Therapeutic Implications of Natural Bioactive Compounds E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Bioactive Compounds
- Sprache: Englisch
This volume is a comprehensive compilation of contributions on the state of the art knowledge about bioactive compounds including their sources, isolation methods, biological effects, health benefits and potential applications. These bioactive compounds could serve as alternatives in the prevention or treatment of multifactorial diseases for vulnerable population groups. Chapters in the book incorporate the knowledge based on traditional medicine with recent findings on bioactive molecules and their pharmaceutical implications in neurodegenerative diseases, cancer, COVID 19, diabetes, immunomodulation and farm animal diseases. The book also highlights the latest breakthroughs in the field of screening, characterization, and novel applications of natural bioactive compounds from diverse group of organisms ranging from bacteria, algae, fungi, higher plants, and marine sources. Authors from renowned institutions of India, Japan and China have shared their expertise in the contributed chapters with the goal of enhancing readers’ knowledge about the significance of use of bioactives in therapeutics and nutraceuticals. It is an informative reference for researchers, professors, graduate students, science enthusiasts, and all those who wish to gain insights into various aspects of bioactive compounds, and the development of new pharmaceutical constituents and nutraceuticals.
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Seitenzahl: 469
Veröffentlichungsjahr: 2002
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FOREWORD
We take the opportunity to communicate with you, through this foreword message of the book series with thematic focus on ‘Frontiers in Bioactive Compounds (Volume 3) Title: Therapeutic implications of Natural Bioactive Compounds’.
The nature has provided us enormous genetic potential which has evolved through ages and appears not only in form of biological diversity but also in form of biologically active molecules called bio-active compounds. Many bioactive compounds obtained from natural sources include, phenolics, alkaloids, tannins, saponins, lignin, glycosides, terpenes etc. have been studied thoroughly for therapeutic applications with potential use in pharmaceutical industry.
The assessment of wide-ranging therapeutic potentials of these bioactive compounds has led to the discovery of many modern drugs in recent times. In the present era, it is believed that the natural product-based medicine is considered as the most suitable and safe to be used as an alternative medicine due to their low or no side effects at the effective doses. Moreover, World Health Organization aims to increase the integration of traditional medicine in order to improve health care system. Therefore, natural products research has become a thrust area among scientific community aimed toward understanding the chemistry, analytical methodologies, biosynthetic mechanisms, and pharmacological activities of several natural bioactive compounds. Thus, it is prime interest of researchers to develop understanding about various natural bio-active compounds in order to promote the drug discovery research and to complement the medical world by developing novel drug molecules with superior bioactivities.
The present book series entitled ‘Frontiers in Bioactive Compounds (Volume Title: Therapeutic implications of Natural Bioactive Compounds)’ includes 13 chapters contributed by many academicians, scientists, and researchers from various leading institutes from India and abroad. The editors have made enormous and successful effort to assemble a huge variety of knowledge on structures and therapeutic potential of various natural bioactive compounds present in plants, fungi, algae, marine organisms etc. Chapter contributors have extensively reviewed the therapeutic role of various bioactive compounds against many health disorders in human such as COVID-19, cancer, diabetes, immuno-modulators, neurodegenerative changes and many diseases of farm animals.
We believe this book surely provides updated information on the structure, properties and much therapeutic application of various natural bioactive compounds to graduate, undergraduate students, teachers, food scientists, nutritionists, pharmaceuticals, physicians, food industrials, as well as for health-conscious consumers. We congratulate the editors Dr. Mukesh Kumar Sharma and Dr. (Mrs.) Pallavi Kaushik, and all contributing authors for bringing the collection of their noble piece of work and also for the grand success of this book.
PREFACE
Bioactive compounds have been used as traditional medicines since ancient times. Therefore, the study of therapeutic potential of various bioactive compounds against many diseases and health disorders has been an important area for scholars, academicians, doctors and pharmaceutical industry people.
There are very few books available currently to cover such a wide spectrum of topics. Therefore, this book is a definitive compilation of chapters which are mainly focused on the therapeutic implications of bioactive compounds derived from natural sources like bacteria, algae, fungi, plants and animals. Various chapters in the book incorporate the knowledge based on traditional medicine with recent advances in bioactive molecular research and their pharmaceutical and industrial importance.
A brief note on the 13 chapters of this book is given as follows:
Chapter 1 highlights the recent development strategies of flavonoids prevailing in the field of neurodegenerative diseases like Alzheimer’s, Parkinson’s, and multiple sclerosis, along with their limitations and strategies to encounter the challenges.
Chapter 2 deals with recently discovered plant and marine originated natural compounds for cancer therapeutics. This is an attempt to consolidate data on various bioactive compounds concerning with more targeted and innoxious approach along future outlook.
Chapter 3 gives a comprehensive idea about natural bioactives from plants and other sources with antibiofilm activity. Clinical validation of these bioactives will aid the medical field with alternate preventive and treatment methods against pathogenic biofilms.
Chapter 4 is a compilation of research on SARS CoV-2 with its life cycle, pathogenesis, and currently used drugs for treatment, including the synthetic ones, medicinal herbs and the specific bioactive compounds found efficacious against COVID- 19.
Chapter 5 discusses the common groups of plant derived bioactive compounds with anti-diabetic potential by virtue of their potential to modulate various pathways involved in the regulation of blood glucose levels.
Chapter 6 focuses on therapeutics and industrial application of the algae derivatives’ primary and secondary metabolites.
Chapter 7 presents an overview of the traditional uses, phytochemical constituents and various pharmacological properties of F.vulgare and T.ammi seeds.
Chapter 8 is an attempt to consolidate information on recently observed bioactive compounds which have aided in unrelenting research to explore their potential use for the treatment of various livestock diseases.
Chapter 9 provides an overview on the isolation and characterization of the bioactive compounds derived from Indian medicinal plant H. indicus, their biological properties with particular emphasis on anti-diabetic potential.
Chapter 10 deals with different works and approaches employed for utilizing tea polyphenols against pesticide induced toxicity carried out internationally and nationally, along with their future prospects.
Chapter 11 emphasizes upon the role of various bioactive compounds derived from fungal sources with their pharmacological importance.
Chapter 12 focuses on a few extensively scrutinized immunomodulatory phytocompounds from medicinal plants such as Tinospora cordifolia, Andrographis paniculata, Curcuma longa, Zingiber officinale, Allium sativum, Terminalia chebula and Piper longum which have been studied in experimental (in vitro and in vivo) models and few compounds have exhibited good therapeutic potential in clinical trials also.
Chapter 13 describes the bacteria-derived bioactive compounds like antibiotics, enzymes and other secondary metabolites like Gallic acid, Amicoumacin, Prodigiosin, Nystatin, Spinosad, Milbemycin, Lipstatin, Subtilin, Albaflavenone, Mollemycin A which have been studied for their inhibitory action against bacteria, fungi, insects, pests, etc.
We appreciate the tremendous efforts of the authors from renowned institutions of India, Japan and China for sharing their pieces of expertise in the contributed chapters. We shall also extend a hearty thanks to Bentham Science Publishers for providing the opportunity to contribute as editors of this book.
List of Contributors
Flavonoid Based Bioactive for Therapeutic Application in Neurological Disorders
S.J.S. Flora1,*,Rahul Shukla1,Mayank Handa1Abstract
Flavonoids belong to a class of natural, polyphenolic dietary compounds which modify the neuropathological state of the brain. Some flavonoids like quercetin and other, reduce the inflammation, carcinogenicity, and oxidation promotes neuroprotection and comprises the major component of cosmetics, medicinal and dietary supplements. Daily intake of flavonoids helps to mitigate the risk of several neurological disorders like Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, etc. Flavonoids exhibit their pharmacological effect through various mechanisms like cholinesterase inhibition, scavenging free radicals, memory enhancement via attenuation of amyloid plaques, tau targeting detoxification and neural antiinflammation. Administration of flavonoids to biological system has to pass through several biological checkpoints like first pass metabolism, intestinal absorption, and entry into blood brain barrier. Flavonoids exhibit difference in pharmacokinetic and pharmacodyanmic profile due to difference in their structures. Recent literature reports have proved promising therapeutic potential in neurological disorders. This chapter highlights the recent development of flavonoids prevailing in the field of neurodegenerative, its limitations and drug delivery approaches to encounter the challenges.
INTRODUCTION
Flavonoids are plant derived secondary metabolites [1]. Flavonoids are long-serving in treatment of diseases [2]. Flavonoids have been considered as good therapeutic agents due to their easy extraction, diversification, and abundance. To date, around 7,000 or more different types of flavonoids have been discovered from plants (vegetables and fruits). These naturally occurring metabolites possess numerous beneficial effects and mitigate plenty of health problems thus plays a
significant role in drug designing and discovery [3, 4]. Flavonoids own good affinity for several body proteins, excellent antioxidant activity, metal chelation ability, and additionally can alter enzymes, receptors, and transporters [3, 5, 6]. There are ample amount of research studies advocating its anti-cancer, anti-inflammatory, anti-diabetic, neuroprotective, antimicrobial activities, and as cardiovascular drugs [6-10]. Some studies reported it as a cognitive enhancer, while others claim flavonoids as therapeutic against Alzheimer’s disease (AD). These results were observed in preclinical evaluation [11-13]. It was also reported that flavonoids and its derivative metabolites can interact with several subcellular targets [14] for example, interaction of flavonoids with PI3-kinase/Akt and ERK signalling pathways receptors can accelerate the neuroprotective proteins expression and increase neuronal count [15-18]. Flavonoids enhance cerebrovascular functionality thus improving blood flow the brain and triggers the generation of neurons that ultimately results in better cognition. There are numerous other mechanisms that reported the beneficial effects of flavonoids.
Flavonoids have ability to suppress the inflammation mediated neuronal apoptosis, inhibition of abnormal β and γ secretase and curb the oxidative stress, thus can debilitate the progression and onset of AD [19, 20]. Thus, flavonoids can act as neuroprotectants by improving the quality and quantity of neurons.
Flavonoids Chemistry and its Classification
Flavonoids are polyphenols with chemical structure involving two benzene rings interconnected with a pyran ring, one is amalgamated with pyran ring while the other is attached as a substitute in pyran ring. On the basis of benzene ring substitution, saturation of pyran ring, derivatization can be possible that owned physicochemical properties suitable for neuroprotectant.
Fig. (1))(a) Flow chart presentation of flavonoids.Flavonoids Classification
Depending on the benzene ring position and pyran attachment along with extent of oxidation and unsaturation of pyran ring, flavonoids are chemically classified into different groups having different pharmacological properties discussed below (Fig. 1 and Table 1).
Isoflavones
Flavonoids benzene ring attachment to pyran ring at 3rd position is called isoflavones. Soybean is a major natural source of isoflavones [23]. Isoflavones are biodegradable and possess good antioxidant activity. A research study claimed to synthesize its derivative by Suzuki coupling reaction [24] while others used triazin for derivatization of isoflavone. It was reported that application of enzymes or heterogonous catalyst are promising methods for isoflavone synthesis [25, 26]. Structures of few isoflavones are:
Neoflavonoids
When benzene ring is attached to 4th position of pyran ring then the compound is called neoflavonoids. Neoflavonoids exhibit potential antidiabetic pharmacological activity [27]. Neoflavonoids are comprised of neoflavenes and neoflavones. Neoflavonoids can be obtained from both natural as well as synthetic source. Natural sources of this heterocyclic compound are Dalbergia odorifera [28], Echinops niveus [29], Polygonum perfoliatum [30], and Nepalese propolis [31].
Flavones
Chemical structure of flavones contains carbonyl group attached to pyran ring at position 4 and double bond between positions 2 and 3. Flavones have two hydroxyl groups at each aromatic ring. This compound can obtain by both natural and synthetic source although natural is more common source [32].
Flavonols
Flavonols, also known as 3-hydroxyflavones, contain hydroxyl group on pyran ring at 3rd position. Flavonols are synthesized chemically by derivatizing flavones using oxidation, followed by cyclization by chalcones. Further, replacing hydrogen associated with hydroxyl group of glucose that yields flavonol glycoside.
Pachypodol is a unique example of flavonol as it does not actually belong to this group but considering its chemical structure, pachypodol comes under flavonols.
Flavanones and Flavanonols
Flavanones are 2,3-dihydroflavones and flavanonols are 3-hydroxy flavanones. Chemically flavanonols have saturated pyran ring with hydroxyl group at 3rdposition and 4th position for carbonyl.
Flavanols
Flavonoids that do not contain carbonyl group at position 4 are called flavanols. Chemically, flavanols have saturated pyran ring and di-substitution at positions 2 and 3 allowing 4 possible diastereomers. Position 2 of pyran ring is substituted by the benzene ring while 3 is attached with hydroxyl group. The prominent difference between flavonoids and flavanol is the absence of hydroxyl group at position 3. For this reason, flavonoids classified under this group without being fit in definition of flavanols.
Anthocyanidins
These are the pigmented flavonoids widely available in cationic form (as chloride salt). Anthocynadins are salt forms of 2-phenylchromenylium (flavylium) cation. Anthocyanidins group contains petunidin, capensinidin, hirsutidin, aurantinidin, delphinidin, cyaniding, pelargonidin, malvidin, europinidin, pulchellidin, peonidin, and rosinidin. All are different due to their substitution.
Chalcones
Chalcones do not contain pyran ring but due to the same synthetic approach, these are classified under flavonoids. Chalcones have pyran moiety present as an open structure. The carbonyl group of this open structure conjugated with double bond yields α,β- unsaturated ring. This can act as Michael acceptor for several organic reactions.
Flavonoids and its Abundancy in Nature
Flavonoids are secondary products widely distributed in plant kingdom. Most of the flavonoids contain colour and promote some essential pharmacological functions such as pollination. Flavonoids are classified based on aglycone ring and state of oxidation and reduction (see Fig. 2). Some other criteria for differentiation of flavonoids are hydroxylation degree of aglycon, saturation of pyran ring, hydroxyl group position, derivatization of hydroxyl group. Generally, fruits, vegetables, juices, cereals are major sources of flavonoids [21].
Fig. (2)) Chemical structure of some common flavonoids.Quercetin, myricetin, and kaempferol (flavonols) are few examples of flavonoids obtained from vegetables whereas luteolin and apigenin are found in celery, chamomile, and green peppers. Genistein and daidzein are isoflavones naturally present in soy and its products; flavanones such as, naringenin and hesperidin are found in tomatoes and citrus fruits. Some other flavans like epicatechin, epigallocatechin gallate (EGCG), epigallocatechin and catechin are present in green tea, chocolate and red wine. Berry fruits and red wine are enriched with anthocyanidins like malvidin, cyanidinare, and pelargonidin [22].
Flavonoids and its Pathological Targets in Neurological Disorders
Cholinesterase Inhibitors
Enzymes cholinesterases like AChE (acetylcholinesterase) and BChE (butylcholinestrase) cause the hydrolysis of acetylcholine (ACh) neurotransmitter, which regulates the impulse neurotransmission between different neuron synapses. As the AD pathogenesis includes scarceness of ACh, the cholinesterase inhibitors are being one of the essential therapeutics for maintaining the neurotransmitter levels at the synapse for longer durations [33]. The clinical data available currently shows that using this method is the most effective treatment for AD symptoms, thus reducing clinical approval at the end of the four drugs [34]. It was effectively applied in the treatment of ataxia and dementia, Parkinson’s disease (PD). Due to adverse effects and inadequate effectiveness of available marketed drugs, more effective and safer drugs are to be developed in urge.
Various flavonoid compounds like naringin, apigenin, quercetin, kaempferol, diosmin, genistein, silibinin, and silymarin have shown anti-cholinesterase effects. Quercetin, was being most effective with 76.2% anti-cholinesterase activity against AChE while, other flavonoids have shown genistein -65.7%, luteolin -54.9% and silibinin - 51.4% inhibitory activity against enzyme BChE [35].
As per the published reports of 2011 by Uriarte-Pueyo and Calvo co-workers report 128 flavonoids in relation to their ability to inhibit AChE. Depending on their potential as ChE inhibitors, they are considered therapeutic potential for AD [97].
Scavengers of Free Radical
Aerobic respiration causes the formation of free radicals, which get countered by the various antioxidants present in the body. If free radicals are formed in excess amounts, oxidative stress occurs leading to the disturbances in physiological functions of essential body elements like proteins and lipids [36]. Together with the part of free radicals in diseases, they are well prone to inflammation of neurons leading to AD development. Oxidative stress markers with their increased levels confirmed that oxidative stress is the main feature of AD [36]. The lower antioxidant levels and activity was observed in plasma of AD diagnosed patients [37]. It was also detected that there was increased levels of various protein and lipid oxidation byproducts in the preclinical AD based transgenic animal models [38]. The higher amounts of pathogenic markers for AD like neurofibrillary tangles (NFTs) and Aβ in animals containing oxidative stress indication of free radicals as the initiating agents of AD [39]. Almost all reactive oxygen species (ROS) are formed in mitochondria [40]. The lack of cytochrome c oxidase in AD patients causes mitochondrial dysfunction and leads to the formation of excess ROS [41]. In the metal ions Aβ presence leads to an overrun of the free radicals and is known as mitochondrial poison [42]. In response to this, the usage of ions such as clioquinol in AD mimicked transgenic animal models is known to provide beneficial effects. Neurodegenerative disorders and AD have other characteristics like glial cells activation [43, 44]. By using NADPH oxidase (NOX), there is generation of pro-inflammatory cytokines and enhanced production of superoxide anions by the microglia activation. The occurrence of increased amounts of NOX subunits and removal of NOX gene in transgenic animals lead to improved cognitive and cerebrovascular functions indicating its role in the pathophysiology of AD [45]. In addition, glial cells activation releases NO from inducible nitric oxide synthase (iNOS) and reacts with superoxide along with the production of peroxinitrite thereby causing nitrosative stress. Their involvement was based on the genetic removal of iNOS leading to improved gliosis, reduced Aβ load and the reduced phosphorylation of tau protein in mutant animals. Components of green tea like catechins and polyphenols are stronger antioxidative agents that scavenge free radicals by chelating metal ions [46]. EGCG prevention from DNA induced stress damage by transference of electron to active ROS-induced areas [46]. Green tea components suppress the lipid peroxidation in chain reaction and origination by iron ascorbate in brain components of mitochondria. Amongst catechins, EGCG is considered to be the most effective compound [47]. EGCG suppresses fibrils production during Aβ synthesis and reduces lipid peroxidation which was formed by Aβ [48, 49]. It also inhibits apoptosis induced by Aβ, caspase activity, thereby increasing the surviving capacity of hippocampal neurons [49].
Memory Enhancers
Certain literature reports that the flavonoids are effective in preventing AD and impairment of cognition in animal models, which makes them potential therapeutics for treatment of neurological diseases. Anti-amyloidogenic effect of flavonoids was intermediated by targeting the key enzymes, which caused the pathogenesis and accumulation of amyloid plaques (Aβ). It was currently stated that anthocyanin-rich flavonoid compounds available in bilberry and black currant have the ability of preventing behavioural changes and altering APP dispensation in APP/PS1 AD induced mouse model [50]. Similarly, chronic treatment with tannic acid by means of the AD transgenic induced animal model of PS/APP for cerebral amyloidosis with improvements in transgene between animal behaviour and memory. Nobiletin, a citrus flavonoid was reported that it has the ability to reduce Aβ load and suppress Aβ induced memory deficits in the hippocampus of mutated animals [51]. In addition, chronic delivery of grape polyphenols leads to increased memory as well as decreases solubilised oligomer levels in Tg2576 animal's brain tissue [52]. Luteolin, a flavonoid based citrus, is shown to reduce the Aβ peptides formation in transgenic APP neuronal cells and reduce BACE1 activity (see Figs. 3 and 4) [53].
Fig. (3)) Schematic presentation of molecular ways of Flavonoid action.In addition, continuous polyphenol administration containing curcumin and grape seed extract for 9 months inhibits Aβ placement in the brains of AD induced animals [53]. Numerous studies report various beneficial properties of green tea due to the presence of EGCG. EGCG, a green tea-based polyphenol reduces the Aβ load by inhibiting the APP-converting enzyme [54, 55]. Naturally available flavonoids like EGCG and curcumin are reported to inhibit the modification of BACE1-mediated Aβ neuronal cultures [56]. Isorhamnetin reports neuroprotective activity against memory impairment induced by Aβ [57]. It improves comprehension and memory by building defence system of cholinergic signalling, antioxidant, and synaptic plasticity [58]. Kaempferol reduces cognitive deficits by monitoring neuro-inflammation and antioxidants [59], and increases retaining of memory and proliferation of CA1 neurons in hippocampus [60]. Quercetin, another flavonoid, has proficient therapeutic applications in AD. It produces a decrease in plaque load and mitochondrial impairment through AMPK activation and it improves brain function [61].
Fig. (4)) Signaling pathway for Flavonoids mechanism in Alzheimer’s brain.The increase in EGCG production of APP processing non-amyloidogenic shows that phosphoinositide 3-kinase/ estrogen receptor-a/ Ak-transforming based processes. Depletion of post-menopausal estrogen is interlinked with the enhanced risk of AD in the patients, where selective receptor modulates AD therapeutic approach. EGCG regulated estrogen receptor modulation may be a substitute for estrogen-based treatment in managing AD [62]. It also provides beneficial effects of neuroprotection by inhibiting amyloid fibrils sheets rich in Aβ and inhibits fibrillogenesis. This fibrillogenesis reticence is regulated through binding with unopened polypeptides and suppressing their conversion into intermediate neurotoxic compounds [63]. In addition, EGCG is able to differentiate large amounts of Aβ fibrils into smaller proteins and as a result, they are unable to synthesize and thus have no toxic effects [64]. Myricetin has prominent potency as an In-vitro anti-amyloid and therefore has a potential therapeutic effect on neurodegeneration-related psychiatric disorders [65, 66]. In general, literature suggests flavonoids have the potential to disrupt the Aβ fibrillization formation process, inhibiting the important enzyme BACE1 involved in the Aβ formation, leading to Aβ product inhibition. However, more research is needed to determine neuromodulatory potency and lower processes of flavonoids in use of clinics.
Tau Targeting
Several studies indicate the effects of flavonoids on the production of highly phosphorylated tau protein, an important characteristic of AD [67, 68]. For example, epicatechin-5-gallate (EG) and myricetin have been stated to hinder the formation of heparin-mediated tau [69]. EG treatment in AD-induced transgenic animal models predicted modified tau profiles by inhibiting the generation of tau isoforms of sarkosyl-soluble phosphorylated [70]. In some projects working with grape seed proanthocyanidin extract (GSPE) and tau based neuropathology was considerably decreased in AD animal models by inhibiting tau peptide synthesis, its termination and its final clearance [71]). NFTs and accumulation of hyperphosphorylated tau proteins are chief majorly contributes the impairment of brain. The phosphorylation of tau proteins is mainly catalysed by various kinases such as GSK-3b, thus involved in the pathophysiology of AD. Flavonoids suppress the activity of different enzymes like kinases and hence help prevent AD. For example, indirubins inhibit the activity of protein kinases along with GSK-3b as well as CDK5 / p25, which are involved in the hyperphosphorylation of tau proteins seen in AD patients.
Morin, a flavonoid, is stated with the activity of constraining GSK-3b activity and tau protein phosphorylation. It also reduces Aβ-induced phosphorylation based on tau protein and prevents cytotoxicity induced by Aβ in human neuroblastoma cells. Additionally, morin treatment has decreased tau protein hyperphosphorylation in hippocampal neurons AD mice mutant animals of 3xTg [72]. Cyanidin 3-O-glucoside (Cy3G) protects significantly against abnormalities caused by Aβ administration in GSK-3b / tau mutations mediated animal models [73].
Neuro Anti-inflammation and Detoxifier
Neurodegenerative outcomes, which are observed in several neurological disorders appear to be provoked by numerous events neuro-inflammation, glutamatergic excitotoxicity, endogenous antioxidants depletion as well as neurotoxicity, which are mediated by different metabolic products [74]. There are various scientific pieces of evidences suggest flavonoids might also respond to internalise neuronal injuries mechanism and could basket the development of neurodegenerative disorders [17, 75]. Green tea consumption was reported to reduce PD threat, and deteriorate ischemic hippocampal injury and neurodegeneration that could be attributed to EGCG presence [76]. It was found that EGCG is known for modulating numerous signalling pathways basically PI3-kinase and protein kinase C role in neuroprotection and minimizes nigral damage by chelation of free radicals [76, 77]. Some of the in vitro studies also substantiated that flavonoid prevents the Parkinson’s disease pathological aspects by obstructing the endogenous neurotoxin formation thus inhibits the nitric oxide production in activated microglia cells. It was found that blueberry flavonoids also exhibit TNF-α, nitric oxide, IL-1b production in microglia cells [78]. Some other flavonoids like wogonin, quercetin, EGCG, baicalein modulates neuro-inflammation and production of astrocyte/ microglial-mediated nitric oxide [79, 80]. The above actions are arbitrated by lipid kinase based signalling pathways, transformation of protein, pro-inflammatory based transcription factors, nitric oxide production, cyclooxygenase (COX-2) expression and iNOS downstream regulation, scavenging of free radicals, liberation of cytokine and NOX activation [81]. It was also reported that genistein and EGCG enhances the glutathione production by PI3-kinase-reliant based nuclear factor erythroid 2–related factor 2 (Nrf2)-induced antioxidant pathway regulation [82].
Targeting Other Pathways
It was found that flavonoids bind preferentially with neuronal receptors which include tyrosine receptor kinase B (TrkB), GABA-A, d-opioid, nicotinic, testosterone, estrogen, adenosine receptors and mediate numerous neuropharmacological actions [55, 83]. There were many reports related to good flavonoids neuroprotective effects and their metabolites by interacting with neuronal signalling pathways [84]. All the above interact with several lipid kinase, protein kinase signalling pathways like mitogen-activated kinase (MAPK), tyrosine kinase, nuclear factor-kB PI3K/Akt and protein kinase C pathway [84-86]. Flavonoids on binding to receptors might either inhibit or excite receptors and thus, they mediate their own actions via phosphorylation or gene expression modulation. They modulate the neuronal plasticity, synaptic protein synthesis as well as morphological changes, which are accountable for cognition impairment and neurodegenerative disorders. Metabolites of flavonoids also interacts with MAPKs signalling pathways (MEK2 and MEK1 receptors) resulting in cAMP downstream activation, thereby leading to alterations in memory and synaptic plasticity [87]. Anthocyanins and flavanols rich blueberry supplementation had also been reported for enhancing cognitive performance in case of animals by CREB activation and BDNF level elevation in the hippocampus.
Fig. (5)) Molecular binding of flavonoids which act on activation and inhibition.Green tea catechins chronic administration could reduce Aβ1–42 oligomers levels as well as up-regulates protein related synaptic plasticity action in hippocampus and elevates cAMP/ kinase A-response element binding protein (PKA/CREB) pathway [88]. Flavonoids activate peroxisome proliferator-activated receptor-g coactivator-1 (PGC-1a) pathway, stabilizing Nrf2 transcription factors and hypoxia inducible factor-1 (HIF-1) and acting as peroxisome proliferator-activated receptor gamma (PPAR-ɤ) modulators [89]. All the above flavonoid based molecular changes might recover AD pathophysiology as they protect neurons against reduced insulin resistance, oxidative stress, attenuates mitochondrial dysfunction and thus enhance cognitive impairment. Flavonoids direct interaction with ATP binding site and possess PI3-kinase modulating potentials [90]. Metabolites of Quercetin inhibit PI3-kinase activity thus inhibits prosurvival Akt/PKB signalling pathways (Fig. 5). Hesperidin on the contrary activates Akt/PKB signalling pathway and imparts prosurvival features in cortical neurons [16].
Pathways of Various Signaling Proteins
EG moreover had also been reported for modulating, neurotransmission, reliant raise of PI3K in CREB phosphorylation, plasticity regulation via extracellular signal regulated kinase (ERK) stimulation, as well as GluR2 levels in neuronal corticol upregulation [91]. In one of the studies, chronic blueberry ingestion was reported to enhance mammalian target of rapamycin (mTOR) receptor downstream activation, Akt phosphorylation as well as increase Arc/Arg3.1 (activity-regulated cytoskeletal associated protein) content in hippocampus. As BDNF regulates Arc and is vital in long term potentiation (LTP), thus all these changes might be centred towards cognition and spatial memory improvement [92]. The above has been also proved by many experimental studies which are related to flavonoids effect on neuronal morphologies changes [93].
Toxicological Aspects of Flavonoids
Flavonoids wider accessibility, as well as their increased human consumption, also created major questions related to dietary components potential toxicity. Most of the natural products are better tolerated; but flavonoids as well as related phytochemicals exhibit neurobehavioral along with endocrine disrupting effects [94]. Flavonoids toxicity lies in the minimum range in case of animals, such as in rats, the LD50 found as 2–10 g/kg. Similar doses in humans are quite impracticable. Thus, as a preventive measure, doses less than 1 mg/adult/day were commended for humans [9]. In one study, quercetin, when administered as dietary supplement in both male and female albino rat in 27.8 mmol of concentration as daily dose, possesses carcinogenicity property. However, the exact mechanism of quercetin carcinogenicity is not specified. But these studies established that quercetin does not directly induce mutagenicity but indirectly activates mixed glucosidases [95]. Human cytochrome P450 (CYPs) could be either induced or inhibited by flavonoids depending upon their concentrations and structures. Flavonoids interacts with CYP3A4 is region of interest. Administering clinically used drugs and flavonoids might cause flavonoid–drug interactions as they modulate certain drug pharmacokinetics [9, 96].
CONCLUSION
Flavonoid-rich foodstuff's dietary usage may restore memory functions and possess the tendency of slowing down age-related decline in cognition as well as attenuate for the development of dementia conditions. The natural products' therapeutic importance in neurodegeneration attributes to modulatory neuropharmacological features. There are many further studies that need especially properly designed clinical trials for endorsing the flavonoids’ clinical effectiveness with more prominent examples in clinical symptoms and signs of neurodegeneration. Several In vivo studies must be designed for obtaining a better insight related to efficacy of flavonoids related to their toxicities, bioavailability as well as accumulation in aging brain at targeted sites. By connecting a link among behavioural responses in test humans/ animals to hippocampal and cortical area changes, primary molecular events which are connected to neuronal stem cells, synaptic plasticity proliferation effects and cerebral blood flow changes would provide guidelines for dietary uses of flavonoids along with subsequent clinical endorsements in various neurological disorders. Employing spectroscopic and imaging techniques like NMR and MRI could provide a good idea of flavonoids attenuated changes in blood flow to cerebral, and electrophysiological changes as well as quantitative alterations in progenitor cells, grey matter density and neuronal stem cells. Coming to dementia and AD, it is vital to explore flavonoid anti-amyloid as well as tau modification properties both in in vivo and in vitro models. Considering the above, flavonoid tau modifying potential was investigated at a preliminary level, but there exist many detailed protocols on destabilization effects of tau proteins, β-amyloid and microglial activation effects which need to be explored. Further, endorsement related to the dose/daily intake and as well as duration of therapy should be given for efficacious and safe results. Molecular improvement CREB function reported for consolidating memory as they promote gene expression responsible for long term memory and synaptic morphology. Though there is a significant understanding of the biology of flavonoids, most clinicians consider them mistakenly as simple antioxidants, thus that remains barrier in the bioactive flavonoids development in preclinical studies. Presently it has been found that flavonoids by molecular brain and modulating
cellular functions prevent both normal as well as disease-related deterioration in cognitive functions.
Therefore, flavonoids represent vital precursor molecules group in the quest for discovering newer memory enhancing agents that might be proven beneficial for counteracting and perhaps even suppressing decline in age-related cognitive functions.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
The authors acknowledge Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, GOI, India.
