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ArticleLiterature Review
The impact of flavonoids on memory: Physiological and molecular considerations
Chemical Society Reviews 38(4):1152-61
DOI:10.1039/b800422f
Jeremy Paul Edward Spencer
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Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory acquisition, consolidation, storage and retrieval. These low molecular weight polyphenols are widespread in the human diet, are absorbed to only a limited degree and localise in the brain at low concentration. However, they have been found to be highly effective in reversing age-related declines in memory via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. These interactions include an ability to activate signalling pathways, critical in controlling synaptic plasticity, and a potential to induce vascular effects capable of causing new nerve cell growth in the hippocampus. Their ability to activate the extracellular signal-regulated kinase (ERK1/2) and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the cAMP response element-binding protein (CREB), a transcription factor responsible for increasing the expression of a number of neurotrophins important in defining memory, will be discussed. How these effects lead to improvements in memory through induction of synapse growth and connectivity, increases in dendritic spine density and the functional integration of old and new neurons will be illustrated. The overall goal of this critical review is to emphasize future areas of investigation as well as to highlight these dietary agents as promising candidates for the design of memory-enhancing drugs with relevance to normal and pathological brain ageing (161 references).
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... It has also been shown that R. damascena provides protection against DNA oxidative damage through its significant antioxidant effects [73]. Emerging evidence suggests that flavonoids are able to activate signalling pathways, which are critical in controlling synaptic plasticity [74]. Their ability to activate the ERK1/2 and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the CREB. ...
... Their ability to activate the ERK1/2 and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the CREB. These molecular events, which converge on CREB activation and neurotrophin synthesis, are able to induce synaptic plasticity [74]. In addition to ERK and CREB activation, flavonoids results in an activation of mechanistic target of rapamycin (mTOR) and an increased expression of hippocampal activity-regulated cytoskeleton-associated protein (Arc) [75]. ...
... Arc is known to be important in LTP and has been proposed to be under regulatory control of both BDNF [76] and the ERK signaling [77]. Also, flavonoids lead to improvements in synaptic plasticity through induction of synapse growth and connectivity, increases in synaptic activity, increases in dendritic spine density and the functional integration of old and new neurons [74]. Flavonoids are also capable of influencing neurogenesis through the activation of PI3 kinase-Akt-eNOS [78]. ...
Effects of the hydroalcoholic extract of Rosa damascena on hippocampal long-term potentiation in rats fed high-fat diet
Seyed Asaad Karimi
Somayeh Komaki
Masoumeh Taheri
Alireza Komaki
High-fat diets (HFDs) and obesity can cause serious health problems, such as neurodegenerative diseases and cognitive impairments. Consumption of HFD is associated with reduction in hippocampal synaptic plasticity. Rosa damascena ( R. damascena ) is traditionally used as a dietary supplement for many disorders. This study was carried out to determine the beneficial effect of hydroalcoholic extract of R. damascena on in vivo hippocampal synaptic plasticity (long-term potentiation, LTP) in the perforant pathway (PP)—dentate gyrus (DG) pathway in rats fed with an HFD. Male Wistar rats were randomly assigned to four groups: Control, R. damascena extract (1 g/kg bw daily for 30 days), HFD (for 90 days) and HFD + extract. The population spike (PS) amplitude and slope of excitatory post-synaptic potentials (EPSP) were measured in DG area in response to stimulation applied to the PP. Serum oxidative stress biomarkers [total thiol group (TTG) and superoxide dismutase (SOD)] were measured. The results showed the HFD impaired LTP induction in the PP-DG synapses. This conclusion is supported by decreased EPSP slope and PS amplitude of LTP. R. damascena supplementation in HFD animals enhanced EPSP slope and PS amplitude of LTP in the granular cell of DG. Consumption of HFD decreased TTG and SOD. R. damascena extract consumption in the HFD animals enhanced TTG and SOD. These data indicate that R. damascena dietary supplementation can ameliorate HFD-induced alteration of synaptic plasticity, probably through its significant antioxidant effects and activate signalling pathways, which are critical in controlling synaptic plasticity.
... Flavonoids are widely distributed polyphenols in plants and valuable secondary metabolites with significant roles for human health [1][2][3]. Importantly, flavonoids are naturally conjugated with carbohydrate moieties, leading to significantly enhanced stability and solubility [4]. In addition, the sugar structures predominantly affect the bioavailabilities and the adsorption in the human body [5,6]. ...
... The products were eluted at flow rate 0.8 mL min − 1 with acetonitrile/water (30:70, v/v) containing formic acid (0.1%) and analyzed with an ultraviolet (UV) detector under the optimized wavelengths of respective flavonoid product (varied from 220 to 380 nm). 1 H and 13 C NMR spectra were recorded on a 400 MHz spectrometer (JEOL, Tokyo, Japan) with methanol-d 4 as the solvent. Mass data for transfer products were ...
... Yellow powder (42.7 mg, isolation yield 92%). 1 ...
pH-Promoted O-α-Glucosylation of Flavonoids Using an Engineered α-Glucosidase Mutant
Chao Li
Jetendra Kumar Roy
Ki-Cheul Park
Young-Wan Kim
Retaining glycosidase mutants lacking its general acid/base catalytic residue are originally termed thioglycoligases which synthesize thio-linked disaccharides using sugar acceptor bearing a nucleophilic thiol group. A few thioglycoligases derived from retaining α-glycosidases have been classified into a new class of catalysts, O-α-glycoligases which transfer sugar moiety to a hydroxy group of sugar acceptors, resulting in the formation of O-linked glycosides or oligosaccharides. In this study, an efficient O-α-glucosylation of flavonoids was developed using an O-α-glycoligase derived from a thermostable α-glucosidase from Sulfolobus solfataricus (MalAD416A). The O-glycoligase exhibited efficiently transglycosylation activity with a broad substrate spectrum for all kinds of tested flavonoids including flavone, flavonol, flavanone, flavanonol, flavanol and isoflavone classes in yields of higher than 90%. The glucosylation by MalA-D416A preferred alkaline conditions, suggesting that pHpromoted deprotonation of hydroxyl groups of the flavonoids would accelerate turnover of covalent enzyme intermediate via transglucosylation. More importantly, the glucosylation of flavonoids by MalA-D416A was exclusively regioselective, resulting in the synthesis of flavonoid 7-O-α-glucosides as the sole product. Kinetic analysis and molecular dynamics simulations provided insights into the acceptor specificity and the regiospecificity of O-α-glucosylation by MalA-D416A. This pH promoted transglycosylation using O-α-glycoligases may prove to be a general synthesis route to flavonoid O-α-glycosides.
... However, growing evidence shows that these natural substances are able to interact with the molecular and cellular components of the brain accountable for memory. Flavonoids have the potential to encourage neurogenesis, trigger neuronal regeneration, increase existing neuronal function, and prevent neuronal dysfunction ( Table 2) [104,105]. It was assumed that the potential role of flavonoids in stimulating cognitive functions, learning, and memory is mediated by their antioxidant capabilities [104]. ...
... However, growing evidence shows that these natural substances are able to interact with the molecular and cellular components of the brain accountable for memory. Flavonoids have the potential to encourage neurogenesis, trigger neuronal regeneration, increase existing neuronal function, and prevent neuronal dysfunction (Table 2) [104,105]. Luteolin STZ-induced AD rat 10 and 20 mg/kg Improves spatial learning and memory impairment [111] Diosmin 3xTg-AD mice 1 and 10 mg/kg/day Enhances inhibitory GSK-3β phosphorylation and lessen γ-secretase activity, Aβ generation, as well as tau hyperphosphorylation [112] Wogonin 3xTg-AD mice 10 mg/kg ...
... The tyrosine kinase receptor B (TrkB) [155], as well as nicotinic acetylcholine [156,157], δ-opioid [158,159], type A gamma-aminobutyric acid (GABA A ) [160][161][162], adenosine [163], testosterone [164] and estrogen [132] receptors, represent potential flavonoid-binding sites on neurons [165]. Interestingly, flavonoids and their metabolites were found to exert effects on neurons via their interactions with various protein kinase-and lipid kinase-signaling cascades, for instance, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway as well as the protein kinase C (PKC), tyrosine kinase, phosphoinositide-3-kinase (PI3K)/Akt, and mitogen-activated kinase (MAPK) signaling pathways [104,105,152,[166][167][168][169][170][171][172]. ...
Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer's Disease
Md. Sahab Uddin
Md. Tanvir Kabir
Kamal Niaz
Lotfi Aleya
Alzheimer's disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer's pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.
... Polyphenols-rich foods/beverages have received much attention with regards to their neuroprotective effects [44], including a potential to protect neurons against neurotoxin-induced injury [45,46], to suppress neuroinflammation [47], and to promote memory and learning [48][49][50][51]. Despite the well-established harmful effects of heavy alcohol intake [1], epidemiological data suggest that moderate wine consumption may reduce the incidence of age-related dementia, including Alzheimer's disease [4,52,53]. ...
... The development of cardiovascular and cognitive impairment is a complex process that begins even in the absence of a symptomatic disease [78]. Human clinical trials and animal studies have identified polyphenolrich foods and beverages as being capable of delaying the onset of age-related vascular and cognitive impairment [44,[79][80][81][82][83]. Polyphenols present in such foods have been postulated to evoke protection through the actions of absorbed flavonoids and their metabolites at the cellular level, enhancing existing endothelial and neuronal function and/or stimulating cell regeneration [44,79,83,84]. ...
... Human clinical trials and animal studies have identified polyphenolrich foods and beverages as being capable of delaying the onset of age-related vascular and cognitive impairment [44,[79][80][81][82][83]. Polyphenols present in such foods have been postulated to evoke protection through the actions of absorbed flavonoids and their metabolites at the cellular level, enhancing existing endothelial and neuronal function and/or stimulating cell regeneration [44,79,83,84]. Although antioxidant mechanisms cannot be excluded [85], recent data sets suggest that such effects are mediated by their ability to modulate endothelial and neuronal signalling [86,87], to stimulate neurotransmitter release [88], to increase vascular blood flow [89] and even to stimulate hippocampal neurogenesis [90]. ...
The impact of Champagne wine consumption on vascular and cognitive functions
Giulia Corona
David Vauzour
... These secondary metabolites include alkaloids, stilbenoids, saponins, glycosides, steroidal lactones, bilobalide, caffeine, xanthones, isoflavonoids, catechins, anthocyanins, thymocyanin, sallylcysteine, oligosaccharide esters, and some of these have neuroprotective potential due to which they can be used against PD (Singh et al., 2005;Hatti et al., 2014). Flavonoids (polyphenol group consists of aromatic rings with a phenolic hydroxyl group and a 3-OH), a group with strong antioxidant (scavenge free radicals and reactive oxygen species) and iron-chelating properties, are categorized into flavones, flavonones, isoflavones, flavonols and anthocyanidins based on their glycation, hydroxylation and alkylation patterns (Spencer, 2009). Along with their antioxidant properties, the feasible mechanism of action of flavanoids is the association of flavanoids with neuronal signaling cascades such as protein Kinase C, MAPK and PI3K/Akt, this association increase neuronal survival by decreasing apoptosis (Spencer, 2009). ...
... Flavonoids (polyphenol group consists of aromatic rings with a phenolic hydroxyl group and a 3-OH), a group with strong antioxidant (scavenge free radicals and reactive oxygen species) and iron-chelating properties, are categorized into flavones, flavonones, isoflavones, flavonols and anthocyanidins based on their glycation, hydroxylation and alkylation patterns (Spencer, 2009). Along with their antioxidant properties, the feasible mechanism of action of flavanoids is the association of flavanoids with neuronal signaling cascades such as protein Kinase C, MAPK and PI3K/Akt, this association increase neuronal survival by decreasing apoptosis (Spencer, 2009). They can cause neurogenesis and angiogenesis and have the ability to function directly against neurotoxic agents and pro-inflammatory agents (Vafeiadou et al., 2007). ...
Therapeutic potential of Indian traditional medicines in Parkinson's disease.
Shweta Bhardwaj
Kanwal preet Kochhar
Suman Jain
M.R. Divya
Parkinson's disease (PD) is second most common neurodegenerative disorder, which is a progressive motor disease that affects 10 million people worldwide and around 5.5 million Indian. The hallmark neuropathology in PD are damage to dopaminergic neurons located in the pars compacta of the substantia nigra (SN) that project to the striatum and alpha synuclein containing inclusion bodies in the surviving neurons, resulting in motor impairments, e.g., tremors, bradykinesia (slow movement), poor balance, rigidity and difficulty in walking, as well as non-motor impairments including constipation, autonomic, psychiatric as well as cognitive impairments. The only pharmacology therapy for PD is levodopa but chronic use of this medicine has many side effects. Hence, these impairments are pressing issues that need to be addressed. This review article attempts to describe the usage of Indian traditional medicines to treat PD. In India, the references to the curative properties of dietary spices in the Rigveda and Atharvaveda arguably seem to be the earliest records of the use of herbs in medicine.
Therapeutic potential of Indian traditional medicines in Parkinson's disease
Shweta Sharma
... Flavonoids, the abundant phytonutrients found in fruits and vegetables, can modulate molecular signaling pathways that influence these cognitive processes (Spencer, 2009). Prominent examples of flavonoids and polyphenols are resveratrol (found in the skin of red grapes and in red wine) and epigallocatechin-3-gallate (EGCG; found in green tea). ...
... In both databases, pathways involved in ''cell cycle,'' ''endogenous antioxidative activity,'' and ''cell survival'' were significantly enriched, as was mitogen-activated protein kinase (MAPK) signaling. It is known that, depending on their specific chemical structure, flavonoids can either inhibit or activate these (legend continued on next page) pathways (reviewed by Spencer, 2009). The flavonoids were reported to exert their effect on cell survival through modulation of the MAPK and phosphoinositide-3 kinase (PI3K-AKT) pathways. ...
Apple Peel and Flesh Contain Pro-neurogenic Compounds
Muhammad Ichwan
Tara L Walker
Zeina Nicola
Gerd Kempermann
As mammals evolved with exposure to particular diets, naturally abundant compounds may have become part of the set of environmental co-determinants that shaped brain structure and function. Here we investigated whether bioactive factors found in apples directly affect hippocampal neurogenesis in the adult mouse. We found that quercetin, the most abundant flavanol in apple peel, was anti-proliferative at high concentrations but pro-neurogenic at low concentrations. This was confirmed in vivo, with intraperitoneally delivered quercetin promoting survival and neuronal differentiation, without affecting proliferation. Using a bioassay-guided fractionation approach we also identified additional pro-neurogenic compounds in apple flesh that were not related to flavonoids. We found that 3,5-dihydroxybenzoic acid significantly increased neural precursor cell proliferation and neurogenesis. This work shows that both flavonoids and 3,5-dihydroxybenzoic acid are pro-neurogenic, not only by activating precursor cell proliferation but also by promoting cell-cycle exit, cellular survival, and neuronal differentiation.
... The presence ofsteroidal lactones, alkaloids, stilbenoids, bilobalide, saponins, glycosides, Polymethoxyflavones, anthocyanins, lycopene, thymocyanin, flavonoids, ginsenosides, caffeine, ginkgolides, xanthones, oligosaccharide esters, isoflavonoids, catechins, Sallylcysteine, thymoquinoflavones are the neuroprotective potential of natural products derived from fruits and vegetables, herbs, and spices against PD. The main polyphenol group of flavonoids consists of aromatic rings with a phenolic hydroxyl group and a 3-OH 18,19,20 Flavonoids are categorized into flavones, flavanonols, flavanonesflavonols, anthocyanidins, isoflavones, and anthocyanidins, based on their alkylation, glycation, and hydroxylation patterns. 18 The feasible mechanism of action of flavonoids, besides their antioxidant properties, is their association with neuronal signaling cascades such as PI3K/Akt, protein kinase C, and MAPK, leading to decreased apoptosis and increased neuronal survival. ...
... 18 The feasible mechanism of action of flavonoids, besides their antioxidant properties, is their association with neuronal signaling cascades such as PI3K/Akt, protein kinase C, and MAPK, leading to decreased apoptosis and increased neuronal survival. 19 Flavonoids also cause angiogenesis and neurogenesis and function directly against neurotoxic agents and pro-inflammatory agents. 20 Moreover, through scavenging free radicals and reactive oxygen species (ROS), flavonoids induce antioxidant impact. ...
Plants as a promising source for the treatment of parkinson disease: A systematic review
A. Jothilin Subitsha
Sofia Khanam
Sneha Sabu
Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of the nigrostriatal system's pigmented dopaminergic neurons with a subsequent drop in dopamine. PD refers to such motor disorders such as resting tremor, muscle stiffness, and slow motion. Recent studies have shown that there has been an increasing interest in natural products particularly plants, for the treatment of Parkinson's disease. The anti-PD effects of these natural products are considered to be due to their regulation ability; development of reactive oxygen species, neuroinflammation, production of dopamine, excitotoxicity, metal homeostasis, mitochondrial function, and cellular signaling pathways, all of which are disordered in the PD brain.This review explores neuronal degeneration observed in Parkinson's disease has been slowed down or reversed by medicinal plants and natural products and their constituents.
... A recent study showed that small molecules could protect mitochondria in neurodegenerative diseases [24]. These metabolites seem to have a multi-target mechanism of action and interact with different signaling cascades, which can lead to neuronal survival [25,26]. ...
... The experiments were carried out as triplicates, and the data was stated as mean AE SD. SPSS software v. 25.0 was used to study the statistically significant differences between the control and experimental groups. Unpaired Student's t-test and one-way ANOVA were used to analyze the significant differences between the groups and within the groups, respectively. ...
Multiple neuroprotective features of Scutellaria pinnatifida–derived small molecule
Soha Parsafar
Zahra Nayeri
Farhang Aliakbari
Dina Morshedi
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders with no precise etiology. Multiple lines of evidence support that environmental factors, either neurotoxins or neuroinflammation, can induce Parkinsonism. In this study, we purified an active compound, neobaicalein (Skullcapflavone II), from the roots of Scutellaria pinnatifida (S. pinnatifida). Neobaicalein not only had protective impacts on rotenone-induced neurotoxicity but in glial cultures, it dampened the inflammatory response when stimulated with lipopolysaccharide (LPS). Neobaicalein had high antioxidant activity without any obvious toxicity. In addition, it could raise the cell viability, decrease early apoptosis, reduce the generation of reactive oxygen species (ROS), and keep the neurite's length normal in the treated SH-SY5Y cells. Pathway enrichment analysis (PEA) and target prediction provided insights into the PD related genes, protein-protein interaction (PPI) network, and the key proteins enriched in the signaling pathways. Furthermore, docking simulation (DS) on the proteins of the PD-PPI network revealed that neobaicalein might interact with the key proteins involved in PD pathology, including MAPK14, MAPK8, and CASP3. It also blocks the destructive processes, such as cell death, inflammation, and oxidative stress pathways. Our results demonstrate that neobaicalein alleviates pathological effects of factors related to PD, and may provide new insight into PD therapy.
... In different experimental models of neurological diseases, phytoconstituents have exposed to have modulatory properties on the nervous system [55]. However, the pathogenesis of nervous system disorders is not fully understood up till now but most of the studies on dissimilar nervous disorder models mimicking critical properties of the disease have decorated vital factors like oxidative stress, mitochondrial dysfunction, and neuroinflammation [66,67]. However, the models for neurotoxicity have been established to be an important tool for rising new therapeutic techniques and addressing the efficiency and side effects of symptomatic management [58]. ...
... However, alkaloids, on the other hand, absolutely adapt the binding of muscimol to GABA receptor compound [74,75]. Likewise, a few flavonoids have established an affinity for binding to benzodiazepine location on the GABAA receptor [65], and also, work as a scavenger to pro-inflammatory as well as neurotoxic genus [66]. Numerous plants including Arisaema amurense, Biota orientalis, Mentha arvensis, Salvia miltiorrhiza, Albizia julibrissin, Astragalus membranaceus, Glycyrrhiza uralensis have been established to have an inhibitory outcome on mono-amine oxidase-B (MAO-B)enzyme action [67]. ...
Prospective Function of Different Antioxidant Containing Natural Products in the Treatment of Neurodegenerative Disease
Md. Habibur Rahman
Rokeya Akter
Mohammad Amjad Kamal
Nature has bestowed humanity through additional resources natural products (NPs) on earth with water. However, NPs have a significant function in the avoidance of disease by boosting health in humans as well as animals. These NPs have been scientifically acknowledged to have a range of biological characteristics like antioxidant, anti-inflammatory actions. Both In vitro and in vivo studies have more recognised the convenience of NPs in different preclinical models of neurodegenerative disorders. Moreover, most NPs comprise phytoconstituents, including polyphenolic antioxidants; originate in herbs, fruits, nuts, vegetables as well as also in marine with freshwater flora. These phytoconstituents might actively repress neuro-degeneration and recover memory as like cognitive actions of the brain. Moreover, they are well recognized to participate in an essential position in the prevention like heal of different neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, epilepsy, and additional neuronal disorders. In general, the large-scale neuro-pharmacological actions of NPs have been familiar owing to the consequence of also the inhibition of inflammatory processes, or the up-regulation of various cell endurance proteins or a mixture of together. Owing to the shortage of human studies on neuroprotective belongings of NPs, this review highlights a variety of documented actions of NPs in vitro and in vivo preclinical models and their possible neuro-protection applications by the accessible awareness in writing.
... It also appears to improve the cognitive deficits associated with aging and those related to malnutrition in children. [1][2][3][4][5] These phenomena have been at least partially associated with the vascular effects of these substances, which include angiogenesis or increased blood flow. 6,7 A number of effects on signaling pathways have been reported at the cellular level, 8,9 yet mechanistic data is on the whole scarce, particularly regarding the electrophysiological effects of polyphenols on specific brain structures. ...
The dietary polyphenol metabolite protocatechuic acid produces acute and sustained effects on hippocampal electrical activity
Marta Montero
Ricardo Munoz-Arnaiz
Julia Makarova
Oscar Herreras
Dietary polyphenols and in particular bioavailable metabolites resulting from gut microbiota transformations appear to have beneficial effects in situations of impaired cognition, combatting memory deficits in acute pathological models of neurodegeneration. Modifications to blood flow may underlie the effects of these molecules and although some such metabolites cross the blood-brain barrier, their targets and electrophysiological effects remain unknown. Hence, we explored the systemic and direct effects of protochatechuic acid (PCA) on electrical activity in the hippocampus and cortex of anesthetized female rats, recording evoked and spontaneous high-density field potentials (FPs) to mathematically derive pathway-specific FP generators. We found transient and sustained effects of PCA on evoked activity in the CA1 field, including paradoxical actions on excitatory transmission that depend on the route of administration. Systemic delivery of PCA altered the ongoing activity of some FP generators, albeit with marked inter-animal variation. Interestingly, PCA induced the detachment of infraslow cortico-hippocampal activities over a scale of minutes. These results point to direct actions of polyphenols on cell and network electrical activity, some of which reflect non-specific actions. Thus, dietary-derived polyphenols appear to fulfill neuromodulatory roles, encouraging the search for additional targets to better guide their use in preventing brain pathologies.
... α-synuclein aggregation, c-Ju N-terminal kinase (JNK) activation, and monoamine oxidase synthesis are all inhibited by these substances, which function as agonists for dopaminergic neurons [91]. Apart from their anti-oxidative characteristics, flavonoids may interact with neuronal signaling pathways such as PI3K/Akt, protein kinase C, and MAPK, which results in reduced apoptosis and increased neuronal survival [92]. Flavonoids also promote neurogenesis as well as physiological angiogenesis and directly inhibit neurotoxic and pro-inflammatory chemicals [93]. ...
Stem Cells and Natural Agents in the Management of Neurodegenerative Diseases: A New Approach
NEUROCHEM RES
Aranka Brockmüller
Negin Mahmoudi
Amir Kian Movaeni
Masoumeh Majidi Zolbin
Neurodegenerative diseases refer to a group of neurological disorders as a consequence of various destructive illnesses, that predominantly impact neurons in the central nervous system, resulting in impairments in certain brain functions. Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neurodegenerative disorders represent a major risk to human health. In order to optimize structural and functional recovery, reconstructive methods integrate many approaches now, to address the complex and multivariate pathophysiology of neurodegenerative disorders. Stem cells, with their unique property of regeneration, offer new possibilities in regenerative and reconstructive medicine. Concurrently, there is an important role for natural products in controlling many health sufferings and they can delay or even prevent the onset of various diseases. In addition, due to their therapeutic properties, they have been used as neuroprotective agents to treat neurodegenerative disorders. After decades of intensive research, scientists made advances in treating these disorders so far, but current therapies are still not capable of preventing the illnesses from progressing. Therefore, in this review, we focused on a new perspective combining stem cells and natural products as an innovative therapy option in the management of neurodegenerative diseases.
... In addition to redox activity, their modes of action include inhibiting key enzymes, modulation of transcription factors or cell receptors, and finally, perturbation of protein aggregates. Furthermore, they regulate cell function in the areas of proliferation and growth, apoptosis, inflammation, metastasis, angiogenesis, and various immune responses by affecting signal processing (Packer et al. 1999;Sang et al. 2005;Spencer 2009;Yang et al. 2009). ...
Plant Based Polyphenol Associations with Protein: A Prospective Review
Diana Tazeddinova
Md. Rezaur Rahman
Sinin Hamdan
Mohammed M. Rahman
This review discusses the classes of plant polyphenols along with their binding mechanisms with protein molecules. Generally, polyphenols bind in covalent and non-covalent orientations with protein molecules. Their addition to the protein usually results in undesirable flavors and tastes inside the proteins. They also affect the color of the food. Plant polyphenols are found to act in a protective way against cardiovascular disease, neurodegenerative diseases, diabetes, and cancer. In addition to redox activity, their modes of action include the inhibition of key enzymes, modulation of transcription factors or cell receptors, and finally, perturbation of protein aggregates. Dietary polyphenols usually play a key role in protein digestion by forming covalent and non-covalent bonds with proteins. In addition, polyphenols and plant phenolics possess the scavenging ability of reactive oxygen species (ROS), including radical/non-radical oxygen species including HOC•, H2O2, HOCl, 1O2 (singlet oxygen), and oxidatively generated radicals derived from LDL biomolecules such as ROOC• and oligonucleic acids.
... Dietary flavonoids exhibit neuroprotective properties that involve several effects on the brain, including the protection of neurons against injury and promotion of memory, learning and cognitive function [52][53] . Flavonoid compounds benefited humans in overcoming oxidative damage -related diseases like Parkinson's disease and Alzheimr's disease [54] . ...
Flavonoids: Its working mechanism and various protective roles
Jaya Gupta
A.K. Gupta
... A combination of preclinical and epidemiological studies suggests that (poly)phenols may be effective in reversing neurodegenerative pathology and age-related declines in neurocognitive performance, although at present, a direct association between (poly)phenol consumption and improvement in neurological health has not been made. The potential of (poly)phenols to improve neurological health appears to be related to a number of mechanisms, including their ability to interact with intracellular neuronal and glial signaling, to influence the peripheral and cerebrovascular blood flow, and to reduce neuronal damage and losses induced by neurotoxins and neuroinflammation (148,327,424,428,(430)(431)(432)492). This section will examine the beneficial effects of flavonoids on memory, learning, and neurocognitive performance. ...
COMPREHENSIVE INVITED REVIEW Dietary (Poly)phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases
Daniele Del Rio
Ana Rodriguez-Mateos
Alan Crozier
... Flavonoids are shown to enhance spatial memory in animal models. Both factors increase BDNF expression by causing induction of Akt/PKB (Spencer, 2009;Bechara and Kelly, 2013). Thus, common links and pathways provide excellent therapeutic targets and thus warrant interventional studies. ...
Brain-Derived Neurotrophic Factor: A Connecting Link Between Nutrition, Lifestyle, and Alzheimer's Disease
Bin Xue
Shah Mohammad Abbas Waseem
Zhixin Zhu
Monika Sharma
Brain-derived neurotrophic factor (BDNF) involving tropomyosin kinase B and low affinity p75 neurotropin receptors is the most abundant and researched neurotropins in mammal's brain. It is one of the potential targets for therapeutics in Alzheimer's disease (AD) owing to its key role in synaptic plasticity. Low levels of BDNF are implicated in the pathophysiology of neurological diseases including AD. However, a healthy lifestyle, exercise, and dietary modifications are shown to positively influence insulin regulation in the brain, reduce inflammation, and up-regulate the levels of BDNF, and are thus expected to have roles in AD. In this review, the relationship between BDNF, mental health, and AD is discussed. Insights into the interrelationships between nutrition, lifestyle, and environment with BDNF and possible roles in AD are also provided in the review. The review sheds light on the possible new therapeutic targets in neurodegenerative diseases.
... As anticipated, the cranberry intervention had no impact upon differences in structural grey matter between groups, nor did it influence differences in WMH over the 12-week period of investigation. However, in line with results suggesting that the cranberry intervention led to improved episodic memory performance, differences in perfusion in response to the intervention were detected between cranberry and placebo groups in key cerebral regions supporting memory consolidation and retrieval (59). A relative increase in perfusion was detected in the cranberry group between baseline and follow-up compared to the placebo group in medial temporal (entorhinal) and prefrontal (orbitofrontal) regions, as well as in the nucleus accumbens, which would provide optimal distribution of the essential nutrients for neuronal activity, such as oxygen and glucose (60). ...
Chronic Consumption of Cranberries (Vaccinium macrocarpon) for 12 Weeks Improves Episodic Memory and Regional Brain Perfusion in Healthy Older Adults: A Randomised, Placebo-Controlled, Parallel-Groups Feasibility Study
Emma C Flanagan
Donnie Cameron
Rashed Sobhan
Background Ageing is highly associated with cognitive decline and modifiable risk factors such as diet are believed to protect against this process. Specific dietary components and in particular, (poly)phenol-rich fruits such as berries have been increasingly recognised for their protection against age-related neurodegeneration. However, the impact of cranberries on cognitive function and neural functioning in older adults remains unclear. Design A 12-week parallel randomised placebo-controlled trial of freeze-dried cranberry powder was conducted in 60 older adults aged between 50 and 80 years. Cognitive assessment, including memory and executive function, neuroimaging and blood sample collection were conducted before and after the intervention to assess the impact of daily cranberry consumption on cognition, brain function and biomarkers of neuronal signalling. Results Cranberry supplementation for 12 weeks was associated with improvements in visual episodic memory in aged participants when compared to placebo. Mechanisms of action may include increased regional perfusion in the right entorhinal cortex, the accumbens area and the caudate in the cranberry group. Significant decrease in low-density lipoprotein (LDL) cholesterol during the course of the intervention was also observed. No significant differences were, however, detected for BDNF levels between groups. Conclusions The results of this study indicate that daily cranberry supplementation (equivalent to 1 small cup of cranberries) over a 12-week period improves episodic memory performance and neural functioning, providing a basis for future investigations to determine efficacy in the context of neurological disease. This trial was registered at clinicaltrials.gov as NCT03679533 and at ISRCTN as ISRCTN76069316.
... Fruits and vegetables represent a rich source of antioxidants including vitamins (vitamin C, B complex and E etc.), carotenoids and polyphenols, which have been shown to improve cognition [6][7][8]. A number of potential underlying mechanisms have been identified including the interaction of fruit polyphenols, carotenoids and vitamins with intracellular neuronal and glial signalling pathways, regulation of cerebral blood flow, and protection against neurotoxins and neuroinflammation [8][9][10]. A doseresponse meta-analysis including nine studies (five cohort studies and four cross-sectional studies) with a total of 31,104 participants suggested approximately a 13% (OR = 0.87, 95% CI 0.77-0.99) ...
Effects of chronic consumption of specific fruit (berries, cherries and citrus) on cognitive health: a systematic review and meta- analysis of randomised controlled trials
EUR J CLIN NUTR
Yueyue Wang
Jose Lara
John K. Lodge
Objectives The cognitive-protective effects related to the consumption of a variety of fruits are supported by several intervention studies. This systematic review and meta-analysis compared the magnitude of effects following chronic (≥1 week) consumption of frozen, freeze-dried powder including extracts and juices of fruits, covering berries, cherries and citrus, on cognition and mood in adults. Methods PubMed, Web of Science, Scopus, and psycARTICLES were searched from inception until February, 2021. Inclusion criteria were randomised controlled trials assessing memory, executive function, psychomotor speed, mood and mini mental state examination in adult participants ≥18 years of age. Cognition was tested by global or domain specific tasks. Results Out of 13,861 articles identified, 16 papers were included; 11 studies provided suitable data for meta-analysis. Fourteen studies reported improvement or trend for improvement in cognition, five studies assessed mood and one study supplementing grape juice found trend for mood improvement. From the meta-analysis, cherry juice supplementation was suggested to improve psychomotor speed by −0.37 of standardised mean difference (95% CI [−0.74, 0.01]) in reaction time ( P = 0.05). Conclusions The meta-analysis did not sufficiently support a role for fruits or fruit forms to improve cognition and mood.
... Fruits and drinks such as tea, red wine, cocoa, and coffee are the main sources of dietary polyphenols. They affect peripheral and cerebrovascular blood flow, interact with intracellular neuronal and glial signaling, and help protect neurons from damage [159][160][161]. Research results show that polyphenols have a positive effect on cognition and memory and reduce neuronal damage [162][163][164]. ...
Can Nutrients and Dietary Supplements Potentially Improve Cognitive Performance Also in Esports?
Monika Szot
Ewa Karpęcka-Gałka
Remigiusz Dróżdż
Barbara Frączek
Factors influencing brain function and cognitive performance can be critical to athletic performance of esports athletes. This review aims to discuss the potential beneficial effects of micronutrients, i.e., vitamins, minerals and biologically active substances on cognitive functions of e-athletes. Minerals (iodine, zinc, iron, magnesium) and vitamins (B vitamins, vitamins E, D, and C) are significant factors that positively influence cognitive functions. Prevention of deficiencies of the listed ingredients and regular examinations can support cognitive processes. The beneficial effects of caffeine, creatine, and probiotics have been documented so far. There are many plant products, herbal extracts, or phytonutrients that have been shown to affect precognitive activity, but more research is needed. Beetroot juice and nootropics can also be essential nutrients for cognitive performance. For the sake of players' eyesight, it would be useful to use lutein, which, in addition to improving vision and protecting against eye diseases, can also affect cognitive functions. In supporting the physical and mental abilities of e-athletes the base is a well-balanced diet with adequate hydration. There is a lack of sufficient evidence that has investigated the relationship between dietary effects and improved performance in esports. Therefore, there is a need for randomized controlled trials involving esports players.
... The most common group of polyphenolic compounds is represented by flavonoids and the main subclasses flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones, largely contained in fruits and vegetables [3]. The potential of these molecules in preventing and/or counteracting neurodegenerative phenomena has been recently considered [4][5][6]. Other classes of polyphenols largely investigated for their potential role in neurodegenerative diseases include stilbenes (such as resveratrol, contained in red wine), tyrosol (such as oleuropein, contained in olive oil), and curcuminoid (such as curcumin, contained in turmeric) [2]. ...
Phenolic Acids and Prevention of Cognitive Decline: Polyphenols with a Neuroprotective Role in Cognitive Disorders and Alzheimer's Disease
Giuseppe Caruso
Justyna Godos
Anna Privitera
Giuseppe Grosso
Cognitive impairment, also known as cognitive decline, can occur gradually or suddenly and can be temporary or more permanent. It represents an increasingly important public health problem and can depend on normal aging or be linked to different neurodegenerative disorders, including Alzheimer's disease (AD). It is now well-established that lifestyle factors including dietary patterns play an important role in healthy aging as well as in the prevention of cognitive decline in later life. Among the natural compounds, dietary polyphenols including phenolic acids have been recently the focus of major attention, with their supplementation being associated with better cognitive status and prevention of cognitive decline. Despite their therapeutic potential, human studies investigating the relation between phenolic acids intake and cognitive outcomes are rather scarce. In this review, we provide preclinical evidence that different dietary polyphenols such as rosmarinic acid, ellagic acid, and cinnamic aldehyde can exert neuroprotective and pro-cognitive activities through different molecular mechanisms including the modulation of pro-oxidant and antioxidant machinery as well as inflammatory status. Future and more numerous in vivo studies are needed to strengthen the promising results obtained at the preclinical level. Despite the excellent pharmacokinetic properties of phenolic acids, which are able to be accumulated in the brain at pharmacologically relevant levels, future studies should also identify which among the different metabolites produced as a consequence of phenolic acids' consumption may be responsible for the potential neuroprotective effects of this subgroup of polyphenols.
... Flavonoids also normalize mood due to antidepressant properties [35]. Many studies suggested the protective effect of flavonoids in learning and memory dysfunction [36][37][38]. ...
Neuroprotective effect of hesperidin and its combination with coenzyme Q10 on an animal model of ketamine-induced psychosis: behavioral changes, mitochondrial dysfunctions, and oxidative stress
Monu Yadav
Background Psychosis is a complex mental illness divided by positive symptoms, negative symptoms, and cognitive decline. Clinically available medicines are associated with some serious side effects which limit their use. Treatment with flavonoids has been associated with delayed onset and development, decreased risk, or increased improvement of various neuropsychiatric disorders including psychosis with negligible side effects. Therefore, the present study was aimed to investigate the protective effects of hesperidin (flavonoid) alone or its combination with coenzyme Q10 against ketamine-induced psychotic symptoms in mice. Results Ketamine (50 mg/kg, i.p.) was given for 21 days to induce psychosis in Laca mice of either sex. Locomotor activity and stereotypic behaviors, immobility duration (forced swim test), and increased transfer latency (elevated plus maze) were performed to test the effect of hesperidin (50 mg/kg, 100 mg/kg, 200 mg/kg, p.o.) and coenzyme Q10 (20 mg/kg, 40 mg/kg, p.o.) and combination of hesperidin + coenzyme Q10 followed by biochemical and mitochondrial complexes assays. For 21 days, ketamine (50 mg/kg, i.p.) administration significantly produced increased locomotor activity and stereotypic behaviors (positive symptoms), increased immobility duration (negative symptoms) and cognitive deficits (increases transfer latency) weakens oxidative defense and mitochondrial function. Further, 21 days' administration of hesperidin and coenzyme Q10 significantly reversed the ketamine-induced psychotic behavioral changes and biochemical alterations and mitochondrial dysfunction in the discrete areas (prefrontal cortex and hippocampus) of mice brains. The potential effect of these drugs was comparable to olanzapine treatment. Moreover, the combination of hesperidin with coenzyme Q10 and or a combination of hesperidin + coenzyme Q10 + olanzapine treatment did not produce a significant effect compared to their per se effect in ketamine-treated animals. Conclusions The study revealed that hesperidin alone or in combination with coenzyme Q10 could reduce psychotic symptoms and improve mitochondrial functions and antioxidant systems in mice, suggesting neuroprotective effects against psychosis.
... Focusing on their benefits on memory, the exact mechanisms by which flavonoids affect brain biochemistry are not precisely known, although it is speculated that they act as a promoter of new protein synthesis in neurons and thus induce morphological changes which have a direct influence on memory acquisition and consolidation. One of these changes is the activation of cAMP-response element-binding protein (CREB), a transcription factor which binds to the promoter regions of many genes associated with synapse re-modelling, synaptic plasticity and memory [47,48]. It also includes key components in the regulation of brain derivate neurotrophic factor (BDNF), a neurotrophin that is involved in the survival and function of neurons in the central nervous system and is an essential part of the formation of appropriate synaptic connections during development and for learning and memory in adults [49,50]. ...
Neurocognitive Effects of Cocoa and Red-Berries Consumption in Healthy Adults
Joaquín Garcia Cordero
Alicia Pino
Constanza Cuevas Estancona
Sonia de Pascual-Teresa
In recent decades, the elderly population has increased at higher rates than any other population group, resulting in an increase in age-related diseases such as neurodegenerative and cognitive impairment. To address this global health problem, it is necessary to search for new dietary strategies that can prevent the main neurocognitive problems associated with the ageing process. Therefore, the aim of the present study was to analyze the effect of cocoa flavanols and red berry anthocyanins on brain-derived neurotrophic factor (BDNF) and nerve growth factor receptor (NGF-R) and to stablish the possible improvement in cognitive performance by using a battery of neurocognitive tests that included the Verbal Learning Test Spain-Complutense, the Spatial Recall Test 10/36 BRB-N, the Wechsler Adult Intelligence Scale III and IV, the STROOP Task and the Tower of London Test. A randomized, double-blind, parallel-group study was performed in 60 healthy volunteers between 50 and 75 years old who consumed a cocoa powder, a red berries mixture or a combination of both for 12 weeks. After the intervention, we observed a reduction in the time needed to start (p = 0.031) and finish (p = 0.018) the neurocognitive test known as the Tower of London in all groups, but the decrease in time to finish the task was more pronounced in the intervention with the combination of cocoa-red berries group. We failed to show any significant difference in BDNF and NGF-R sera levels. However we found a negative correlation between BDNF and the number of movements required to finish the TOL in women (p = 0.044). In conclusion, our study showed an improvement in executive function, without any change in neurotrofin levels, for all intervention arms.
... Polyphenols have been proposed to have antiinflammatory effect and antioxidant activity, polyphenols inhibit molecular signaling pathways which are activated by oxidative stress and the reactive oxygen species (ROS) [53]. Polyphenols also activate the extracellular signal-regulated kinase (ERK1/2) and the protein kinase B (PKB/Akt) signaling pathways, leading to the activation of the cAMP response element-binding protein (CREB), a transcription factor in the expression of neurotrophins involved in adult hippocampal neurogenesis [107]. Resveratrol is a phenolic compound abundant in berries, grapes, red wine and peanuts have a neuroprotective mechanism against oxidative stress, inhibits proinflammatory enzyme expression and reduces nuclear factor-κB activation and cytokine release [108]. ...
How Brain Changes as We Learn
De Frías Virginia
... Moreover, Tualang honey treated rats exhibit significantly higher BDNF concentration and lower brain acetylcholinesterase levels [42]. Flavonoids have been demonstrated to enhance memory function via activating the extracellular signal-regulated kinase (ERK1/2) and protein kinase B (PKB/Akt) signalling pathways, leading to the activation of cAMP response element-binding protein (CREB), a transcription factor responsible for increasing BDNF expression [43]. Hence, we hypothesise that the memory preserving and neuroprotective effects of Tualang honey are due to its flavonoid contents acting on the ERK-CREB-BDNF pathway. ...
Tualang Honey: A Decade of Neurological Research
Khairunnuur Fairuz Azman
Che Badariah Abdul Aziz
Rahimah Zakaria
Che Aishah Nazariah Ismail
Tualang honey has been shown to protect against neurodegeneration, leading to improved memory/learning as well as mood. In addition, studies have also demonstrated its anti-inflammatory and antioxidant properties. However, a substantial part of this research lacks systematization, and there seems to be a tendency to start anew with every study. This review presents a decade of research on Tualang honey with a particular interest in the underlying mechanisms related to its effects on the central nervous system. A total of 28 original articles published between 2011 and 2020 addressing the central nervous system (CNS) effects of Tualang honey were analysed. We identified five main categories, namely nootropic, antinociceptive, stress-relieving, antidepressant, and anxiolytic effects of Tualang honey, and proposed the underlying mechanisms. The findings from this review may potentially be beneficial towards developing new therapeutic roles for Tualang honey and help in determining how best to benefit from this brain supplement.
... As shown by studies, flavonoids and their metabolites moderate several neurological processes that involve interaction with neuronal-glial signaling pathways and neuronal survival and their function was observed (Spencer, 2010). With this, flavonoids induce alterations in cerebral blood flow Williams and Spencer, 2012), increase antioxidant enzymes and proteins functions which are involved in synaptic plasticity and neuronal repair (Mann et al., 2007, Eggler et al., 2008, Spencer, 2009 ...
Bioactive Nutraceuticals and Functional Foods in Neurodegeneration
Zunera Chauhdary
Muhammad Ajmal Shah
Azhar Rasul
... Similarly, some phytochemicals like flavonoids also proven their binding ability on the GABAA receptor specifically at the benzodiazepine site [138,139] and established as a scavenger against pro-inflammatory and neurotoxic radical species [140]. Moreover, many medicinal plants such as Mentha arvensis, Arisaema amurense, Salvia miltiorrhiza, Glycyrrhiza uralensis Biota orientalis, Albizia julibrissin, and Astragalus membranaceus have proven their inhibitory efficacy on monoamine oxidase-B (MAOB) enzyme [141]. Previous results obtained from various experimental results found that α-asarone, a compound isolated from Acorus gramineus, exhibits its anti-convulsing, antileptic, as well as sedative action in the hippocampus of CNS by increasing tonic GABAergic neuronal activity [142,143]. ...
The neuroprotective attribution of Ocimum basilicum: a review on the prevention and management of neurodegenerative disorders
Mohamed Ali Seyed
Siddiqua Ayesha
Norazrina Azmi
Yousef Hawsawi
Background Bioactive principles from various natural resources including medicinal herbs have always played a crucial role in healthcare settings and increasingly became key players in drug discovery and development for many biopharmaceutical applications. Additionally, natural products (NPs) have immense arrangement of distinctive chemical structures with diverse functional groups that motivated numerous investigators including synthetic chemists to discover new therapeutic entities. Numerous pre-clinical investigations involving the animal models have evident the usefulness of these NPs against various human diseases including neurodegenerative disorders (NDs). Main text Ocimum basilicum Linn ( O . basilicum L.), also known as sweet basil, is well practiced in traditional healthcare systems and has been used to treat various human illnesses, which include malaria, skin disease, diarrhea, bronchitis, dysentery, arthritis, eye diseases, and insect bites and emphasize the significance of the ethno-botanical approach as a potential source of novel drug leads With the growing interest in advanced techniques, herbal medicine and medicinal plants explorations are still considered to be a novel resource for new pharmacotherapeutic discovery and development. O . basilicum L and its bioactive principles including apigenin, eugenol, myretenal, β-sitosterol, luteolin, rosmarinic acid, carnosic acid, essential oil (EO)-rich phenolic compounds, and others like anthocyanins and flavones could be of therapeutic values in NDs by exhibiting their neuro-protective efficacy on various signaling pathways. The present comprehensive review collected various related information using the following searching engines such as PubMed, Science Direct, Google Scholar, etc. and focused mainly the English written documents. The search period comprised of last two decades until present. Conclusion Although these efficacious plant genera of prime importance and has potential medical and socioeconomic importance, yet the pivotal evidence for its neuroprotective potential in novel clinical trials remains lacking. However, with the available wealth of obtainable literature on this medicinal plant, which supports this review and concludes that O . basilicum L may function as a promising therapeutics for the treatment of NDs.
... In different experimental models of neurological diseases, phytocon- stituents have been exposed to have modulators properties on the nervous system [75]. However, the pathogenesis of nervous system disorders is not fully understood up till now but most of the studies on dissimilar nervous disorder models mimicking critical properties of the disease have decorated vital factors like oxidative stress, mitochondrial dysfunction, and neuroinflammation [76]. Within this segment, we discuss the most commonly studied nervous antioxidants, focusing on their action mechanism Table 1. ...
Flavonoids and Polyphenolic Compounds as Potential Talented Agents for the Treatment of Alzheimer's Disease and their Antioxidant Activities
CURR PHARM DESIGN
Md. Arifur Rahman Chowdhury
Aging is a normal human cycle and the most important risk factor for neurodegenerative diseases. Alternations in cells due to aging contribute to loss of the nutrient-sensing, cell function, increased oxidative stress, loss of the homeostasis cell, genomic instability, the build-up of malfunctioning proteins, weakened cellular defenses, and a telomere split. Disturbance of these essential cellular processes in neuronal cells can lead to life threats including Alzheimer's disease (AD), Huntington's disease (HD), Lewy's disease, etc. The most common cause of death in the elderly population is AD. Specific therapeutic molecules were created to alleviate AD's social, economic, and health burden. In clinical practice, almost every chemical compound was found to relieve symptoms only in palliative treatment. The reason behind these perfect medicines is that the current medicines are not effective in targeting the cause of this disease. In this paper, we explored the potential role of flavonoid and polyphenolic compounds, which could be the most effective preventative anti-Alzheimer 's strategy.
Nutraceutical for Multiple Sclerosis
Pardis Mohammadi Pour
Abdul Haleem Khan
... A healthy diet supplies a myriad of phenolic compounds (PC) that may affect neural function in multiple ways [46]. PC are capable of interacting with intracellular and glial signaling pathways; they modulate brain flux, protect against neurotoxins and neuroinflammation [47,48]. Some neural cells possess PC, GABA [49,50] and opioid receptors [51,52], which may activate pathways related to plasticity and the synthesis of new synaptic routes. ...
Diet and depressive disorders
Mariane Lutz
Camila Vargas
Jana Stojanova
Marcelo Arancibia
Background: The importance of foods or food constituents in mental health is increasingly recognized, and "nutritional psychiatry" is a growing discipline. Objective: This narrative review aims to present work supporting associations between food or food constituents and mental health, specifically depressive disorders. Methods: The data presented is derived from preclinical and clinical work, including in vitro and in vivo assays, as well as observational studies and randomized clinical trials of dietary interventions. The focus of the review is the mediation of inflammatory processes and oxidative stress by dietary constituents that are an integral part of a healthy diet, such as the Mediterranean diet and similar. Results and Discussion: We present evidence for the role of the diet in prevention and management of depressive disorders, beyond the effect of individual nutrients. The findings indicate that among the dietary components with higher degree of evidence to influence depressive disorders are long chain n-3 polyunsaturated fatty acids (EPA and DHA), and various dietary bioactive compounds, especially plant-derived secondary metabolites represented by polyphenols such as flavonoids and resveratrol. Conclusion: Diet exerts an important role on mental health, and evidence indicates that some dietary constituents contribute to the prevention of depressive disorders.
Nutrition and Nutraceuticals for Brain Cancer
Iqra Sarfraz
Ghulam Mujtaba Shah
... Strawberries are one of the most highly valued fruits due to their abundance of vitamins, minerals, anthocyanin, flavonoids, and phenolic acids (Ayala-Zavala, Wang, Wang, & González-Aguilar, 2004;Halbwirth et al., 2006), which give rise to appearance, nutritional, and organoleptic qualities that appeal to human consumers. Epidemiological studies have indicated that consuming food containing micronutrients and phytochemical compounds found in strawberry is linked with decreased risk of developing non-communicable diseases such as cancers, heart diseases, neurodegenerative diseases, attenuate cognitive decline, and neuronal dysfunction (Aune et al., 2017;Knee, 2002;Spencer, 2009;Vauzour, Vafeiadou, Rodriguez-Mateos, Rendeiro, & Spencer, 2008). ...
Mapping QTL underlying fruit quality traits in an F1 strawberry population
J HORTIC SCI BIOTECH
Rashed Alarfaj
Richard Harrison
Paul Hand
Mohamed El-Soda
Understanding how strawberry (Fragaria x ananassa) nutritional and quality traits are genetically regulated and correlated is an essential step towards improving marker-assisted breeding programmes in this crop. A first step to achieve this goal was to construct a single nucleotide polymorphism (SNP)-based genetic map of 140 F1 individuals of a cross between the 2 octoploid parents 'Redgauntlet' and 'Hapil'. The map consisted of 3933 SNPs distributed over 28 linkage groups, representing the 7 homoeologous groups expected in Fragaria (2n = 8x = 56), and covered a total length of 2624.7 cM with an average resolution of 0.7 cM/SNP. Two overlapping subsets of F1 individuals were evaluated in the field and glasshouse at East Malling Research and the University of Reading, respectively. Negative correlation was observed between Pelargonidin and the three traits L*, a*, and b*, whereas positive correlations were observed within L*, a*, and b*, and between Ellagic acid, Pelargonidin, and Cyanidin at both trial locations. Quantitative trait loci (QTL) mapping revealed 29 significant QTL associated with the measured traits and mapped over 16 linkage groups. Two QTL for fruit fresh weight were co-located between day 1 and day 4 of shelf life, accounting for over 62% of the variation. These data will enhance our understanding of the genetic basis and correlation of strawberry quality traits and provide the basis for refining QTL that underpin the genetic regulation of these quality traits.
... It was shown to be able to reduce brain Aβ 40 and Aβ 42 levels by preventing APP cleavage by BACE-1 in a 3xTg mouse model for AD (Sabogal-Guaqueta et al., 2015). Treatment with quercetin was shown to modulate both soluble and insoluble Aβ levels in the brain (Sabogal-Guaqueta et al., 2015;Moreno et al., 2017;Zaplatic et al., 2019), and promotes learning and memory functions (Devi and Ohno, 2012;Spencer, 2009). Moreover, quercetin has been shown to be more effective than Vitamin C and E, glutathione or beta carotene (Choi et al., 2003;Heijnen et al., 2002;Rice-Evans et al., 1995) at scavenging free radicals and preventing oxidant-induced apoptosis. ...
Development of grape polyphenols as multi-targeting strategies for Alzheimer's disease
Farida El Gaamouch
Kalena Liu
Hsiao-Yun Lin
Jun Wang
Alzheimer′s disease (AD) is by far the most prevalent neurodegenerative disease of aging and is a major burden for patients, caregivers, and the overall health care system. The complexity of AD pathophysiology and the lack of deep understanding of disease mechanisms impeded the development of AD therapy. Currently approved treatments for AD only modestly improve cognitive function but do not modify disease course. The lack of pharmacological approaches has led to the consideration of alternative strategies to prevent or to slow down the progression of AD. There has been a growing interest in the scientific community regarding the impact of diet and nutrition on AD. Grape derived nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory and neurotrophic properties and present as potential novel strategies for AD treatment. In this review, we summarize promising grape derived polyphenols that have been shown to modulate AD pathophysiology including amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation and synaptic dysfunction.
... Flavonoids are ubiquitous components of plants that have been consumed for health-boosting purposes since the beginning of life on earth. These phytoconstituents are known to cause modulation and upregulation of CREB ( cAMP response element-binding protein) expression which acts to increase the expression of neurotrophins crucial for memory (Spencer, 2009). ...
Chemical characterization and evaluation of the neuroprotective potential of Indigofera sessiliflora through in-silico studies and behavioral tests in scopolamine-induced memory compromised rats
Muhammad Sajjad Haider
Waseem Ashraf
Sana Javaid
Imran Imran
In the current study, we investigated the phytochemical and neuropharmacological potential of Indigofera sessiliflora, an indigenous least characterized plant widely distributed in deserted areas of Pakistan. The crude extract of the whole plant Indigofera sessiliflora (IS.CR) was preliminary tested in-vitro for the existence of polyphenol content, antioxidant and anticholinesterase potential followed by detailed chemical characterization through UHPLC-MS. Rats administered with different doses of IS.CR (100–300 mg/kg) for the duration of 4-weeks were behaviorally tested for anxiety and cognition followed by biochemical evaluation of dissected brain. The in-silico studies were employed to predict the blood–brain barrier crossing tendencies of secondary metabolites with the elucidation of the target binding site. The in-vitro assays revealed ample phenols and flavonoids content in IS.CR with adequate anti-oxidant and anticholinesterase potential. The dose-dependent anxiolytic potential of IS.CR was demonstrated in open field (OFT), light/dark (L/D) and elevated plus maze (EPM) tests as animals spent more time in open, illuminated and elevated zones (P
... Dietary flavonoids possess several neuroprotective properties, including protection against neuronal injury and amelioration of memory, learning, and cognitive function [9,10]. Quercetin is a flavonoid commonly found in the edible plants and is among the most potent antioxidants of plant origin [11]. ...
Enlightening the neuroprotective effect of quercetin in epilepsy: From mechanism to therapeutic opportunities
EPILEPSY BEHAV
Enes Akyüz
Yam Nath Paudel
Kristina Polat
Efthalia Angelopoulou
Epilepsy is a devastating neurological disorder characterized by the repeated occurrence of epileptic seizures. Epilepsy stands as a global health concern affecting around 70 million people worldwide. The mainstream antiepileptic drugs (AEDs) only exert symptomatic relief and drug-resistant epilepsy occurs in up to 33 percent of patients. Hence, the investigation of novel therapeutic strategies against epileptic seizures that could exert disease modifying effects is of paramount importance. In this context, compounds of natural origin with potential antiepileptic properties have recently gained increasing attention. Quercetin is a plant-derived flavonoid with several pharmacological activities. Emerging evidence has demonstrated the antiepileptic potential of quercetin as well. Herein, based on the available evidence, we discuss the neuroprotective effects of quercetin against epileptic seizures and further analyze the plausible underlying molecular mechanisms. Our review suggests that quercetin might be a potential therapeutic candidate against epilepsy that deserves further investigation, and paves the way for the development of plant-derived antiepileptic treatment approaches.
... For example, the consumption of flavanone-rich orange juice and chocolate (sources of flavonols) has been shown to improve memory in randomized trials with healthy subjects [49][50][51]. Similar to other flavonoids, flavonols modulate important cerebral processes such as synaptic plasticity, neuroplasticity phenomena, neuronal signaling pathways, and vascular regulation [52]. The multivariate analysis allowed us to establish the degree of associations with other variables, and we observed a positive correlation with the postpartum period and short and long-term memory. ...
Memory enhancement in Argentinian women during postpartum by the dietary intake of lignans and anthocyanins
NUTR RES
Agustín Ramiro Miranda
Mariela Valentina Cortez
Ana Scotta
Elio Andrés Soria
Due to their polyphenolic content, vegetable foods have neuroprotective effects which provide health benefits for specific human groups. Thus, they may be a useful dietary component for women who experience mnesic variations during postpartum, and here we examined the hypothesis that polyphenols can differentially enhance memory functioning. In particular, we aimed to associate the dietary intake of polyphenols with different memory systems in Argentinian postpartum women. The daily intakes of polyphenol groups were calculated using a validated food frequency questionnaire and the Phenol-Explorer database. Short-term memory (STM), long-term memory (LTM), learning (L), lexical-semantic memory (LSM), and working memory (WM) were assessed. Partial Least Squares (PLS) regression models were used to analyze the dietary polyphenols (predictors) and memory domains (responses), taking into account demographic, obstetric, and psychological factors. The sample included 71 women, with an average age of 29.59 years (SE = 0.73). Most of these women lived in a couple (91%), were unemployed (63%), and had ≥ 12 years of formal education (72%). STM, LTM, L and LSM correlated with lignans and anthocyanins, with LTM also being correlated with flavanones, flavonols, and tyrosols, and L and LSM also being associated with flavonols. A significant correlation was also found between WM and lignans. In conclusion, a cognitive improvement was demonstrated, mainly associated with the intake of lignans and anthocyanins, in the STM, LTM, WM, L, and LSM systems of postpartum women. This is the first study to our knowledge suggesting a role of polyphenolic effects on memory functioning during postpartum.
... Also, these compounds act as inhibitors for α-synuclein aggregation and monoamine oxidase production, and some of those are agonists for dopaminergic neurons [24]. Besides, flavonoids can decrease neuronal apoptosis and enhance neuronal survival [25,26]. They induce intensified angiogenesis and neurogenesis and counteract neurotoxic and pro-inflammatory agents [27,28]. ...
Beneficial Effects of Coconut Oil in Treatment of Parkinson's Disease
Khadiga Ibrahim
Eman M El-Sayed
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder, characterized by depletion of dopamine resulted from the death of dopaminergic neurons in the substantia nigra. The prevalence and incidence of PD is influenced by several factors, such as age, gender, ethnicity, genetic susceptibilities, and environmental exposures. Coconut oil (Coc) is a rich source of medium-chain triglycerides that are easily metabolized and give rise to ketones. Also, it contains antioxidants, such as vitamin E and polyphenolic compounds. It has been documented that Coc possesses significant pharmacological activities against obesity, insulin resistance, and neurodegenerative disorders, like Alzheimer's disease and multiple sclerosis. Therefore, the purpose of this review was to describe the use of coconut oil in preventing PD and slowing its progression. Also, we tried to identify possible mechanisms by which Coc may exert its beneficial role in PD. The available literature related to Coc PD effects , in both animal models and clinical trials was screened. This review showed that Coc can be supplemented to decrease the risk of PD.
... Flavonoids, a group of important naturally occurring compounds found in several edible vegetables, fruits, and medicinal plants, are structured by connecting two benzene rings with phenolic hydroxyl groups through the central three-carbon chain (C 6 -C 3 -C 6 ) [212]. It is reported that flavonoids can be used to protect the cardiovascular system, lower diabetes risk, cure neurodegenerative disorders, restore cognition after stroke, and suppress cancer progression [213][214][215]. Although flavonoids do not seem to be potent enough to be used as a monotherapy in the treatment of cancers, these compounds have been suggested to render considerable clinical benefits when applied in combination with radiotherapy or chemotherapy. ...
ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer
OXID MED CELL LONGEV
Gan Huang
Shu-Ting Pan
Head and neck cancer is a highly genetic and metabolic heterogeneous collection of malignancies of the lip, oral cavity, salivary glands, pharynx, esophagus, paranasal sinuses, and larynx with five-year survival rates ranging from 12% to 93%. Patients with head and neck cancer typically present with advanced stage III, IVa, or IVb disease and are treated with comprehensive modality including chemotherapy, radiotherapy, and surgery. Despite advancements in treatment modality and technique, noisome recurrence, invasiveness, and resistance as well as posttreatment complications severely influence survival rate and quality of life. Thus, new therapeutic strategies are urgently needed that offer enhanced efficacy with less toxicity. ROS in cancer cells plays a vital role in regulating cell death, DNA repair, stemness maintenance, metabolic reprogramming, and tumor microenvironment, all of which have been implicated in resistance to chemo-/radiotherapy of head and neck cancer. Adjusting ROS generation and elimination to reverse the resistance of cancer cells without impairing normal cells show great hope in improving the therapeutic efficacy of chemo-/radiotherapy of head and neck cancer. In the current review, we discuss the pivotal and targetable redox-regulating system including superoxide dismutases (SODs), tripeptide glutathione (GSH), thioredoxin (Trxs), peroxiredoxins (PRXs), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/keap1), and mitochondria electron transporter chain (ETC) complexes and their roles in regulating ROS levels and their clinical significance implicated in chemo-/radiotherapy of head and neck cancer. We also summarize several old drugs (referred to as the non-anti-cancer drugs used in other diseases for a long time) and small molecular compounds as well as natural herbs which effectively modulate cellular ROS of head and neck cancer to synergize the efficacy of conventional chemo-/radiotherapy. Emerging interdisciplinary techniques including photodynamic, nanoparticle system, and Bio-Electro-Magnetic-Energy-Regulation (BEMER) therapy are promising measures to broaden the potency of ROS modulation for the benefit of chemo-/radiotherapy in head and neck cancer. 1. Introduction Head and neck cancer (HNC) is the seventh most frequently occurring malignancy worldwide in 2018 (accounting for 4.9% of all cancer sites) [1]. It is reported that lip, oral cavity, and pharyngeal cancers could be responsible for the 529,500 new cancer cases (accounting for about 3.8% of all cancer cases) and the 292,300 cancer-related deaths (accounting for about 3.6% of all cancer deaths) in 2012 globally, and the incidence is predicted to increase by 62% to 856,000 cases in 2035 [2]. Due to the tenacious resistance of cancer cells to therapy, the five-year survival rate has not been significantly improved during past decade [3]. Commonly used radiation and chemotherapy drugs affect the prognosis of HNC through reactive oxygen species (ROS) regulation directly and indirectly [4]. The balance of cellular ROS is levered by ROS generators including mitochondrial ROS, NADPH oxidases, and other enzymes and ROS eliminators such as superoxide dismutases (SODs), tripeptide glutathione (GSH), and nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) [5]. ROS has been implicated in cancer initiation, formation, and development as well as therapy resistance [6]. In spite of some inspiring clinical trials concerning ROS modulation in comprehensive treatment of HNC, the personalized treatments call for multiple therapeutic strategies. During the past years, genetic or pharmaceutic methods for modulating ROS in HNC are showing great preclinical and clinical significance in the combined modality of chemo-/radiotherapy. Ongoing researches from other groups and our own are making efforts in modulating the cellular ROS level to enhance the efficacy of chemo-/radiotherapy and to decrease side effects and toxicity without compromising therapeutic efficacy in the treatment of HNC. 2. The Epidemiology of Head and Neck Cancer and Leading Therapeutic Challenges Head and neck cancer incorporates multiple organs from complex anatomical topographies which include the lip (C00), oral cavity (C02-06), salivary glands (C07-08), oropharynx (C01, C09-C10), nasopharynx (C11), hypopharynx (C12-14), esophagus (C15), paranasal sinuses (C30-31), and larynx (C32) [1, 2, 7–9] (Figure 1(a)). About 85-90% of HNC are squamous carcinoma that originated from epithelial cells (HNSCC) [9, 10]. There are more than 800,000 new cases and 500,000 deaths of esophageal, lip, oral cavity, and nasopharyngeal cancers worldwide [11, 12]. In 2020, there are 84,070 estimated new cases and 30,670 estimated deaths of HNC in the United States. The oral cavity and pharynx cancers rank first among the new cases of HNC, while they rank eighth (4%) among all cancer sites in males. The esophageal cancers top the list of HNC mortality [13]. In general, males are more inclined to suffer from HNC [1]. Advancing age is a disadvantage to HNC prognosis. HPV status of HNC influences the therapeutic outcome; HPV-positive HNC are associated with a better response to chemotherapy and radiotherapy even with stage IV disease [8, 14]. The five-year survival rates of HNC range from 12% to 93% from among different ages, gender, educational levels, race, and geographical locations as well as different cancer sites, pathological grades, and received therapy [2, 3, 12, 15, 16]. (a)
... These results suggest that the treatment with pomegranate extract could enhance learning and behavioral memory indicated that the rats exhibited the formation of reference memory as compared to the rats treated with morphine alone. In the learning and memory processes, LTP is one of the main cellular mechanisms in the brain that facilitate information storage [47]. There are various signaling pathways associated with the synthesis of new proteins in the LTP phase which include cAMPdependent PKA, protein kinase B, PKC, and ERK [48,49]. ...
Pomegranate-derived anthocyanin regulates MORs-cAMP/CREB-BDNF pathways in opioid-dependent models and improves cognitive impairments
J Ayurveda Integr Med
Norhaslinda R.
Mimie Noratiqah Jumli
Atif Baig
Ts. Dr. Mohd Adzim Khalili Rohin
Background Pomegranate (Punica granatum) is one of the oldest known edible fruit. Recently, there has been an increased interest in this fruit as a functional food for health benefits due to its use in disease prevention and promotion of overall health wellness. Objective This study aims to investigate the effects of pomegranate extract for the development of non-opioid substitution therapy for in-vitro and in-vivo studies. Materials and methods Anthocyanin contents consisting of cyanidin 3-glucoside, diglucoside, and pelargonidin 3-glucoside, diglucoside were detected and quantified in pomegranate extract using high-performance liquid chromatography. The optimum dosage of the extract was determined based on the regulation of MORs and cAMP proteins in U-87 cells. Co-treatment of the extract with morphine was performed to evaluate its potency in reducing the concentration levels of MORs and cAMP. For animal studies, rats were divided into two major groups representing both acute and chronic morphine-induced treatments and the Morris water maze (MWM) study was employed after treatment for each rat. The rats were sacrificed after the treatments and serum samples were collected to evaluate the levels of CREB and BDNF. Results The results indicated that each of the anthocyanin content tested in the study was present in the pomegranate extract. Additionally, in-vitro studies using pomegranate extract treatment showed that the extract was effective in decreasing the MORs and cAMP protein levels in U-87 cells at a concentration of 0.125 mg/mL. The memory impairment based on the MWM study in rats was also subsequently improved after treatment with pomegranate extract as compared to treatment with morphine. The blood serum derived from the rats treated with pomegranate extract also showed a significant decrease in CREB level and an increase in BDNF as compared to rats treated with morphine. Conclusion In conclusion, this study substantiates the potency of pomegranate extract as a non-opioid substitution therapy for in-vitro and in-vivo studies.
... In addition, the flavonoids may modulate the protein kinases, as MAP-kinase and PI3-kinase [59][60][61][62], the alteration on activation of kinase may influence directly on modulation of activity-dependent plasticity and morphological changes in synapses involved in memory acquisition, consolidation, and storage [63]. ...
Flavonoids as Modulators of Synaptic Plasticity: Implications for the Development of Novel Therapeutic Strategies for Healthy Lifestyle
João Henrique Rodrigues Castello Girão
Adriana Aparecida Ferraz Carbonel
Marianna Cecyn
Daniela Rodrigues de Oliveira
Castello Girão
Flavonoids are potential group of phytochemicals found in normal diets capable of mediating improvements in cognition and may reverse age-related declines in memory. Aging is associated with alteration of hippocampal synaptic plasticity and contribute to decline in cognitive functions. The current studies are directed at a greater understanding of how and why the brain modifies synaptic strength with dietary-derived phytochemicals (flavonoids) and age-related declines in cognitive functions (such as learning and memory). Flavonoids modulate neuronal function and thereby influence cognition. In addition, it has been suggested that flavonoids may delay the development of Alzheimer's diseaselike pathology, anxiety, and depression disorders, suggesting a novel therapeutic strategy. Emerging evidence suggest that flavonoids are modulators of signaling pathways critical for controlling synaptic plasticity in the brain. For example, phosphatidylinositol-3 kinase (PI3K)/Akt, mitogen-activated protein kinase, protein kinase C, pathways could be involved Ca2+ signaling. Significants questions such as: (i) How does flavonoids affect plasticity? (ii) What receptors are modulating by flavonoids and how are they regulated? (iii) Do flavonoids have a neuroprotective effect in aging? are asked.
... 129 (Poly)phenols and their metabolites reportedly act in rodent models by enhancing synaptic plasticity 130 and potentially improve memory by altering cellular architecture (long-term potentiation) that would otherwise deteriorate with aging. 131,132 Aside from brain-specific mechanisms, evidence suggests that CVD is related to cognitive decline and neurodegeneration. 80,[133][134][135][136][137] Greater hemodynamic response with Concord grape juice treatment was observed in cortical brain regions of older adults with mild cognitive impairment during working memory tasks. ...
Potential health benefits of (poly)phenols derived from fruit and 100% fruit juice
NUTR REV
Kacie Ho
Mario G. Ferruzzi
JoLynne D Wightman
(Poly)phenol-rich diets have been associated with reduced risk of various diseases. Coffee and tea are typically identified as dietary sources of chlorogenic acid and flavan-3-ols; however, 100% fruit juice greatly contributes to anthocyanin, flavonol, flavan-3-ols, and flavanone intake, making them complementary sources of dietary (poly)phenols. Thus, the aim of this narrative review was to provide an overview of fruit (poly)phenols and their potential health benefits. Fruit (poly)phenols have been associated with several health benefits (eg, reduced risk of cardiovascular disease and neurocognitive benefits). Although perspectives on 100% fruit juice consumption are controversial due to the perception of sugar content, growing evidence supports the role of fruit in whole and 100% juice forms to provide consumer benefits in alignment with dietary guidance. However, differences in (poly)phenol profiles and bioavailability likely exist between whole fruit and 100% fruit juice due to processing and the presence/absence of fiber. Ongoing studies are better defining similarities and differences between whole fruit and 100% fruit juice to elucidate protective mechanisms and align with processing and consumer products.
... It is approved that the learning process involves reversible modifications in synaptic plasticity in the hippocampal neuronal circuitry, which allow MRPAM [32]. The procedures of the effects of FV in the brain are not evident; however, there is proof that FV may cross the blood-brain barrier, affecting various elements of SP, modulating of signaling streams, regulating of receptor activation, activating of transcription factors, gene regulating and protein expression, and promoting of long-term potentiation [33]. FV may boost phosphorylation rates of hippocampal CREB and may boost BDNF and Bcl-2 concentrations. ...
Intracerebroventricular microinjection of kaempferol on memory retention of passive avoidance learning in rats: Involvement of cholinergic mechanism(s)
Mohammad Zarei
Saeed Mohammadi
Sajjad Jabbari
Siamak Shahidi
Purpose of the study: Kaempferol (KM) is a flavonoid found in plant-derived foods and medicinal plants. Recently, it is well established that KM plays a protective role to develop Alzheimer's disease. The current study aimed at evaluating the effect of intracerebroventricular micro-injection of KM on memory retention of passive avoidance learning (MRPAM) and identifying the potentially related cholinergic mechanisms (ChMs) in rats. Materials and methods: In the current study, male Wistar rats randomly divided into control, vehicle and KM (10, 20 and 40 μg/rat) groups. Moreover, MRPAM was evaluated by shuttle box test. The role of ChM was studied using non-selective and selective acetylcholine antagonists (scopolamine [SCN], 4-DAMP and methoctramine [MN], respectively) as well as pirenzepine (PZ) in combination with KM. Results: The employment of KM (40 μg/rat) improved the SCN-induced memory impairment in MRPAM. Co-treatment with KM (40 μg/rat) plus 4-DAMP significantly increased the step-through latency (STL, P < 0.05; 167 ± 28 s) and decreased the total dark chamber (TDC, P < 0.05; 121 ± 31 s) compared with those of the 4-DAMP group (STL: 75 ± 13 s; TDC: 178 ± 46 s). Co-treatment with KM (40 μg/rat) plus PZ attenuated STL, and also increased TDC (P < 0.01; 220 ± 28 s) compared with those of the PZ group. Co-treatment with KM (10 and 20 μg/rat) and MN increased STL (P < 0.05), and deceased TDC compared with those of the MN group (P < 0.01). Conclusions: Totally, the results of the present study showed that cholinergic system may be involved in improving effect of KM on SCN-induced memory impairment.
Nano-based phytodrug delivery systems for the management of neurodegenerative disorders
A unique ternary Ce(III)-quercetin-phenanthroline assembly with antioxidant and anti-inflammatory properties
J INORG BIOCHEM
Eleftherios Halevas
Sevasti Matsia
Antonios G. Hatzidimitriou
A. Salifoglou
Quercetin is one of the most bioactive and common dietary flavonoids, with a significant repertoire of biological and pharmacological properties. The biological activity of quercetin, however, is influenced by its limited solubility and bioavailability. Driven by the need to enhance quercetin bioavailability and bioactivity through metal ion complexation, synthetic efforts led to a unique ternary Ce(III)-quercetin-(1,10-phenanthroline) (1) compound. Physicochemical characterization (elemental analysis, FT-IR, Thermogravimetric analysis (TGA), UV–Visible, NMR, Electron Spray Ionization-Mass Spectrometry (ESI-MS), Fluorescence, X-rays) revealed its solid-state and solution properties, with significant information emanating from the coordination sphere composition of Ce(III). The experimental data justified further entry of 1 in biological studies involving toxicity, ROS-suppressing potential, cell metabolism inhibition in Saccharomyces cerevisiae (S. cerevisiae) cultures, and plasmid DNA degradation. DFT calculations revealed its electronic structure profile, with in silico studies showing binding to DNA, DNA gyrase, and glutathione S-transferase, thus providing useful complementary insight into the elucidation of the mechanism of action of 1 at the molecular level and interpretation of its bio-activity. The collective work projects the importance of physicochemically supported bio-activity profile of well-defined Ce(III)-flavonoid compounds, thereby justifying focused pursuit of new hybrid metal-organic materials, effectively enhancing the role of naturally-occurring flavonoids in physiology and disease.
Phytochemical constituents and protective efficacy of Schefflera arboricola L. leaves extract against thioacetamide-induced hepatic encephalopathy in rats
Ali El Hagrassi
Abeer Osman
Mostafa E. El-Naggar
Manal Hamed
Context: Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome resulting from liver failure. Objective: To evaluate the protective effect of Schefflera arboricola L. leaves methanol extract against thioacetamide (TAA) induced HE in rats. Materials and methods: GC/MS, LC-ESI-MS, and the total phenolic and flavonoid contents were determined. The methanol extract was orally administrated (100 and 200 mg/kg body weight) for 21 days. TAA (200 mg/kg body weight) was given intraperitoneally on day 19 and continued for three days. The evaluation was done by measuring alanine aminotransferase (ALT), alkaline phosphatase (ALP), ammonia, reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), tumour necrosis factor-alpha (TNF-α), toll-like receptor 4 (TLR4), interleukin-1 beta (IL-1β), interlukin-6 (IL-6), cyclooxygenase 2 (COX2), B cell lymphoma 2 (BCL2), alpha-smooth muscle actin (α-SMA), and the cluster of differentiation 163 (CD163). The histological features of the liver and brain were conducted. Results: Forty-five compounds were identified from the n-hexane fraction, while twenty-nine phenolic compounds were determined from the methanol extract. Pre-treatment with the plant extract returned most of the measurements under investigation to nearly normal. Conclusion: Due to its richness with bioactive compounds, Schefflera arboricola L. leaves methanolic extract succeeded to exert anti-fibrotic, anti-inflammatory, and antioxidants properties in TAA-induced HE in rats with more efficacy to its high protective dose.
Effect of Polyphenols on Cognitive Function: Evidence from Population-Based Studies and Clinical Trials
Wenzhe Yang
Kaiwang Cui
X. Li
Weili Xu
Due to progressive population aging, a new dementia case occurs at every 3 seconds, placing a heavy burden of disease. Identifying potential risk or preventive factors is emphasized owing to a lack of effective treatment for dementia. There has been emerging evidence on the link of certain dietary components, particularly polyphenols, to brain wellness and cognitive outcomes. Findings from animal and in vitro studies appear more consistent and conclusive. However, such an association has not been investigated in depth in human beings. In this review, we examined studies on the effect of dietary polyphenols (including flavonoids, curcumin, and resveratrol) on cognitive function. Intervention in early stages of dementia/Alzheimer's disease might be a target to slow down age-related cognitive decline before disease onset. We summarized 28 epidemiological studies (8 cross-sectional and 20 cohort studies) and 55 trials in this review. Preliminary evidence from epidemiological data provides the necessity for intervention trials, even though the measures of polyphenol intake tend to be less precise. Clinical trials are in favor of the role of some polyphenols in benefiting specific domains of cognition. This review also describes the divergence of results and current limitations of research in this field.
Learning, Neurogenesis, and Effects of Flavonoids on Learning
Esen Yılmaz
Rasim Mogulkoc
Abdulkerim Kasim Baltaci
Dervis Dasdelen
Learning and memory are two of our mind's most magical abilities. Different brain regions have roles in processing and storing different types of memories. The hippocampus is the part of the brain responsible for receiving information and storing it in the neocortex. One of the most impressive characteristics of the hippocampus is its capacity for neurogenesis, which is a process in which new neurons are produced and then transformed into mature neurons and finally integrated into neural circuits. The neurogenesis process in the hippocampus, an example of neuroplasticity in the adult brain, is believed to aid hippocampal-dependent learning and memory. New neurons are constantly produced in the hippocampus and integrated into the pre-existing neuronal network; this allows old memories already stored in the neocortex to be removed from the hippocampus and replaced with new ones. Factors affecting neurogenesis in the hippocampus may also affect hippocampal-dependent learning and memory. The flavonoids can particularly exert powerful actions in mammalian cognition and improve hippocampal-dependent learning and memory by positively affecting hippocampal neurogenesis.
Antioxidant as Talented Drug Applicants for the Treatment of Alzheimer's Disease and their Molecular Mechanism Insights
Hyaluronidase and Gelatinase (MMP-2, MMP-9) Inhibitor Plants
Ceylan Aka Dönmez
Gökşen Dilşat Durbilmez
Hesham El-Seedi
Ufuk Koca
Neuroprotective effects of hesperidin against methotrexate-induced changes in neurogenesis and oxidative stress in the adult rat
Jariya Umka Welbat
Salinee Naewla
Wanassanan Pannangrong
Peter M Wigmore
Methotrexate (MTX) induces the formation of reactive oxygen species (ROS) and leads to neurotoxicity. The drug also negatively impacts neurogenesis and memory. Hesperidin (Hsd) is a major flavanoid with multiple beneficial pharmacological effects such as anti-oxidation, anti-inflammation, and neuroprotective effects. The aim of our study was to investigate the neuroprotective effects of Hsd against MTX-induced alterations in oxidative stress and neurogenesis. Sprague Dawley rats were divided into four groups: 1) a vehicle group, which received saline and propylene glycol, 2) an Hsd group, which was orally administered with Hsd (100 mg/kg) for 21 days, 3) an MTX group, which received MTX (75 mg/kg) by intravenous injection on days 8 and 15, and 4) an MTX+Hsd group, which received both MTX and Hsd. After treatment with MTX, p21-positive cells had increased significantly and doublecortin (DCX) expression in the hippocampus had decreased significantly. Treatment with MTX also increased malondialdehyde (MDA) in both the hippocampus and prefrontal cortex and decreased levels of brain-derived neurotropic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus and prefrontal cortex. Additionally, there were significant decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus and prefrontal cortex in the MTX group. However, co-treatment with Hsd ameliorated the negative effects of MTX on neurogenesis, oxidative stress, and antioxidant enzymes. These findings suggest that Hsd may be able to prevent neurotoxic effects of MTX by reducing oxidative stress and enhancing hippocampal neurogenesis.
Reversals of Age-Related Declines in Neuronal Signal Transduction, Cognitive, and Motor Behavioral Deficits with Blueberry, Spinach, or Strawberry Dietary Supplementation
James A Joseph
Barbara Shukitt-Hale
Natalia A. Denisova
Paula C Bickford
Cell Survival Promoted by the Ras-MAPK Signaling Pathway by Transcription-Dependent and -Independent Mechanisms
Azad Bonni
Anne Brunet
Anne E West
Michael E. Greenberg
A mechanism by which the Ras–mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor–dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element–binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.
Green tea consumption and cognitive function: A cross-sectional study from the Tsurugaya Project
Shinichi Kuriyama
Atsushi Hozawa
Kaori Ohmori
Ichiro Tsuji
Although considerable experimental and animal evidence shows that green tea may possess potent activities of neuroprotection, neurorescue, and amyloid precursor protein processing that may lead to cognitive enhancement, no human data are available. The objective was to examine the association between green tea consumption and cognitive function in humans. We analyzed cross-sectional data from a community-based Comprehensive Geriatric Assessment (CGA) conducted in 2002. The subjects were 1003 Japanese subjects aged > or =70 y. They completed a self-administered questionnaire that included questions about the frequency of green tea consumption. We evaluated cognitive function by using the Mini-Mental State Examination with cutoffs of <28, <26, and <24 and calculated multivariate-adjusted odds ratios (ORs) of cognitive impairment. Higher consumption of green tea was associated with a lower prevalence of cognitive impairment. At the <26 cutoff, after adjustment for potential confounders, the ORs for the cognitive impairment associated with different frequencies of green tea consumption were 1.00 (reference) for < or =3 cups/wk, 0.62 (95% CI: 0.33, 1.19) for 4-6 cups/wk or 1 cup/d, and 0.46 (95% CI: 0.30, 0.72) for > or =2 cups/d (P for trend = 0.0006). Corresponding ORs were 1.00 (reference), 0.60 (95% CI: 0.35, 1.02), and 0.87 (95% CI: 0.55, 1.38) (P for trend = 0.33) for black or oolong tea and 1.00 (reference), 1.16 (95% CI: 0.78, 1.73), and 1.03 (95% CI: 0.59, 1.80) (P for trend = 0.70) for coffee. The results were essentially the same at cutoffs of <28 and <24. A higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans.
The interactions of flavonoids within neuronal signalling pathways
Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects in the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by promoting neurocognitive performance, through changes in synaptic plasticity. It is likely that flavonoids exert such effects in neurons, through selective actions on different components within a number of protein kinase and lipid kinase signalling cascades, such as phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase. This review details the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to affect cellular function through changes in the activation state of target molecules and/or by modulating gene expression. Although, precise sites of action are presently unknown, their abilities to: (1) bind to ATP binding sites on enzymes and receptors; (2) modulate the activity of kinases directly; (3) affect the function of important phosphatases; (4) preserve neuronal Ca(2+) homeostasis; and (5) modulate signalling cascades lying downstream of kinases, are explored. Future research directions are outlined in relation to their precise site(s) of action within the signalling pathways and the sequence of events that allow them to regulate neuronal function in the central nervous system.
Double Dissociation of Fornix and Caudate Nucleus Lesions on Acquisition of Two Water Maze Tasks: Further Evidence for Multiple Memory Systems
Mark G Packard
James L Mcgaugh
The present study examined the effect of lesions of the caudate nucleus or fimbria-fornix on the acquisition of two water maze tasks. In both tasks, two rubber balls with different visual patterns were used as platforms (i.e., cues). The "correct" cue was attached to a submerged rectangular platform and could be mounted by an animal to escape the water. The "incorrect" cue was attached to a thin round pedestal and could not be mounted. In a spatial version of the task, the correct cue was located in the same quadrant of the maze on all trials, whereas the visual pattern on the cue was varied from trial to trial. Lesions of the fornix, but not the caudate nucleus, impaired acquisition of this spatial task in relation to control animals. In a simultaneous visual discrimination version of the task, the correct cue on all trials was one with a specific visual pattern, and the spatial location of the correct cue was varied from trial to trial. Lesions of the caudate nucleus, but not the fornix, impaired acquisition of this visual discrimination task in relation to control animals. The double dissociation observed supports the hypothesis that the hippocampus and caudate nucleus are parts of systems that differ in the type of memory they mediate.
Zola-Morgan, S. & Squire, L. R. The primate hippocampal formation: Evidence for a time-limited memory storage. Science 250, 288-290
Stuart M Zola
Larry R. Squire
Clinical and experimental studies have shown that the hippocampal formation and related structures in the medial temporal lobe are important for learning and memory. Retrograde amnesia was studied prospectively in monkeys to understand the contribution of the hippocampal formation to memory function. Monkeys learned to discriminate 100 pairs of objects beginning 16, 12, 8, 4, and 2 weeks before the hippocampal formation was removed (20 different pairs at each time period). Two weeks after surgery, memory was assessed by presenting each of the 100 object pairs again for a single-choice trial. Normal monkeys exhibited forgetting; that is, they remembered recently learned objects better than objects learned many weeks earlier. Monkeys with hippocampal damage were severely impaired at remembering recently learned objects. In addition, they remembered objects learned long ago as well as normal monkeys did and significantly better than they remembered objects learned recently. These results show that the hippocampal formation is required for memory storage for only a limited period of time after learning. As time passes, its role in memory diminishes, and a more permanent memory gradually develops independently of the hippocampal formation, probably in neocortex.
Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PFArc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14:433-445
Gregory L. Lyford
Kanato Yamagata
Walter Kaufmann
Paul Worley
Neuronal activity is an essential stimulus for induction of plasticity and normal development of the CNS. We have used differential cloning techniques to identify a novel immediate-early gene (IEG) cDNA that is rapidly induced in neurons by activity in models of adult and developmental plasticity. Both the mRNA and the encoded protein are enriched in neuronal dendrites. Analysis of the deduced amino acid sequence indicates a region of homology with alpha-spectrin, and the full-length protein, prepared by in vitro transcription/translation, coprecipitates with F-actin. Confocal microscopy of the native protein in hippocampal neurons demonstrates that the IEG-encoded protein is enriched in the subplasmalemmal cortex of the cell body and dendrites and thus colocalizes with the actin cytoskeletal matrix. Accordingly, we have termed the gene and encoded protein Arc (activity-regulated cytoskeleton-associated protein). Our observations suggest that Arc may play a role in activity-dependent plasticity of dendrites.
A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002)
Chris J. Vlahos
William F. Matter
K. Y. and Hui
R.F. Brown
Phosphatidylinositol (PtdIns) 3-kinase is an enzyme implicated in growth factor signal transduction by associating with receptor and nonreceptor tyrosine kinases, including the platelet-derived growth factor receptor. Inhibitors of PtdIns 3-kinase could potentially give a better understanding of the function and regulatory mechanisms of the enzyme. Quercetin, a naturally occurring bioflavinoid, was previously shown to inhibit PtdIns 3-kinase with an IC50 of 1.3 microgram/ml (3.8 microM); inhibition appeared to be directed at the ATP-binding site of the kinase. Analogs of quercetin were investigated as PtdIns 3-kinase inhibitors, with the most potent ones exhibiting IC50 values in the range of 1.7-8.4 micrograms/ml. In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 > 30 micrograms/ml). Since quercetin has also been shown to inhibit other PtdIns and protein kinases, other chromones were evaluated as inhibitors of PtdIns 3-kinase without affecting PtdIns 4-kinase or selected protein kinases. One such compound, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (also known as 2-(4-morpholinyl)-8-phenylchromone, LY294002), completely and specifically abolished PtdIns 3-kinase activity (IC50 = 0.43 microgram/ml; 1.40 microM) but did not inhibit PtdIns 4-kinase or tested protein and lipid kinases. Analogs of LY294002 demonstrated a very selective structure-activity relationship, with slight changes in structure causing marked decreases in inhibition. LY294002 was shown to completely abolish PtdIns 3-kinase activity in fMet-Leu-Phe-stimulated human neutrophils, as well as inhibit proliferation of smooth muscle cells in cultured rabbit aortic segments. Since PtdIns 3-kinase appears to be centrally involved with growth factor signal transduction, the development of specific inhibitors against the kinase may be beneficial in the treatment of proliferative diseases as well as in elucidating the biological role of the kinase in cellular proliferation and growth factor response.
Dendritic Spines: Cellular Specializations Imparting Both Stability and Flexibility to Synaptic Function
Kristen M. Harris
Ben Kater
Molecular Enhancement of Memory Formation
Thomas J. Carew
As the work presented in this review attests, important progress has been made in Drosophila and Aplysia, implicating a particular class of transcription factors in memory formation. This progress takes on added significance in light of the recent demonstration that CREB-induced transcription may play an important role in long-term memory induction in mice as well (Bourtchuladze et al. 1994xBourtchuladze, R, Frenguelli, B, Blendy, J, Cioffi, D, Schutz, G, and Silva, A.J. Cell. 1994; 79: 59–68Abstract | Full Text PDF | PubMed | Scopus (1285)See all ReferencesBourtchuladze et al. 1994). Despite this exciting progress, it is still premature to order a CREB cocktail and sign up for Jeopardy. Important questions remain. For example, in Drosophila a major step will be identifying the neurons and circuits specifically activated in memory formation, while in Aplysia it will be important to relate the CREB-induced changes in sensory neurons (and perhaps other neural elements) directly to the behavioral expression of long-term memory. In addition, since multiple signal transduction pathways can modulate CREB activation and repression, the current insights gained from Drosophila and Aplysia are likely to be only the tip of the molecular iceberg in memory formation; greater complexities are sure to emerge. But the good news is that we can realistically expect rapid progress as the behavioral, cellular, and molecular tools of the trade continue to be refined and expanded in a variety of experimental systems. The recent work in Drosophila and Aplysia provides an excellent case study of the kind of progress that can be made when different preparations bring their unique strengths to bear on fundamental molecular questions in memory formation.
Long-Term Dietary Strawberry, Spinach, or Vitamin E Supplementation Retards the Onset of Age-Related Neuronal Signal-Transduction and Cognitive Behavioral Deficits
J.A. Joseph
Recent research has indicated that increased vulnerability to oxidative stress may be the major factor involved in CNS functional declines in aging and age-related neurodegenerative diseases, and that antioxidants, e.g., vitamin E, may ameliorate or prevent these declines. Present studies examined whether long-term feeding of Fischer 344 rats, beginning when the rats were 6 months of age and continuing for 8 months, with diets supplemented with a fruit or vegetable extract identified as being high in antioxidant activity, could prevent the age-related induction of receptor-mediated signal transduction deficits that might have a behavioral component. Thus, the following parameters were examined: (1) oxotremorine-enhanced striatal dopamine release (OX-K+-ERDA), (2) cerebellar beta receptor augmentation of GABA responding, (3) striatal synaptosomal 45Ca2+ clearance, (4) carbachol-stimulated GTPase activity, and (5) Morris water maze performance. The rats were given control diets or those supplemented with strawberry extracts (SE), 9.5 gm/kg dried aqueous extract (DAE), spinach (SPN 6.4 gm/kg DAE), or vitamin E (500 IU/kg). Results indicated that SPN-fed rats demonstrated the greatest retardation of age-effects on all parameters except GTPase activity, on which SE had the greatest effect, whereas SE and vitamin E showed significant but equal protection against these age-induced deficits on the other parameters. For example, OX-K+-ERDA enhancement was four times greater in the SPN group than in controls. Thus, phytochemicals present in antioxidant-rich foods such as spinach may be beneficial in retarding functional age-related CNS and cognitive behavioral deficits and, perhaps, may have some benefit in neurodegenerative disease.
Temporally Graded Retrograde Amnesia of Contextual Fear after Hippocampal Damage in Rats: Within-Subjects Examination
Stephan G Anagnostaras
Stephen Maren
Michael Fanselow
We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.
Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation
Axel Behrens
Maria Sibilia
Erwin F Wagner
c-Jun is a major component of the heterodimeric transcription factor AP-1 and is essential for embryonic development, as fetuses lacking Jun die at mid-gestation with impaired hepatogenesis and primary Jun-/- fibroblasts have a severe proliferation defect and undergo premature senescence in vitro. c-Jun and AP-1 activities are regulated by c-Jun N-terminal phosphorylation (JNP) at serines 63 and 73 through Jun N-terminal kinases(JNKs). JNP is thought to be required for the anti-apoptotic function of c-Jun during hepatogenesis, as mice lacking the JNK kinase SEK1 exhibit liver defects similar to those seen in Jun-/- fetuses. To investigate the physiological relevance of JNP, we replaced endogenous Jun by a mutant Jun allele with serines 63 and 73 mutated to alanines (Jun(tm1wag); hereafter referred to as JunAA). Here we show that primary JunAA fibroblasts have proliferation- and stress-induced apoptotic defects, accompanied by reduced AP-1 activity. JunAA mice are viable and fertile, smaller than controls and resistant to epileptic seizures and neuronal apoptosis induced by the excitatory amino acid kainate. Primary mutant neurons are also protected from apoptosis and exhibit unaltered JNK activity. Our results provide evidence that JNP is dispensable for mouse development, and identify c-Jun as the essential substrate of JNK signalling during kainate-induced neuronal apoptosis.
Impey, S., Smith, D. M., Obrietan, K., Donahue, R., Wade, C. & Storm, D.R. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat. Neurosci. 1, 595-601
Soren Impey
Karl Obrietan
Daniel R Storm
Recent studies suggest that the CREB-CRE transcriptional pathway is pivotal in the formation of some types of long-term memory. However, it has not been demonstrated that stimuli that induce learning and memory activate CRE-mediated gene expression. To address this issue, we used a mouse strain transgenic for a CRE-lac Z reporter to examine the effects of hippocampus-dependent learning on CRE-mediated gene expression in the brain. Training for contextual conditioning or passive avoidance led to significant increases in CRE-dependent gene expression in areas CA1 and CA3 of the hippocampus. Auditory cue fear-conditioning, which is amygdala dependent, was associated with increased CRE-mediated gene expression in the amygdala, but not the hippocampus. These data demonstrate that learning in response to behavioral conditioning activates the CRE transcriptional pathway in specific areas of brain.
The past, the future and the biology of memory storage
Christopher Pittenger
Eric R. Kandel
We here briefly review a century of accomplishments in studying memory storage and delineate the two major questions that have dominated thinking in this area: the systems question of memory, which concerns where in the brain storage occurs; and the molecular question of memory, which concerns the mechanisms whereby memories are stored and maintained. We go on to consider the themes that memory research may be able to address in the 21st century. Finally, we reflect on the clinical and societal import of our increasing understanding of the mechanisms of memory, discussing possible therapeutic approaches to diseases that manifest with disruptions of learning and possible ethical implication of the ability, which is on the horizon, to ameliorate or even enhance human memory.
Fruit Polyphenolics and Brain Aging
Rachel L Galli
Kuresh Youdim
Nutritional interventions, in this case, increasing dietary intake of fruits and vegetables, can retard and even reverse age-related declines in brain function and in cognitive and motor performance in rats. Our lab has shown that as Fischer 344 rats age their brains are increasingly vulnerable to oxidative stress. Dietary supplementation with fruit or vegetable extracts high in antioxidants (e.g., blueberry, BB, spinach, respectively) can decrease this vulnerability to oxidative stress as assessed in vivo by examining reductions in neuronal signaling and behavioral deficits and in vitro via H2O2-induced decrements in striatal synaptosomal calcium buffering. Examinations have also revealed that BB supplementations are effective in antagonizing other age-related changes in brain and behavior, as well as decreasing indices of inflammation and oxidative stress in gastrocnemius and quadriceps muscles. In ongoing studies we are attempting to determine the most effective BB polyphenolic components. To date, the anthocyanins show the most efficacy in penetrating the cell membrane and in providing antioxidant protection. In sum, our results indicate that increasing dietary intake of fruits and vegetables high in antioxidant activity may be an important component of a healthy living strategy designed to maximize neuronal and cognitive functioning into old age.
Protein kinase C inhibition by flavonoids
P Ferriola
Vivian Cody
Elliott Middleton
Making New Connections
The robust translocation of MAPK during synaptic plasticity (11xMartin, K.C, Michael, D, Rose, J.C, Barad, M, Casadio, A, Zhu, H, and Kandel, E.R. Neuron. 1997; 18: 899–912Abstract | Full Text | Full Text PDF | PubMed | Scopus (411)See all References, 9xImpey, S, Obrietan, K, Wong, S.T, Poser, S, Yano, S, Wayman, G, Deloulme, J.C, Chan, G, and Storm, D.R. Neuron. 1998; 21: 869–883Abstract | Full Text | Full Text PDF | PubMed | Scopus (644)See all References, 15xSgambato, V, Pages, C, Rogard, M, Besson, M.J, and Caboche, J. J. Neurosci. 1998; 18: 8814–8825PubMedSee all References) indicates that there are likely additional nuclear targets of MAPK signaling other than CREB. For example, several recent reports suggest that the transcription factor Elk1 is a major nuclear target of MAPK during synaptic plasticity and memory consolidation (2xBerman, D.E, Hazvi, S, Rosenblum, K, Seger, R, and Dudai, Y. J. Neurosci. 1998; 18: 10037–10044PubMedSee all References, 15xSgambato, V, Pages, C, Rogard, M, Besson, M.J, and Caboche, J. J. Neurosci. 1998; 18: 8814–8825PubMedSee all References).The prominent dendritic localization of activated MAPK following synaptic activity (Impey et al. 1998xImpey, S, Obrietan, K, Wong, S.T, Poser, S, Yano, S, Wayman, G, Deloulme, J.C, Chan, G, and Storm, D.R. Neuron. 1998; 21: 869–883Abstract | Full Text | Full Text PDF | PubMed | Scopus (644)See all ReferencesImpey et al. 1998) suggests that it may also have important cytosolic targets. The best example of such a target is the Aplysia cell adhesion molecule ApCAM. MAPK activity is required for the downregulation and internalization of ApCAM, a key step in the induction of LTF. This is an important observation because the Drosophila (Fas II) and murine (NCAM) homologs of ApCAM have also been implicated in neuronal plasticity.Collectively, these studies indicate that the MAPK pathway is a fundamental component of LTM formation in invertebrates and vertebrates. Thus, the MAPK cascade joins the cAMP/PKA pathway and the CREB transcriptional pathway as an evolutionarily conserved regulator of LTM consolidation (Figure 1Figure 1). Work showing that MAPK is a major activator of plasticity-associated CREB-dependent gene expression also strongly suggests that MAPK signaling facilitates memory consolidation and L-LTP by promoting de novo CREB-regulated gene expression. There are a number of unanswered questions regarding the role of MAPK in neuronal plasticity and memory formation. Is CREB a target of Ras/MAPK signaling during memory consolidation? How is MAPK activated during adaptive neuronal plasticity and memory consolidation? What are the cytosolic and nuclear targets of MAPK that facilitate memory formation and modulate synaptic efficacy? Additional research using temporally and spatially restricted transgenic technologies should help clarify and confirm the role of Ras/MAPK signaling in LTM.*To whom correspondence should be addressed (e-mail: dstorm@u.washington.edu).
The effects of dietary antioxidants on psychomotor performance in aged mice
EXP GERONTOL
Mohsen Meydani
Male C57BL/6NIA mice were provided one of six different antioxidant diets: vitamin E, glutathione, vitamin E plus glutathione, melatonin, strawberry extract, or control, beginning at 18 months of age. A battery of motor tests—rod walk, wire hang, plank walk, and inclined screen—was administered either: 1) before dietary treatment and then 6 months later at 24 months of age; or 2) only after 6 months of dietary treatment at age 24 months. An untreated group of 4-month-old mice served as young controls. Psychomotor performance was lower in 18-month-old mice compared with 4-month-old mice in the rod walk, wire hang, and inclined screen tests; however, no further decline was seen from 18 to 24 months on any measure. Chronic dietary antioxidant treatments were not effective in reversing age-related deficits in psychomotor behavior, except for the glutathione diet on inclined screen performance. It seems that motor performance deteriorates profoundly with age, because deficits at 18 months of age were as severe as they were at 24 months, and these age-associated motor deficits may be difficult to reverse, even with antioxidant treatment.
Flavonoids and the inhibition of PKC and PI 3-kinase
Gen Pharmacol Vasc Syst
Stéphane Manenti
Marie-Pierre Gratacap
Laurence Gamet-Payrastre
Bernard Payrastre
Flavonoids provide a large number of interesting natural compounds that are consumed daily and exhibit more or less potent and selective effects on some signaling enzymes as well as on the growth and proliferation of certain malignant cells in vitro. Among the identified signal transducers, phosphoinositide 3-kinase (PI 3-kinase) and protein kinase C (PKC) are now considered key players in many cellular responses including cell multiplication, apoptosis, and transformation. Despite their lack of strict specificity, some flavonoids provide valuable bases for the design of analogues that could be used to specifically block particular isoforms of PI 3-kinase or PKC and their downstream-dependent cellular responses.
Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: A comparison with tyrosine kinase and protein kinase C inhibition
Georgine Agullo
Depending on their structure, flavonoids display more or less potent inhibitory effects on the growth and proliferation of certain malignant cells in vitro, and these effects are thought to be due to inhibition of various enzymes. We investigated the inhibitory action of fourteen flavonoids of different chemical classes on phosphatidylinositol 3-kinase a (PI 3-kinase a) activity, an enzyme recently shown to play an important role in signal transduction and cell transformation. Of the fourteen flavonoids tested, myricetin was the most potent PI 3-kinase inhibitor (ic50 = 1.8 μM), while luteolin and apigenin were also effective inhibitors, with ic50 values of 8 and 12 μM, respectively. Fisetin and quercetin, as previously reported, were also found to significantly inhibit PI 3-kinase activity. The same flavonoids were also analyzed for inhibition of epidermal growth factor receptor (EGF-R), intrinsic tyrosine kinase and bovine brain protein kinase C (PKC). At elevated doses, some of these flavonoids were found to also cause significant inhibition of PKC and tyrosine kinase activity of EGF-R. A structure-activity study indicated that the position, number and substitution of the hydroxyl group of the B ring, and saturation of the C2C3 bond are important factors affecting flavonoid inhibition of PI 3-kinase. They may also play a significant role in specificity of inhibition and could help to provide a basis for the further design of specific inhibitors of this lipid kinase. Finally, possible relationships between the antitumoral properties of these flavonoids and their biological activities are discussed.
TOR Signaling in Growth and Metabolism
Stephan Wullschleger
Robbie Loewith
Michael N Hall
The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
Learning deficit in BDNF mutant mice
Sten Linnarsson
Anders Björklund
Patrik Ernfors
Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, processes that are also thought to be involved in the learning of spatial tasks such as the Morris water maze. In order to determine whether BDNF is required for normal spatial learning, mice carrying a deletion in one copy of the BDNF gene were subjected to the Morris water maze task. Young adult BDNF mutant mice were significantly impaired compared with wild-type mice, requiring twice the number of days to reach full performance. Aged wild-type mice performed significantly worse than young wild-type mice and the effect was even more pronounced in the BDNF mutant mice, which did not learn at all. Although there was no difference in mean swimming speed between BDNF mutant and wild-type mice, we cannot exclude the possibility that developmental or peripheral deficits also contribute to the learning deficits in these mice. In situ hybridization and RNase protection analysis revealed that BDNF mRNA expression was indeed decreased in BDNF mutant mice. Furthermore, a pronounced effect of age on BDNF mRNA expression was seen, displayed as both a reduced level of mRNA expression and a reduced or entirely absent layer-specific expression pattern in the cerebral cortex of aged animals. Thus, our data suggest that BDNF expression may be linked to learning.
The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs
Raymond F. Brown
Phosphatidylinositol (PtdIns) 3-kinase is an enzyme involved in cellular responses to growth factors. Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyrano-4-one), a naturally occuring bioflavinoid, was found to inhibit PtdIns 3-kinase with an IC50 of 1.3 micrograms/ml (3.8 microM); inhibition appears to be directed towards the ATP binding site of the kinase. Analogs of quercetin were also investigated as PtdIns 3-kinase inhibitors, with the most potent compounds exhibiting IC50's in the range of 1.7-8.4 micrograms/ml (5-19 microM). In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 greater than 30 micrograms/ml). These findings suggest that flavinoids may serve as potent inhibitors of PtdIns 3-kinase. Furthermore, the enzyme is much more sensitive to substituents at the 3-position of the flavinoid ring than are other protein and PtdIns kinases, suggesting that specific inhibitors of PtdIns 3-kinase can be developed to explore the biological role of the enzyme in cellular proliferation and growth factor response.
Neurotrophin expression in rat hippocampal slices: A stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs
Susan Patterson
Larry M. Grover
Philip A. Schwartzkroin
Mark Bothwell
We report that stimulation inducing long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus evokes significant increases in both BDNF and NT-3 mRNAs in CA1 neurons. No changes in BDNF or NT-3 mRNA levels were seen in the nonstimulated regions of the pyramidal cell layer or the dentate. No change was seen in the levels of NGF mRNA at the time point examined. These results suggest that relatively normal levels of activity may regulate region-specific neurotrophin levels in the hippocampus. Given that known effects of NGF (and presumably of BDNF and NT-3) include elevation of neurotransmitter levels, elevation of sodium channels, and promotion of axonal terminal sprouting, activity-associated changes in neurotrophin levels may play a role in regulating neural connections in the adult as well as the developing nervous system.
Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors
Thomas J O'Dell
Seth G N Grant
Long-term potentiation (LTP) in the hippocampus is thought to contribute to memory formation. In the Ca1 region, LTP requires the NMDA (N-methyl-D-aspartate) receptor-dependent influx of Ca2+ and activation of serine and threonine protein kinases. Because of the high amount of protein tyrosine kinases in hippocampus and cerebellum, two regions implicated in learning and memory, we examined the possible additional requirement of tyrosine kinase activity in LTP. We first examined the specificity in brain of five inhibitors of tyrosine kinase and found that two of them, lavendustin A and genistein, showed substantially greater specificity for tyrosine kinase from hippocampus than for three serine-threonine kinases: protein kinase A, protein kinase C, and Ca2+/calmodulin kinase II. Lavendustin A and genistein selectively blocked the induction of LTP when applied in the bath or injected into the postsynaptic cell. By contrast, the inhibitors had no effect on the established LTP, on normal synaptic transmission, or on the neurotransmitter actions attributable to the actions of protein kinase A or protein kinase C. These data suggest that tyrosine kinase activity could be required postsynaptically for long-term synaptic plasticity in the hippocampus. As Ca2+ calmodulin kinase II or protein kinase C seem also to be required, the tyrosine kinases could participate postsynaptically in a kinase network together with serine and threonine kinases.
Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science
Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.
Squire, L. R. & Alvarez, P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin Neurobiol. 5, 169-177
CURR OPIN NEUROBIOL
P Alvarez
The fact that information acquired before the onset of amnesia can be lost (retrograde amnesia) has fascinated psychologists, biologists, and clinicians for over 100 years. Studies of retrograde amnesia have led to the concept of memory consolidation, whereby medial temporal lobe structures direct the gradual establishment of memory representations in neocortex. Recent theoretical accounts have inspired a simple neural network model that produces behavior consistent with experimental data and makes these ideas about memory consolidation more concrete. Recent physiological and anatomical findings provide important information about how memory consolidation might actually occur.