of oral alternative nutrients like reduced nicotinamide adenine dinucleotide (NADH), alpha-lipoic acid, coenzyme Q10, alpha-lipoic acid carnitine, membrane phospholipids, and other supplements was evaluated in clinical studies and were found effective against mitochondrial disorders. Combinations of these supplements can substantially alleviate weakness and other symptoms associated with mitochondrial disorders in patients. The frequent intake of these nutrients can also help to reduce the onset of various neurological disorders along with mitochondrial dysfunction. These results have significant effects on the welfare of both the civilian and military communities.
Dementia is a condition in which memory, perception, behavior, and the capacity to do normal tasks deteriorate. While dementia affects the elderly predominantly, it is not a common aspect of aging. Around 50 million people have dementia globally, with almost 60% residing in low- and middle-income countries, and almost 10 million new cases are reported per year (Dementia 2020). There are about 10 million new cases each year. The average percentage at a given time of the general population aged 60 and over with dementia is between 5% and 8%. It is estimated that the overall number of people with dementia will exceed 82 million in 2030 and 152 million in 2050 (Dementia 2020). Dementia in older people worldwide is one of the main causes of disease and dependence. Dementia not only has a physical, mental, social, and economic effect on individuals with dementia but also on their relatives, friends, and community as a whole (Dementia 2020).
Active ingredients of medicinal plants have unique pharmacological and clinical effects. However, conventional extraction technology has many disadvantages, such as long-time and low-efficiency. XynA-assisted extraction may overcome such problems, since the plant cell wall is mainly composed of cellulose. Based on the three-dimensional protein structure, we found the C-terminal domain and N-terminal domain twisted together and resulted in more flexibility. We carried out a series of truncations, with XynA_ΔN36 getting more yields of active ingredients. As shown by HPLC analysis, the efficiencies for extraction of salvianic acid A and berberine from Salvia miltiorrhiza and Phellodendron chinense were increased by approximately 38.14% and 35.20%, respectively, compared with the conventional extraction protocol. The yields of the two compounds reached 2.84 ± 0.05 mg g⁻¹ and 3.52 ± 0.14 mg g⁻¹, respectively. Above all, XynA_ΔN36 can be applied to the extraction of salvianic acid A and berberine, and this study provides a novel enzyme for the extraction technology, which aids rational utilization and quality control of medicinal plants.
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.
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.
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.
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.
Objectives:
The aim of current study was to evaluate improving effects of pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), on brain-derived neurotrophic factor (BDNF) and cytokines as well as tissue oxidative damage criteria in the hippocampus in a rat model of lipopolysaccharide (LPS) induced memory impairment.
Materials and methods:
The rats were classified and treated as follows (10 rats per group): (1) vehicle, (2) vehicle before LPS (1 mg/kg, 120 min before memory tests), (3-5) pioglitazone 10, 20 or 30 mg/kg 30 min before LPS. Finally, the hippocampal tissues were collected for biomedical analyses.
Results:
In the Morris water maze test, the LPS group, had a longer latency to find the platform while they spent a shorter time in the target quadrant in the probe trial. In the passive avoidance test, the animals of the LPS group had shorter delay times to enter the dark compartment than those of the control group. Treatment with 20 and 30 mg of pioglitazone corrected these parameters. In the hippocampus of LPS group interleukin-6, tumor necrosis factor-α, nitric oxide metabolites, and malondialdehyde were higher while thiol, BDNF, and IL-10 concentrations and the activities of catalase (CAT) and superoxide dismutase (SOD) were lower than the control group. Treatment by both doses of 20 and 30 mg of pioglitazone corrected the biochemical parameters in the hippocampus.
Conclusion:
The current findings revealed that pioglitazone protected the rats from learning and memory impairment induced by LPS. The effects were associated with improvement of cytokines, oxidative stress criteria, and BDNF.
Neurodegenerative diseases share the fact that they derive from altered proteins that undergo an unfolding process followed by formation of β-structures and a pathological tendency to self-aggregate in neuronal cells. This is a characteristic of tau protein in Alzheimer’s disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson’s disease, and huntingtin in Huntington disease. Usually, the self-aggregation products are toxic to these cells, and toxicity spreads all over different brain areas. We have postulated that these protein unfolding events are the molecular alterations that trigger several neurodegenerative disorders. Most interestingly, these events occur as a result of neuroinflammatory cascades involving alterations in the cross-talks between glial cells and neurons as a consequence of the activation of microglia and astrocytes. The model we have hypothesized for Alzheimer’s disease involves damage signals that promote glial activation, followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases. These patterns of pathological events can be applied to several neurodegenerative disorders. In this context, the involvement of innate immunity seems to be a major paradigm in the pathogenesis of these diseases. This is an important element for the search for potential therapeutic approaches for all these brain disorders.
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.
Alzheimer disease is a neurodegenerative disease that is signified by cognitive decline, memory loss, and erratic behavior. Till date, no cure for Alzheimer exists and the current Alzheimer medications have limited effectiveness. However, herbal medicines may slow down the disease’s progression, which may hopefully reduce the number of cases in the years to come. Numerous studies have been done on characterizing the neuroprotective properties from plants belonging to Scrophulariaceae family, particularly Bacopa monnieri and its polyphenolic compounds known as bacosides. This review presents the findings on bacosides in therapeutic plants and their impact on Alzheimer disease pathology. These reports present data on the clinical, cellular activities, phytochemistry, and biological applications that may be used in new drug treatment for Alzheimer disease.
Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary human and financial burdens. Studies of pathogenesis are essential for defining targets for discovering disease-modifying treatments. Past studies of AD neuropathology provided valuable, albeit limited, insights. Nevertheless, building on these findings, recent studies have provided an increasingly rich harvest of genetic, molecular and cellular data that are creating unprecedented opportunities to both understand and treat AD. Among the most significant are those documenting the presence within the AD brain of toxic oligomeric species of Aβ and tau. Existing data support the view that such species can propagate and spread within neural circuits. To place these findings in context we first review the genetics and neuropathology of AD, including AD in Down syndrome (AD-DS). We detail studies that support the existence of toxic oligomeric species while noting the significant unanswered questions concerning their precise structures, the means by which they spread and undergo amplification and how they induce neuronal dysfunction and degeneration. We conclude by offering a speculative synthesis for how oligomers of Aβ and tau initiate and drive pathogenesis. While 100 years after Alzheimer's first report there is much still to learn about pathogenesis and the discovery of disease-modifying treatments, the application of new concepts and sophisticated new tools are poised to deliver important advances for combatting AD.
Tau is a phosphoprotein with natively unfolded conformation that functions to stabilize microtubules in axons. Alzheimer's disease pathology triggers several modifications in tau, which causes it to lose its affinity towards microtubule, thus, leading to microtubule disassembly and loss of axonal integrity. This elicit accumulation of tau as paired helical filaments is followed by stable neurofibrillary tangles formation. A large number of small molecules have been isolated from Azadirachta indica with varied medicinal applications. The intermediate and final limonoids, nimbin and salannin respectively, isolated from Azadirachta indica, were screened against tau aggregation. ThS and ANS fluorescence assay showed the role of intermediate and final limonoids in preventing heparin induced cross-β sheet formation and also decreased hydrophobicity, which are characteristic nature of tau aggregation. Transmission electron microscopy studies revealed that limonoids restricted the aggregation of tau to fibrils; in turn, limonoids led to the formation of short and fragile aggregates. Both the limonoids were non-toxic to HEK293T cells thus, substantiating limonoids as a potential lead in overcoming Alzheimer's disease.
Alzheimer’s Disease (AD) is a neurodegenerative disorder related with the increase of age and it is the main cause of dementia in the world. AD affects cognitive functions, such as memory, with an intensity that leads to several functional losses. The continuous increase of AD incidence demands for an urgent development of effective therapeutic strategies. Despite the extensive research on this disease, only a few drugs able to delay the progression of the disease are currently available. In the last years, several compounds with pharmacological activities isolated from plants, animals and microorganisms, revealed to have beneficial effects for the treatment of AD, targeting different pathological mechanisms. Thus, a wide range of natural compounds may play a relevant role in the prevention of AD and have proven to be efficient in different preclinical and clinical studies. This work aims to review the natural compounds that until this date were described as having significant benefits for this neurological disease, focusing on studies that present clinical trials.
Oxidative stress plays an important role in Alzheimer's disease. To arrest oxidative stress, this contribution first identified and quantified phenolic bioactives present in the pulp and peel of pomegranate using high-performance liquid chromatography. Punicalagin β rendered the greatest antiradical activity as evaluated by on-line HPLC-ABTS method, which was followed by punicalagin α, gallic acid, and epicatechin. Furthermore, the scavenging activity against peroxyl and DPPH radicals, as well as the reducing power were investigated. Extracts obtained from the peel showed much higher phenolic contents and antioxidant properties than that of the pulp, hence being selected as potential inhibitor of acetylcholinesterase, a key enzyme involved in the progress of Alzheimer's disease. Phe-nolics from pomegranate peel showed inhibition of acetylcholinesterase, which was dependent on the phenolic concentration. Therefore, pomegranate peel may be considered by the industry as a functional food ingredient and possibly for manufacturing of nutraceuticals.
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.
This study investigated if resveratrol (RES) can protect against cadmium chloride (CdCl2)-induced memory loss and Tau protein hyperphosphorylation in rats and explored its effect on AMPK/PI3K/Akt signaling pathway. Rats (n = 10/group) were divided into seven groups as: control; control + DMSO; control + LY294002, a selective PI3K inhibitor (0.25 µg/100 g, i.p); control + RES (300 mg/kg, orally); CdCl2 (5 mg/kg, orally); CdCl2 + RES and CdCl2 + RES + LY294002. All treatments were carried out for 30 consecutive days on a daily basis. RES improved both short and long-term memory as analyzed by novel object recognition task and significantly increased brain levels of glutathione in both control and CdCl2-treated rats. It also inhibited ROS levels of malondialdehyde in the brains of CdCl2-treated rats. In both groups, RES decreased the phosphorylation rate of Tau at Ser¹⁹⁹ and Ser²⁹⁶. Concomitantly, it significantly increased protein levels of p-GSK3β (Ser9) and p-PP2A and decreased p-GSK3β (Tyr²¹⁶). Also, RES activated PI3K/Akt signaling pathway in both control and CdCl2 treated rats by increasing levels of p-PI3K (Tyr⁶⁰⁷) and p-Akt (Ser⁴⁷³). This was concomitant with significant increase in the levels of AMPK and p-AMPK, known upstream regulators of PI3K/Akt signaling pathway. Interestingly, all the above listed beneficial effects of RES, except their effect on AMPK/p-AMPK, were completely abolished in CdCl2 + RES + LY294002-treated rats. In conclusion, in addition to its antioxidant potential, RES inhibits Tau phosphorylation in rat’s brain by activating PP2A protein and AMPK/PI3K/Akt-induced inhibition of GSK3β.
Tauopathies are neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.
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.
Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer's and Parkinson's diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.
Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer's disease, α-synuclein and synphilin-1 for Parkinson's disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer's and Parkinson's diseases.
The extract of Moringa oleifera seeds has been shown to possess various pharmacological properties. In the present study, we assessed the neuropharmacological effects of 70% ethanolic M. oleifera seed extract (MSE) on cognitive impairment caused by scopolamine injection in mice using the passive avoidance and Morris water maze (MWM) tests. MSE (250 or 500 mg/kg) was administered to mice by oral gavage for 7 or 14 days, and cognitive impairment was induced by intraperitoneal injection of scopolamine (4 mg/kg) for 1 or 6 days. Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity and neurogenesis in the hippocampus. MSE pretreatment significantly ameliorated scopolamine-induced cognitive impairment and enhanced cholinergic system reactivity and neurogenesis in the hippocampus. Additionally, the protein expressions of phosphorylated Akt, ERK1/2, and CREB in the hippocampus were significantly decreased by scopolamine, but these decreases were reversed by MSE treatment. These results suggest that MSE-induced ameliorative cognitive effects are mediated by enhancement of the cholinergic neurotransmission system and neurogenesis via activation of the Akt, ERK1/2, and CREB signaling pathways. These findings suggest that MSE could be a potent neuropharmacological drug against amnesia, and its mechanism might be modulation of cholinergic activity via the Akt, ERK1/2, and CREB signaling pathways.
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.
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.
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA‑induced tau protein hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin‑dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+‑calpain‑p25‑CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative tauopathies.
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.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe +3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD.
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.
Background:
Mental disorders are the most common health problems in the worldwide population. Current medicines against these conditions have undesired side effects or limited effectiveness. These disadvantageous pharmacological and therapeutic characteristics provoke a low adherence to treatment in an important percentage of patients with mental disorders. Since ancient times, ethnically different groups have been using plants extracts as medicines for the treatment of mental conditions including dementia, depression and anxiety disorders. Among them are extracts of Ginkgo biloba, a tree in the division Gingophyta, that has been used by millions of people worldwide.
Objective:
This review aims to discuss current scientific evidence of efficacy, neuroprotective and antioxidant effects as mechanism of action, side effects and potential interaction with other commonly prescribed anxiolytic drugs.
Methods:
A PubMed search of preclinical studies as well as individual clinical trials and meta-analysis were scrutinized.
Results:
Various preclinical and clinical studies have shown a positive effect of Ginkgo biloba to improve cognitive abilities in impaired individuals and reducing anxiety under pathological conditions.
Conclusion:
A more advanced clinical research is needed to confirm the efficacy of Gingko biloba for the treatment of anxiety in different health conditions.
Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer's disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.
Tau is a key protein in the pathogenesis of various neurodegenerative diseases, which are categorized as tauopathies. Because the extent of tau pathologies is closely linked to that of neuronal loss and the clinical symptoms in Alzheimer’s disease, anti-tau therapeutics, if any, could be beneficial to a broad spectrum of tauopathies. To learn more about tauopathy, we developed a novel transgenic nematode (C. elegans) model that expresses either wild-type or R406W tau in all of the neurons. The wild-type tau-expressing worms exhibited uncoordinated movement (Unc) and neuritic abnormalities. Tau accumulated in abnormal neurites that lost microtubules. Similar abnormalities were found in the worms that expressed low levels of R406W-tau, but were not in those expressing comparative levels of wild-type tau. Biochemical studies revealed that tau is aberrantly phosphorylated but forms no detergent-insoluble aggregates. Drug screening performed in these worms identified curcumin, a major phytochemical compound in turmeric, as a compound that reduces not only Unc but also the neuritic abnormalities in both wild-type and R406W tau-expressing worms. Our observations suggest that microtubule stabilization mediates the anti-toxicity effect of curcumin. Curcumin is also effective in the worms expressing tau fragment, although it does not prevent the formation of tau-fragment dimers. These data indicate that curcumin improves the tau-induced neuronal dysfunction that is independent of insoluble aggregates of tau.