Article

Modulation of Hippocampal Plasticity and Cognitive Behavior by Short-term Blueberry Supplementation in Aged Rats

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Abstract

During aging, reductions in hippocampal neurogenesis are associated with memory decline indicating a causal relationship. Indeed, insulin-like growth factor-1 (IGF-1), a major activator of the extracellular receptor kinase pathway that is central in learning and memory processes, is also a key modulator of hippocampal neurogenesis. Previously, we showed that age-related declines in spatial memory tasks can be improved by antioxidant-rich diets containing blueberries. In this study, to begin to understand the mechanisms responsible for the beneficial effects of blueberries, we assessed changes in hippocampal plasticity parameters such as hippocampal neurogenesis, extracellular receptor kinase activation, and IGF-1 and IGF-1R levels in blueberry-supplemented aged animals. Our results show that all these parameters of hippocampal neuronal plasticity are increased in supplemented animals and aspects such as proliferation, extracellular receptor kinase activation and IGF-1 and IGF-1R levels correlate with improvements in spatial memory. Therefore, cognitive improvements afforded by polyphenolic-rich fruits such as blueberries appear, in part, to be mediated by their effects on hippocampal plasticity.

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... Aged rats (19 months) treated for 8 weeks with strawberry (Shukitt-Hale et al. 2015) or blueberry (Casadesus et al. 2004;Shukitt-Hale et al. 2015) showed higher IGF-1 (Casadesus et al. 2004;Shukitt-Hale et al. 2015) and IGF-1 receptor (Casadesus et al. 2004) levels. These findings were related to the improvement in hippocampal neuroplasticity (Casadesus et al. 2004) and neurogenesis (Shukitt-Hale et al. 2015), and to cognitive improvements afforded by strawberry and blueberry extract treatment (Casadesus et al. 2004). ...
... Aged rats (19 months) treated for 8 weeks with strawberry (Shukitt-Hale et al. 2015) or blueberry (Casadesus et al. 2004;Shukitt-Hale et al. 2015) showed higher IGF-1 (Casadesus et al. 2004;Shukitt-Hale et al. 2015) and IGF-1 receptor (Casadesus et al. 2004) levels. These findings were related to the improvement in hippocampal neuroplasticity (Casadesus et al. 2004) and neurogenesis (Shukitt-Hale et al. 2015), and to cognitive improvements afforded by strawberry and blueberry extract treatment (Casadesus et al. 2004). ...
... Aged rats (19 months) treated for 8 weeks with strawberry (Shukitt-Hale et al. 2015) or blueberry (Casadesus et al. 2004;Shukitt-Hale et al. 2015) showed higher IGF-1 (Casadesus et al. 2004;Shukitt-Hale et al. 2015) and IGF-1 receptor (Casadesus et al. 2004) levels. These findings were related to the improvement in hippocampal neuroplasticity (Casadesus et al. 2004) and neurogenesis (Shukitt-Hale et al. 2015), and to cognitive improvements afforded by strawberry and blueberry extract treatment (Casadesus et al. 2004). ...
Article
As the number of older people has grown in recent decades, the search for new approaches to manage or delay aging is also growing. Among the modifiable factors, diet plays a crucial role in healthy aging and in the prevention of age-related diseases. Thus, the interest in the use of foods, which are rich in bioactive compounds such as functional foods with anti-aging effects is a growing market. This review summarizes the current knowledge about the molecular mechanisms of action of foods considered as functional foods in aging, namely berries, curcumin, and virgin olive oil. Moreover, honey is also analyzed as a food with well-known healthy benefits, but which has not been deeply evaluated from the point of view of aging. The effects of these foods on aging are analyzed from the point of view of molecular mechanisms including oxidative stress, mitochondrial dysfunction, inflammation, genomic stability, telomere attrition, cellular senescence, and deregulated nutrient-sensing. A comprehensive study of the scientific literature shows that the aforementioned foods have demonstrated positive effects on certain aspects of aging, which might justify their use as functional foods in elderly. However, more research is needed, especially in humans, designed to understand in depth the mechanisms of action through which they act.
... With respect to berries, there is a large body of animal behavioral evidence that supports the efficacy of flavonoids on memory and learning. Grape, pomegranate, strawberry, and blueberry (1%-2% [w/w] freeze-dried fruit/fruit juice), as well as pure ( -)-epicatechin and quercetin, have been shown capable of affecting several aspects of memory and learning, notably rapid (484) and slow (180,229,230,416,495) memory acquisition, short-term working memory (207,363,368,484,491), long-term reference memory (65,179), reversal learning (207,484), and memory retention/retrieval (473). For example, there is extensive animal evidence suggesting that blueberries are effective at reversing age-related deficits in spatial working memory (9,26,65,368,383,423,491,494). ...
... Grape, pomegranate, strawberry, and blueberry (1%-2% [w/w] freeze-dried fruit/fruit juice), as well as pure ( -)-epicatechin and quercetin, have been shown capable of affecting several aspects of memory and learning, notably rapid (484) and slow (180,229,230,416,495) memory acquisition, short-term working memory (207,363,368,484,491), long-term reference memory (65,179), reversal learning (207,484), and memory retention/retrieval (473). For example, there is extensive animal evidence suggesting that blueberries are effective at reversing age-related deficits in spatial working memory (9,26,65,368,383,423,491,494). In addition, ( -)-epicatechin at a dose of 500 lg/g enhances the retention of rat spatial memory, especially when combined with exercise (473). ...
... Blueberry-derived flavonoids may also act to enhance the efficiency of spatial memory indirectly by acting on the dentate gyrus (DG), the hippocampal subregion most sensitive to the effects of aging (56,425). Blueberry supplementation has been shown to significantly increase the proliferation of precursor cells in the DG of aged rats (65). This link between DG neurogenesis, cognitive performance, and aging is well documented (120,246,260,420,441), and may represent another mechanism by which fruits rich in (poly)phenols may improve memory by acting on the hippocampus. ...
... The beneficial impact of plant polyphenols on the brain may be summarized by their role in increasing brain plasticity and related cognition improvement. Numerous studies investigate the impact of plant-derived polyphenols on brain cell metabolism, neutralization of reactive oxygen species, and cognitive functions related to signal transduction and neuronal plasticity [27][28][29][30]. As reversible MAO (monoamin oxidase) inhibitors, polyphenols are mood modulators and improve neuronal self-being by increasing dopamine, serotonin, and noradrenaline amounts in the brain tissue [31]. ...
... Observed effects were related with enhanced hippocampal plasticity and CREBdependent BDNF production [33]. Blueberry polyphenols consumption also improved object recognition in rats, which was linked with lower oxidative stress due to the lower NFκB (nuclear factor kappa B) level in different brain areas [29]. Apart from berry juice polyphenols, also tea flavanols were able to improve brain functions in mice with cognitive deficits [34,35]. ...
Article
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It is well known that neurodegenerative diseases’ development and progression are accelerated due to oxidative stress and inflammation, which result in impairment of mitochondrial function, cellular damage, and dysfunction of DNA repair systems. The increased consumption of antioxidants can postpone the development of these disorders and improve the quality of patients’ lives who have already been diagnosed with neurodegenerative diseases. Prolonging life span in developed countries contributes to an increase in the incidence ratio of chronic age-related neurodegenerative disorders, such as PD (Parkinson’s disease), AD (Alzheimer’s disease), or numerous forms of age-related dementias. Dietary supplementation with neuroprotective plant-derived polyphenols might be considered an important element of healthy aging. Some polyphenols improve cognition, mood, visual functions, language, and verbal memory functions. Polyphenols bioavailability differs greatly from one compound to another and is determined by solubility, degree of polymerization, conjugation, or glycosylation resulting from chemical structure. It is still unclear which polyphenols are beneficial because their potential depends on efficient transport across the BBB (blood-brain barrier), bioavailability, and stability in the CNS (central nervous system). Polyphenols improve brain functions by having a direct impact on cells and processes in the CNS. For a direct effect, polyphenolic compounds must be able to overcome the BBB and accumulate in brain tissue. In this review, the latest achievements in studies (animal models and clinical trials) on the effect of polyphenols on brain activity and function are described. The beneficial impact of plant polyphenols on the brain may be summarized by their role in increasing brain plasticity and related cognition improvement. As reversible MAO (monoamine oxidase) inhibitors, polyphenols are mood modulators and improve neuronal self-being through an increase in dopamine, serotonin, and noradrenaline amounts in the brain tissue. After analyzing the prohealth effects of various eating patterns, it was postulated that their beneficial effects result from synergistic interactions between individual dietary components. Polyphenols act on the brain endothelial cells and improve the BBB’s integrity and reduce inflammation, thus protecting the brain from additional injury during stroke or autoimmune diseases. Polyphenolic compounds are capable of lowering blood pressure and improving cerebral blood flow. Many studies have revealed that a nutritional model based on increased consumption of antioxidants has the potential to ameliorate the cognitive impairment associated with neurodegenerative disorders. Randomized clinical trials have also shown that the improvement of cognitive functions resulting from the consumption of foods rich in flavonoids is independent of age and health conditions. For therapeutic use, sufficient quantities of polyphenols must cross the BBB and reach the brain tissue in active form. An important issue in the direct action of polyphenols on the CNS is not only their penetration through the BBB, but also their brain metabolism and localization. The bioavailability of polyphenols is low. The most usual oral administration also conflicts with bioavailability. The main factors that limit this process and have an effect on therapeutic efficacy are: selective permeability across BBB, gastrointestinal transformations, poor absorption, rapid hepatic and colonic metabolism, and systemic elimination. Thus, phenolic compounds have inadequate bioavailability for human applications to have any beneficial effects. In recent years, new strategies have been attempted in order to exert cognitive benefits and neuroprotective effects. Converting polyphenols into nanostructures is one of the theories proposed to enhance their bioavailability. The following nanoscale delivery systems can be used to encapsulate polyphenols: nanocapsules, nanospheres, micelles, cyclodextrins, solid lipid nanoparticles, and liposomes. It results in great expectations for the wide-scale and effective use of polyphenols in the prevention of neurodegenerative diseases. Thus far, only natural polyphenols have been studied as neuroprotectors. Perhaps some modification of the chemical structure of a given polyphenol may increase its neuroprotective activity and transportation through the BBB. However, numerous questions should be answered before developing neuroprotective medications based on plant polyphenols.
... Http://www.granthaalayah.com©International Journal of Research -GRANTHAALAYAH [1][2][3][4][5] It is clear from the above table that obtained Chi value for the distribution of children among different categories of academic performance as per their phytochemical intake status is found significant. It also showed that children taking high phytochemical foods were found more in better academic performance category in comparison to children taking low phytochemical foods. ...
... Http://www.granthaalayah.com©International Journal of Research -GRANTHAALAYAH [1][2][3][4][5] The results of present study clearly shows that the academic performance status in terms of percentages of marks of the subjects of low, moderate and high phytochemical intake status. The graph clearly indicates association of percentage of marks with phytochemical intake. ...
Article
Colors contain phytochemicals substances occur naturally only in plants and provide health benefits beyond those that essential nutrients provide. A nutritionally adequate diet is essential for optimal growth and development. Childhood and adolescence are periods of continuous growth and development. So, in this study Phytochemical intake of the school going children was computed by counting the number of serving of colourful fruits and vegetables in their diet per week and association of phytochemical intake status with academic performance was found out. Obtained results showed that the distribution of children among different categories of academic performance as per their phytochemical intake status was found significant. Children taking high phytochemical foods were found more in better academic performance category in comparison to children taking low phytochemical foods. Colourful phytonutrients have tremendous health benefits for the brain. Phytonutrients impart colour to fruits and vegetables and are the basis of the recommendation to "eat your colours. The current recommendation of 5-9 servings of fruits and vegetables is not being met with most children. So, taking colourful diet is important for over all wellbeing of the children.
... A premium source of polyphenols, wild blueberries are of particular interest. Preclinical research has been published in which blueberries reverse agerelated neuronal decline [21], improve cognition and hippocampal neurogenesis [22], and reverse age-related memory decline [23]. Retrospectively, in humans, fifteen years of dietary berry intake were averaged and compared to cognitive decline scores [24]. ...
... Preclinical work [e.g. 22,42] informed the initial clinical work. Now, the results of this and other clinical work will enable the development of an animal model with the potential to determine mechanisms through which the consumption of blueberries supports neural functioning. ...
Article
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Background As the sector of the population over 65y increases, cognitive decline and dementia become a public health issue. Interventions to improve brain health and thus, quality of life for older adults are needed. Objective It was hypothesized that those consuming a flavonoid-rich, lyophilized wild blueberry powder would evidence improvements in cognitive performance as measured behaviorally and electrophysiologically compared to those consuming a placebo powder across a 6-month intervention period. Design In a double-blind, randomized placebo-controlled trial, participants experiencing cognitive issues as determined by scores on the Montreal Cognitive Assessment (MoCA) were randomized to consume either wild blueberry (n = 44) or placebo (n = 42) powder daily for 6 months. Participants who were not experiencing any cognitive issues were included as a reference group (n = 45). Participants were tested at baseline and outcome on the Cambridge Neurological Test Automated Battery (CANTAB) and in an electrophysiological paradigm known as event-related potentials (ERP). Results Tests of specific cognitive abilities using the CANTAB showed speed of processing not only improved in the blueberry intervention group relative to the placebo group across the 6-month intervention, but blueberries also restored speed of processing to the level of the reference group. The ERP results also showed that, relative to those consuming placebo, speed of processing improved for those in the blueberry group; this improvement was most prominent in those 75-80y. Conclusions Consumption of wild blueberries for six months improves cognitive aging sequelae by improving the speed of information processing in older adults. Trial registration: ClinicalTrials.gov identifier: NCT01515098.
... Improved cognitive performance with blueberry supplementation has been observed in aged animals [29][30][31], including enhancements of working memory, learning, and longterm memory [31][32][33][34][35][36]. Animal experiments also have shown anthocyanin accumulation in specific brain regions following blueberry consumption in association with enhanced cognitive performance [37,38] along with upregulation of neurotrophic factors [34,37,39]. ...
... Improved cognitive performance with blueberry supplementation has been observed in aged animals [29][30][31], including enhancements of working memory, learning, and longterm memory [31][32][33][34][35][36]. Animal experiments also have shown anthocyanin accumulation in specific brain regions following blueberry consumption in association with enhanced cognitive performance [37,38] along with upregulation of neurotrophic factors [34,37,39]. ...
Article
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Late-life dementia typically develops over a period of many years beginning in midlife. Prevalence of metabolic disturbance also accelerates in middle age and is a prominent risk factor for dementia. Preliminary studies indicate that blueberry supplementation can improve cognitive performance and influence metabolism and brain function and therefore may have a role in early intervention to prevent neurodegeneration. In a randomized controlled trial, we investigated the effects of daily blueberry supplementation in a middle-aged sample of insulin-resistant participants with elevated risk for future dementia. We enrolled overweight men and women, aged 50 to 65 years, with subjective cognitive decline (SCD) and performed pre- and post-intervention assessments of cognition and metabolism and exploratory measures of peripheral mitochondrial function. We observed improved performances for the blueberry group on measures of lexical access, p = 0.003, and memory interference, p = 0.04, and blueberry-treated participants reported reduced memory encoding difficulty in daily life activities, p = 0.03. The blueberry-treated group also exhibited correction of peripheral hyperinsulinemia, p = 0.04, and a modest trend for increased mitochondrial uncoupling, p = 0.11. The cognitive findings indicated improved executive ability in this middle-aged sample. In addition, the changes in metabolic and bioenergetic measures imply potential mechanistic factors associated with anthocyanin and proanthocyanidin actions. The demonstration of these benefits in middle-aged individuals with insulin resistance and SCD suggests that ongoing blueberry supplementation may contribute to protection against cognitive decline when implemented early in at-risk individuals.
... PPARα regulation [182,183] Quercetin Cholinesterase inhibition [184] Resveratrol - [114][115][116][117]140] Retinoic acid - [185] Rhynchophylline Inhibition of Aβ neurotoxicity [186] Rosmarinic acid Recognition of Aβ1-42 Peptide [177] Rutin Inhibits Aβ aggregation [187,188] Scocycamides - [108] Scopoletin Cholinesterase inhibition [110] Serpentine - [67] Sophoraflavanone G - [78] Sterubin - [137] Tenuifolin - [94] Tetrahydrohyperforin - [189] Tetrandrine Inhibition of NF-κB activation [162] Withanoside IV - [111] α-cyperone Inhibition of Tau protein aggregation [190] α-tomatine - [191] β-carotene - [192] 3.1.6. Theaceae Family 3.1. ...
... This chemical, particularly abundant in blueberries, may also be found in other plants. Simultaneously, some research suggests that this chemical may have anti-cognitive-disorder properties [182,183]. ...
Article
Alzheimer’s disease accounts for high percentages of dementia cases in elderly individuals. This type of brain disease is caused by damage of the brain cells affecting the ability of the patients to communicate, as well as their thinking, behavior, and feelings. Although numerous research laboratories focus on advancements for the treatment of Alzheimer’s disease, the currently approved pharmacological approaches seem to only alleviate the symptoms. Consequently, there is an urgent need for alternative pharmacological options which can prevent the progressive impairment of neurons. Natural substances were used from ancient times for the treatment of various disorders given their biological activities such as antioxidant, anti-inflammatory, and antiapoptotic properties. Besides, their cost-effectiveness as well as their accessibility to anyone who needs them, are their most significant characteristics. Therefore, the possible use of phytochemical compounds for the possible management or even prevention of Alzheimer’s disease is currently under investigation. In this review article, the present status of Alzheimer’s disease diagnosis and underlying mechanisms, the potential phytochemicals, and their carriers along with future perspectives are summarized. It is suggested that in the future natural substances can play a role as an adjunct therapy for neurodegenerative forms of dementia, such as Alzheimer’s disease.
... ERK1/2 pathway Flavonoids such as luteolin [38], spinosin [39], and GE [45] and also extracted flavonoids from Blueberries [46] have been illustrated to act positively on learning and memory by activation of extracellular signal-related kinase (ERK1/2), increased levels of CREB, elevated levels of BDNF. Moreover, some flavonoids such as extracted flavonoids from blueberries activate insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 1 receptor (IGF-1R) leading to the ERK1/2 activation [47]. Some flavonoids by activation of ERK1/2 induce Mitogen-and stress-activated kinase 1 (MSK1) which lead to the CREB phosphorylation [48]. ...
... Blueberry diet, because of having potent components, can bring hippocampal neurogenesis as well as angiogenesis. They are involved in a process over which immature cells turn into the mature one especially in the hiliar zone of DG [47,48]. ...
Article
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Objective: Natural food substances, due to high rates of antioxidants, antiviral and anti-inflammatory properties, have been proposed to have the potential for the prevention or treatment of cognitive deficits, learning and memory deficits and neuro inflammation. In particular, medicinal plants with rich amounts of beneficial components such as flavonoids are one of the most promising therapeutic candidates for the cognitive deficit and memory loss. Herein, we aimed to review the impact of medicinal plants with focus on flavonoids on cognitive dysfunction, learning and memory loss by considering their signaling pathways. Methods: We extracted 93 preclinical and clinical studies related to the effects of flavonoids on learning and memory and cognition from published papers between 2000 and 2021 in the MEDLINE/PubMed, Cochrane Library, SCOPUS, and Airiti Library databases. Results: In the preclinical studies, at least there seem to be two main neurological and biological processes in which flavonoids contribute to the improvement and/or prevention of learning, memory deficit and cognitive dysfunction: (1) Regulation of neurotransmission system and (2) Enhancement of neurogenesis, synaptic plasticity and neuronal survival. Conclusion: Although useful effects of flavonoids on learning and memory in preclinical investigations have been approved, more clinical trials are required to find out whether flavonoids and/or other ingredients of plants have the potent to prevent or treat neurodegenerative disorders.
... These effects appear to extend to the brain, with anthocyanins gaining attention for their protective effects against age-related neurodegeneration and cognitive decline [12,13]. Consistent with these observations, preclinical studies indicate that anthocyanins improve learning and memory across several mammalian species [13,14], with anthocyanin-rich blueberry intake shown to induce spatial memory improvements in young animals [15,16] and ameliorate age-related cognitive decline in old animals [17][18][19][20]. Current human studies are in agreement with pre-clinical research findings. ...
... Anthocyanin-rich foods (specifically blueberries and strawberries) have been shown to be effective at reversing age-related deficits in spatial memory and can enhance different aspects of synaptic plasticity [19,39,40], a process severely affected by ageing [41,42]. For example, a 2% (w/w) blueberry diet significantly improved spatial working memory through activation of the ERK-CREB-BDNF pathway, an important modulatory pathway of synaptic plasticity [17]. ...
Article
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Anthocyanin-rich foods, such as berries, reportedly ameliorate age-related cognitive deficits in both animals and humans. Despite this, investigation into the mechanisms which underpin anthocyanin-mediated learning and memory benefits remains relatively limited. The present study investigates the effects of anthocyanin intake on a spatial working memory paradigm, assessed via the cross-maze apparatus, and relates behavioural test performance to underlying molecular mechanisms. Six-week supplementation with pure anthocyanins (2% w/w), administered throughout the learning phase of the task, improved both spatial and psychomotor performances in aged rats. Behavioural outputs were accompanied by changes in the expression profile of key proteins integral to synaptic function/maintenance, with upregulation of dystrophin, protein kinase B (PKB/Akt) and tyrosine hydroxylase, and downregulation of apoptotic proteins B-cell lymphoma-extra-large (Bcl-xL) and the phosphorylated rapidly accelerated fibrosarcoma (p-Raf). Separate immunoblot analysis supported these observations, indicating increased activation of extracellular signal-related kinase (ERK1), Akt Ser473, mammalian target of rapamycin (mTOR) Ser2448, activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) and brain-derived neurotrophic factor (BDNF) in response to anthocyanin treatment, whilst α-E-catenin, c-Jun N-terminal kinase (JNK1) and p38 protein levels decreased. Together, these findings suggest that purified anthocyanin consumption enhances spatial learning and motor coordination in aged animals and can be attributed to the modulation of key synaptic proteins, which support integrity and maintenance of synaptic function.
... It has been observed that oligomeric proanthocyanidins, which are naturally occurring antioxidants found in a wide variety of foods, including fruits, vegetables, nuts, seeds, flowers, roots, and bark, have pharmacological and therapeutic efficacy against oxidative stress and free radicals. Proanthocyanidin extract from grape seeds offers a far higher level of protection against free radicals and lipid peroxidation caused by free radicals than do vitamins C, E, and α-carotene [42] . Blueberry, spinach, and spirulina dietary supplements were found to reduce overall locomotor deficits and stroke-induced cerebral infarction. ...
... Roedores -3,2 mg kg/dia -via oral durante 30 dias Ameniza a inflamação no encéfalo, melhora a função cerebral, melhora a atividade neural e coordenação motora (Ramirez et al., 2008) Roedores -20 g/kg/dia -via oraldurante 8 semanas Redução de déficits comportamentais relacionados à idade (Youdim et al., 2000) Roedores -20 g/kg/dia -via oraldurante 5 dias Parâmetros de plasticidade neuronal do hipocampo aumentados (Casadesus et al., 2004) Roedores -grupo 1: 0,6 a 1,0 mg/kg/dia e grupo 2: 2,6 a 3,2 mg/kg/dia -via oraldurante 30 dias Melhoria da memória episódica, desempenho cognitivo geral, prevenção do estresse oxidativo, redução de alterações neuronais e comportamentais relacionadas à idade (Barros et al., 2006) ...
Article
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Doenças neurodegenerativas, como a doença de Alzheimer, são relacionadas à idade e caracterizadas pela morte neuronal e fatores entre neuroinflamação e excesso de radicais livres. Estudos com fontes vegetais que possuem propriedades antioxidantes e anti-inflamatórias, têm sido realizados, pois podem neutralizar radicais livres em excesso, mostrando-se promissoras como terapias alternativas, especialmente as espécies de mirtilo, devido seu elevado teor de compostos fenólicos. O objetivo desse artigo foi compilar e discutir informações, em bases de dados de artigos científicos como Pubmed, ScienceDirect, Scielo e Google Scholar, sem limite de ano de publicação, nas línguas inglesa e portuguesa, que englobam compostos fenólicos presentes nos frutos de mirtilo, com propriedades que conferem neuroproteção em condições neurodegenerativas da doença de Alzheimer (DA). Além de proteção contra o envelhecimento, estresse oxidativo e reversão de déficits cognitivos, decorrente da utilização de compostos isolados e extratos brutos dos frutos e das folhas no tratamento e prevenção de doenças neurodegenerativas como a DA, alguns dos estudos compilados neste artigo, apresentam o uso de Rosmarinus spp., Vaccinium spp. e compostos encontrados em morangos, em espinafre e em vitamina E, com resultados promissores em modelos diferentes de neurodegeneração. Compostos como antocianinas, eugenol, taraxerol, resveratrol, quercetina, entre outros, também exibiram resultados relevantes para esta área de pesquisa, pois sugeriram proteção contra a DA. Portanto, é de importância significativa novos estudos com estes compostos como tratamento e prevenção da DA para trazer esperança de melhora em aspectos relacionados à qualidade de vida do paciente e em prejuízos cognitivos associados à doença.
... In aged mice and rats, blueberry intake improved cognitive performance and corrected deficits and/or age-related cognitive decline (38)(39)(40)(41)(42). Also, in pre-clinical studies, blueberry intake protected against cognitive deficits associated with brain insults (43)(44)(45) and poor diet (i.e., high linoleic acid intake) (46). ...
Article
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Mounting evidence indicates that blueberry consumption is associated with a variety of health benefits. It has been suggested that regular consumption of blueberries can support and/or protect against cardiovascular disease and function, pre-diabetes and type 2 diabetes, and brain and cognitive function in individuals with health conditions and age-related decline. Further, mechanistic investigations highlight the role of blueberry anthocyanins in mediating these health benefits, in part through interactions with gut microbiota. Also, nutritional interventions with blueberries have demonstrated the ability to improve recovery following exercise-induced muscle damage, attributable to anti-inflammatory effects. Despite these advancements in blueberry health research, research gaps persist which affects the generalizability of findings from clinical trials. To evaluate the current state of knowledge and research gaps, a blueberry health roundtable with scientific experts convened in Washington, DC (December 6–7, 2022). Discussions centered around five research domains: cardiovascular health, pre-diabetes and diabetes, brain health and cognitive function, gut health, and exercise recovery. This article synthesizes the outcomes of a blueberry research roundtable discussion among researchers in these domains, offering insights into the health benefits of blueberries and delineating research gaps and future research directions.
... Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols by increasing the activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase (GPx) [6]. In addition, various polyphenols reportedly influence neuronal function and have pleiotropic effects on neuronal proliferation and differentiation [7,8]. They also exert indirect neuroprotective effects via modulation of gut microbiota and metabolite production [9]. ...
Article
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Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.
... In recent years, polyphenols have attracted attention for their neuroprotective effects, showing potential effectiveness in reversing neurodegenerative pathology and age-related cognitive decline. Animal studies have shown that blueberries can improve spatial memory deficits in rats, (−)-epigallocatechin enhanced the retention of spatial memory in mice, curcumin could break down plaques and restore neurites in Alzheimer's disease models, and resveratrol reduced Aβ aggregation in rat hippocampal cells by activating specific protein kinases (Casadesus et al., 2004;Dasgupta and Milbrandt, 2007;Garcia-Alloza et al., 2007;Praag et al., 2007). However, the direct link between polyphenols and improvements in neural health has not been clearly established. ...
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In recent years, an increasing trend has been observed in the consumption of specific polyphenols, such as flavonoids and phenolic acids, derived from green tea, berries, and other similar sources. These compounds are believed to alleviate oxidative stress and inflammation resulting from exercise, potentially enhancing athletic performance. This systematic review critically examines the role of polyphenol supplementation in improving aerobic endurance among athletes and individuals with regular exercise habits. The review involved a thorough search of major literature databases, including PubMed, Web of Science, SCOPUS, SPORTDiscus, and Embase, covering re-search up to the year 2023. Out of 491 initially identified articles, 11 met the strict inclusion criteria for this review. These studies specifically focused on the incorporation of polyphenols or polyphenol-containing complexes in their experimental design, assessing their impact on aerobic endurance. The methodology adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the risk of bias was evaluated using the Cochrane bias risk assessment tool. While this review suggests that polyphenol supplementation might enhance certain aspects of aerobic endurance and promote fat oxidation, it is important to interpret these findings with caution, considering the limited number of studies available. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023453321.
... This fact may be explained due to polyphenol's capability of inhibiting Aβ oligomerization, as it may increase Aβ42 monomer clearance. This activity is subsequent to monomer modulation in order to modify interactions as well as to oligomer's remodulation into nontoxic forms [137][138][139][140]. Moreover, recent literature proposed how polyphenols may modulate Tau hyperphosphorylation as well, as they could be responsible for the reduction in Tau B-sheet production [141]. ...
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This comprehensive review explores the dynamic relationship between sports, nutrition, and neurological health. Focusing on recent clinical advancements, it examines how physical activity and dietary practices influence the prevention, treatment, and rehabilitation of various neurological conditions. The review highlights the role of neuroimaging in understanding these interactions, discusses emerging technologies in neurotherapeutic interventions, and evaluates the efficacy of sports and nutritional strategies in enhancing neurological recovery. This synthesis of current knowledge aims to provide a deeper understanding of how lifestyle factors can be integrated into clinical practices to improve neurological outcomes.
... As elucidated by Casadesus et al., a diet enriched with blueberries (at a dose of 20 g/kg), a prominent source of PTE, induced notable alterations in the levels of insulin-like growth factor (IGF)− 1, IGF-2, and ERK, concomitant with a marked enhancement of hippocampal plasticity in aged rats (Casadesus et al., 2004). Furthermore, this dietary intervention yielded improved performance in various memory maze tasks, implying that blueberries exert a more pronounced impact on short-term memory as opposed to long-term memory (Williams et al., 2008). ...
... The dendritogenic effect reported here could be related to the presence of flavonoids in the extract. These polyphenolic compounds, known to stimulate neurogenesis in the hippocampus [51] or reduce oxidative stress in the brain [52], can activate signaling pathways that control synaptic plasticity [53]. Some flavonoids can alter the phosphorylation status of extracellular signal-regulated kinases (ERK1/ERK2) and protein-kinases B (AKT), activating MAPK and PI3K signaling pathways, respectively [54]. ...
Article
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A reduced dendritic complexity, especially in regions such as the hippocampus and the prefrontal cortex, has been linked to the pathophysiology of some neuropsychiatric disorders, in which synaptic plasticity and functions such as emotional and cognitive processing are compromised. For this reason, the identification of new therapeutic strategies would be enriched by the search for metabolites that promote structural plasticity. The present study evaluated the dendritogenic potential of the ethanol extract of Lippia alba, an aromatic plant rich in flavonoids and terpenes, which has been widely used in traditional medicine for its presumed analgesic, anxiolytic, and antidepressant potential. An in vitro model of rat cortical neurons was used to determine the kinetics of the plant's effect at different time intervals. Changes in morphological parameters of the neurons were determined, as well as the dendritic complexity, by Sholl analysis. The extract promotes the outgrowth of dendritic branching in a rapid and sustained fashion, without being cytotoxic to the cells. We found that this effect could be mediated by the phosphatidylinositol 3-kinase pathway, which is involved in mechanisms of neuronal plasticity, differentiation, and survival. The evidence presented in this study provides a basis for further research that, through in vivo models, can delve into the plant's therapeutic potential.
... As elucidated by Casadesus et al., a diet enriched with blueberries (at a dose of 20 g/kg), a prominent source of PTE, induced notable alterations in the levels of insulin-like growth factor (IGF)-1, IGF-2, and ERK, concomitant with a marked enhancement of hippocampal plasticity in aged rats (Casadesus et al., 2004). Furthermore, this dietary intervention yielded improved performance in various memory maze tasks, implying that blueberries exert a more pronounced impact on short-term memory as opposed to long-term memory (Williams et al., 2008). ...
Preprint
The therapeutic potential of natural stilbenes, with a particular focus on pterostilbene (PTE), has emerged as a promising avenue of research targeting age-associated conditions encompassing cardiovascular diseases (CVD), diabetes mellitus (DM), and cognitive decline. This comprehensive investigation delves into the intricate mechanisms through which PTE, a polyphenolic compound abundant in grapes and blueberries, exerts its advantageous effects as an anti-aging agent. Central to its action is the modulation of hallmark aging processes, including oxidative damage, inflammatory responses, telomere attrition, and cellular senescence. PTE’s notable ability to effectively penetrate the blood-brain barrier amplifies its potential for safeguarding neural health, thereby facilitating the regulation of neuronal signalling cascades, synaptic plasticity, and mitochondrial functionality. Through engagement with sirtuin proteins, it orchestrates cellular resilience, longevity, and metabolic equilibrium. Encouraging findings from preclinical studies portray PTE as a robust candidate for counteracting age-linked cognitive decline, augmenting memory consolidation, and potentially ameliorating neurodegenerative maladies such as Alzheimer’s disease (AD). The synthesis of current scientific insights accentuates the promising translational prospects of PTE as a potent, naturally derived therapeutic agent against cognitive impairments associated with aging. Consequently, these collective findings lay a solid groundwork for forthcoming clinical inquiries and innovative therapeutic interventions in this realm.
... For example, polyphenols, which are derived from plant-based diets, are metabolized into bioactive compounds/metabolites by the gut microbiota to promote their beneficial function on cardiovascular health [55]. Some of the phenolic compounds' beneficial effects are linked to their properties and these include antioxidant, anti-inflammatory, antibacterial [56,57], antiadipogenic [58][59][60] and neuro-protective properties [55,61,62]. The hydroxyl group situated on the benzene ring of polyphenols functions to mediate the transfer of the H-atom to free radicals converting them into non-toxic compounds and thus effecting their antioxidant function [63]. ...
Article
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Heart failure is a risk factor for adverse events such as sudden cardiac arrest, liver and kidney failure and death. The gut microbiota and its metabolites are directly linked to the pathogenesis of heart failure. As emerging studies have increased in the literature on the role of specific gut microbiota metabolites in heart failure development, this review highlights and summarizes the current evidence and underlying mechanisms associated with the pathogenesis of heart failure. We found that gut microbiota-derived metabolites such as short chain fatty acids, bile acids, branched-chain amino acids, tryptophan and indole derivatives as well as trimethylamine-derived metabolite, trimethylamine N-oxide, play critical roles in promoting heart failure through various mechanisms. Mainly, they modulate complex signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells, Bcl-2 interacting protein 3, NLR Family Pyrin Domain Containing inflammasome, and Protein kinase RNA-like endoplasmic reticulum kinase. We have also highlighted the beneficial role of other gut metabolites in heart failure and other cardiovascular and metabolic diseases.
... Dietary anthocyanins have been reported to exert neuroprotective effects, reducing age-related cognitive decline, improving cognitive performance, and even mitigating stress-related brain damage (Joseph et al. 1999;Casadesus et al. 2004;Petersen 2004;Rahman et al. 2008;Krikorian et al. 2010a;Albert et al. 2011). In the hippocampal cell line HT22, anthocyanin treatment attenuated cell death and normalised mitochondrial membrane potential and calcium levels associated with Aβ1-42 neurotoxicity (Badshah et al. 2015). ...
Chapter
The gradual ageing of the world population has been accompanied by a dramatic increase in the prevalence of obesity and metabolic diseases, especially type 2 diabetes. The adipose tissue dysfunction associated with ageing and obesity shares many common physiological features, including increased oxidative stress and inflammation. Understanding the mechanisms responsible for adipose tissue dysfunction in obesity may help elucidate the processes that contribute to the metabolic disturbances that occur with ageing. This, in turn, may help identify therapeutic targets for the treatment of obesity and age-related metabolic disorders. Because oxidative stress plays a critical role in these pathological processes, antioxidant dietary interventions could be of therapeutic value for the prevention and/or treatment of age-related diseases and obesity and their complications. In this chapter, we review the molecular and cellular mechanisms by which obesity predisposes individuals to accelerated ageing. Additionally, we critically review the potential of antioxidant dietary interventions to counteract obesity and ageing.KeywordsAgeingObesityMetabolic syndromeOxidative stressInflammationNutraceuticalsDietary interventions
... Asia is the source of among the most medicinal plant since ancient times one of the well-recognized Genera is Rubus which includes more than 750 species in 12 subgenera, the geographical location indicates that it presents all continents except Antarctica 3 . Rubus species have been used in folk medicine because it possesses the ethnomedicinal property and it was always been the subject of research over the last twenty-five years has been performed on Rubus species, a number of the study have been performed including the ability to modulate neuroinflammation 4 , glucoregulation 5 , neurodegeneration 6 and hippocampal neurogenesis 7 . These all effects resembled their phytoconstituents present in Rubus. ...
Article
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From the prehistoric, ancient age to the modern-day, genus Rubus species are already known for their healing properties such as in neurodegenerative and psychological disorders, cancer, diarrhoea, colic pain, diabetes, nephrological, and inflammatory disorders. Based on their phytochemistry and pharmacology it is an attempt to achieve a greater knowledge of the biological significance of these herbal medicinal plants. The ultimate aim of this review is to deliver the magnification of research at the cellular and molecular level in the management of nervous breakdowns and other diseases. An exhaustive literature search was performed by online databases such as Springer, Scopus, and Elsevier. In this review, the different novel medicinal plants belong to the genus Rubus, used to treat enormous ailments based on traditional and literature search, their potential bioactive species belong to the same genus.
... Flavonoids, such as luteolin and spinosin, significantly increase cell proliferation in the hippocampal neurons through multiple pathways. Supplementation with flavonoid-rich blueberry in aged animals improved hippocampal plasticity and cognitive performance via mechanisms involving neurogenesis, IGF-1, and its receptor [171]. It was also demonstrated that multiple flavonoids prolong the function of neurons in Huntington's disease by modulating the activity of FoxO transcription factors [172]. ...
Article
The transcription factor NRF2 and its endogenous inhibitor KEAP1 play a crucial role in the maintenance of cellular redox homeostasis by regulating the gene expression of diverse networks of antioxidant, anti-inflammatory, and detoxification enzymes. Therefore, activation of NRF2 provides cytoprotection against numerous pathologies, including age-related diseases. An age-associated loss of NRF2 function may be a key driving force behind the aging phenotype. Recently, numerous NRF2 inducers have been identified and some of them are promising candidates to restore NRF2 transcriptional activity during aging. Emerging evidence indicates that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their electrophilic derivatives may trigger a protective response via NRF2 activation, rescuing or maintaining cellular redox homeostasis. In this review, we provide an overview of the NRF2-KEAP1 system and its dysregulation in aging cells. We also summarize current studies on the modulatory role of n-3 PUFAs as potential agents to prevent multiple chronic diseases and restore the age-related impairment of NRF2 function.
... Flavonoids, such as luteolin and spinosin, significantly increase cell proliferation in the hippocampal neurons through multiple pathways. Supplementation with flavonoid-rich blueberry in aged animals improved hippocampal plasticity and cognitive performance via mechanisms involving neurogenesis, IGF-1, and its receptor [171]. It was also demonstrated that multiple flavonoids prolong the function of neurons in Huntington's disease by modulating the activity of FoxO transcription factors [172]. ...
Article
Adult neurogenesis deficiency has been proposed to be a common hallmark in different age- related neurodegenerative diseases. The administration of flavonoids is currently reported as a potentially beneficial strategy for preventing brain aging alterations, including adult neurogenesis decline. Flavonoids are a class of plant-derived dietary polyphenols that have drawn attention for their neuroprotective and pro-cognitive effects. Although they undergo extensive metabolism and localize in the brain at low concentrations, flavonoids are now believed to improve cerebral vasculature and interact with signal transduction cascades involved in the regulation of adult neurogenesis. Furthermore, many dietary flavonoids have been shown to reduce oxidative stress and neuroinflammation, improving the neuronal microenvironment where adult neurogenesis occurs. The overall goal of this review is to summarize the evidence supporting the role of flavonoids in modulating adult neurogenesis as well as to highlight how these dietary agents may be promising candidates in restoring healthy brain function during physiological and pathological aging.
... There is evidence that the catechins in green tea (0.025%-0.010% of the weight of the tea leaf) and pure epicatechin (0.025%-0.010% of the weight of the tea leaf) help mice (8-10 weeks old) retain their spatial memory (Li et al. 2009). The dentate gyrus (DG) appears to play a role in the mechanisms (Burke and Barnes 2006;Casadesus et al. 2004). Polyphenol-rich foods may be able to improve memory through a link between hippocampal neurogenesis, cognitive performance, and aging . ...
Book
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Adequate intake of fruits has been linked with the reduction in the risk of chronic diseases and maintenance of body weight. Fruits and Their Roles in Nutraceuticals and Functional Foods covers recent research related to the bioactive compounds present in a variety of fruits
... An alternation is defined as an entry into all three arms (i.e., ABC, BCA, and CAB but not ABA) when a mouse was initially placed in arm A and allowed to move freely for 5 min. The percentage alternation is expressed as the ratio of actual alternations to possible alternations (defined as the total number of arm entries minus two) multiplied by 100 (Casadesus et al. 2004). ...
Article
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Development of neuropsychiatric disorder is associated with stress-related increase in pro-inflammatory cytokines. Chrysophyllum albidum fruit is an edible tropical fruit containing vitamins and phenolic compounds, well known for their anti-inflammatory and antioxidant activities. This study was designed to investigate the neuroprotective effect of C. albidum fruit extract (CAFE) on stress and lipopolysaccharide (LPS)-induced behavioral and neurochemical impairments in mice. Male Swiss mice were divided into 6 groups (n = 6). Groups 1–3 were orally treated daily for 14 days with normal saline (0.1 mL/10 g), CAFE (100 mg/kg) and Ferulic acid (FA, 10 mg/kg), and left in home cage as controls. Groups 4–6 were treated similarly but subjected to repeated social defeat (RSD) stress using the resident-intruder model from days 1–14. The RSD-animals were injected with LPS (125 µg/kg, i.p) 60 min after each RSD session from days 8–14. Neurobehavioral functions: locomotor, cognitive and anxiety-like behaviors were assessed 24 h after the last treatment. Pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), dopamine, acetylcholinesterase, glutamic acid decarboxylase (GAD), malondialdehyde, nitrites, and reduced glutathione (GSH) were determined in brain tissue. CAFE significantly attenuated RSD and LPS-induced hypolocomotion, cognitive impairment and anxiety-like behavior when compared to the control. Treatment with CAFE also significantly reversed the negative effects of RSD and LPS on pro-inflammatory cytokines, dopamine, acetylcholinesterase, GAD, and oxidative-nitrosative stress levels. The findings clearly indicated that Chrysophyllum albidum fruit demonstrated neuroprotective effects and can play a key role in mitigating against chronic stress and inflammation linked to neuropsychiatric disorders.
... The consumption of grapes and its derivatives improved a number of cognitive components (such as attention, executive function, and immediate spatial memory, learning, and driving skill) in the intervention groups compared to control groups. Modulation of neuro inflammation [21], improvement of cerebrovascular function [22], change in intestinal microbiota [23], glucoregulation [24], and increase in spinal density and neurogenesis especially in hippocampus [25] are potential direct and indirect mechanisms in improving cognition by polyphenols. ...
Article
Background: According to the world health organization (WHO), in 2019, around 50 million people suffer from dementia, worldwide; and approximately 60% live in low- and middle-income countries. Dementia has physical, psychological, social, and economic effects on dementia sufferers, their caregivers, families, and the community. Objectives: This systematic review investigated the effect of short-term and long-term interventions with grapes and their derivatives on different cognitive functions, such as executive function, memory, attention and language in all people. Methods: Pubmed, Scopus, and Proquest were searched until June 12, 2020 for English studies. Clinical trials in which grapes and its derivatives were considered as an intervention and changes of cognition and its components as an outcome, were selected. Two independent individuals assessed the quality of the articles according to Jadad checklist and extracted the information of the articles with inclusion criteria based on a specific table. The differences were resolved with the discussion and opinion of a third person. Results: Nine Studies (211 individuals) were included in the content analysis, of which 3 studies had short-term intervention and 6 studies had long-term intervention with grape juice, freeze-dried grape powder, and a syrup made from grapes (Enoant Syrup). It can be said that the consumption of grapes and its derivatives improved various cognitive components (such as attention, executive function, immediate spatial memory, learning, and driving skill) between groups. Conclusion: In general, long-term intervention with grapes and their derivatives has led to the improvement of some cognitive functions, but its short-term intervention is not very effective and only 2 studies showed improvement in attention speed. However, the included studies were highly heterogeneous and more research is needed using similar cognitive assessment tools.
... The neuro-protective effects of dietary polyphenols have received considerable attention in recent years, suggesting that polyphenols may be effective in reversing neurodegenerative pathology and age-related declines in neurocognitive performance. Animal evidence demonstrates that blueberries are effective at reversing age-related deficits in rat spatial working memory, and (−)-epicatechin enhances the retention of mice spatial memory and may relate to their potential to influence the synthesis of neurotrophic factors [31,32]. In addition, curcumin could disrupt existing plaques and partially restore distorted neurites in an Alzheimer mouse model [33]. ...
Article
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Polyphenols, which are probably the most important secondary metabolites produced by plants, have attracted tremendous attention due to their health-promoting effects, including their antioxidant, anti-inflammatory, antibacterial, anti-adipogenic, and neuro-protective activities, as well as health properties. However, due to their complicated structures and high molecular weights, a large proportion of dietary polyphenols remain unabsorbed along the gastrointestinal tract, while in the large intestine they are biotransformed into bioactive, low-molecular-weight phenolic metabolites through the residing gut microbiota. Dietary polyphenols can modulate the composition of intestinal microbes, and in turn, gut microbes catabolize polyphenols to release bioactive metabolites. To better investigate the health benefits of dietary polyphenols, this review provides a summary of their modulation through in vitro and in vivo evidence (animal models and humans), as well as their possible actions through intestinal barrier function and gut microbes. This review aims to provide a basis for better understanding the relationship between dietary polyphenols, gut microbiota, and host health.
... The striatum is affected by polyphenols present in blueberry; it is important to note that this striatum is critical in retrograde learning (Youdim et al., 2000;Kumar et al., 2011). With the supplementation of blueberries increased accumulation of anthocyanin in the hippocampal and neocortex was noticed (Casadesus et al., 2004). ...
Article
Full-text available
The current scientific community is facing a daunting challenge to unravel reliable natural compounds with realistic potential to treat neurological disorders such as Alzheimer’s disease (AD). The reported compounds/drugs mostly synthetic deemed the reliability and therapeutic potential largely due to their complexity and off-target issues. The natural products from nutraceutical compounds emerge as viable preventive therapeutics to fill the huge gap in treating neurological disorders. Considering that Alzheimer’s disease is a multifactorial disease, natural compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs so far used to treat Alzheimer’s disease. A wide range of plant extracts and phytochemicals reported to possess the therapeutic potential to Alzheimer’s disease includes curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and other phytochemicals such as huperzine A, limonoids, and azaphilones. Reported targets of these natural compounds include inhibition of acetylcholinesterase, amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc. We tenaciously aimed to review the in-depth potential of natural products and their therapeutic applications against Alzheimer’s disease, with a special focus on a diversity of medicinal plants and phytocompounds and their mechanism of action against Alzheimer’s disease pathologies. We strongly believe that the medicinal plants and phytoconstituents alone or in combination with other compounds would be effective treatments against Alzheimer’s disease with lesser side effects as compared to currently available treatments.
... Flavonoids are a type of naturally occurring polyphenolic compound present in a wide variety of plants, including fruits, vegetables, cereals, teas, and wines, and they play a significant role in the diet. Flavonoids have numerous biological functions, including neuroprotective effects [1] caused by neurotransmitter regulation and stimulation of hippocampal neurogenesis [2]. Furthermore, dietary flavonoids have been shown to improve memory and learning via neuronal signaling pathways, while also slowing the progression of debilitating brain illnesses such as Parkinson's and Alzheimer's disease [3]. ...
Article
Full-text available
Citation: Thayumanavan, G.; Jeyabalan, S.; Fuloria, S.; Sekar, M.; Ravi, M.; Selvaraj, L.K.; Bala, L.; Chidambaram, K.; Gan, S.H.; Rani, N.N.I.M.; et al. Silibinin and Naringenin against Bisphenol A-Induced Neurotoxicity in Zebrafish Model-Potential
... Flavonoids are a type of naturally occurring polyphenolic compound present in a wide variety of plants, including fruits, vegetables, cereals, teas, and wines, and they play a significant role in the diet. Flavonoids have numerous biological functions, including neuroprotective effects [1] caused by neurotransmitter regulation and stimulation of hippocampal neurogenesis [2]. Furthermore, dietary flavonoids have been shown to improve memory and learning via neuronal signaling pathways, while also slowing the progression of debilitating brain illnesses such as Parkinson's and Alzheimer's disease [3]. ...
Article
Full-text available
Bisphenol A (BPA), a well-known xenoestrogen, is commonly utilised in the production of polycarbonate plastics. Based on the existing evidence, BPA is known to induce neurotoxicity and behavioural issues. Flavonoids such as silibinin and naringenin have been shown to have biological activity against a variety of illnesses. The current research evaluates the neuropharmacological effects of silibinin and naringenin in a zebrafish model against neurotoxicity and oxidative stress caused by Bisphenol A. In this study, a novel tank diving test (NTDT) and light–dark preference test (LDPT) were used in neurobehavioural investigations. The experimental protocol was planned to last 21 days. The neuroprotective effects of silibinin (10 μM) and naringenin (10 μM) in zebrafish (Danio rerio) induced by BPA (17.52 μM) were investigated. In the brine shrimp lethality assay, the 50% fatal concentrations (LC50) were 34.10 μg/mL (silibinin) and 91.33 μg/mL (naringenin) compared to the standard potassium dichromate (13.15 μg/mL). The acute toxicity investigation found no mortality or visible abnormalities in the silibinin- and naringenin-treated groups (LC50 > 100 mg/L). The altered scototaxis behaviour in LDPT caused by BPA was reversed by co-supplementation with silibinin and naringenin, as shown by decreases in the number of transitions to the light zone and the duration spent in the light zone. Our findings point to BPA’s neurotoxic potential in causing altered scototaxis and bottom-dwelling behaviour in zebrafish, as well as the usage of silibinin and naringenin as potential neuroprotectants.
... The hippocampus, a region of the brain that functions in learning and spatial recognition, undergoes new cell formation, although the rate of this neurogenesis declines with ageing. Rats that received blueberries for 8 weeks, followed by bromodeoxyuridine, an analogue of uridine that could be detected histochemically, had a signifi cantly higher density of new cells compared to rats that did not receive blueberries (Casadesus et al., 2004). These rats also had higher levels of an insulin-like growth factor that was a key modulator of hippocampal neurogenesis, and higher activity of a kinase that was critical in neuronal signal transduction. ...
Chapter
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This book has 19 chapters focusing on the beneficial effects of the consumption of fruits and vegetables on human health. Some of the most common fruits and vegetables, their biologically active constituents and their medicinal properties are discussed. Some methodologies used for the extraction, isolation, characterization and quantification of these biologically active compounds and evaluation of their in vitro and in vivo activities are also presented.
... Aged rodents exposed to constituents commonly found in healthy dietary regimens, particularly those that contain high levels of polyphenolic flavonoids (e.g. blueberries) or natural polyphenols such as curcumin, display enhanced performance across a number of behavioral tasks, including object recognition and spatial working memory tests [154][155][156][157][158][159][160][161][162][163][164]. In addition to polyphenols, other organic compounds that are found in healthy diets, such as PUFAs, have also been shown to afford benefits to age-induced cognitive detriments [165]. ...
Article
Given the increasing prevalence of age-related cognitive decline, it is relevant to consider the factors and mechanisms that might facilitate an individual’s resiliency to such deficits. Growing evidence suggests a preeminent role of microglia, the prime mediator of innate immunity within the central nervous system. Human and animal investigations suggest aberrant microglial functioning and neuroinflammation are not only characteristic of the aged brain, but also might contribute to age-related dementia and Alzheimer’s Disease. Conversely, accumulating data suggest that modifiable lifestyle factors (MLFs), such as healthy diet, exercise and cognitive engagement, can reliably afford cognitive benefits by potentially suppressing inflammation in the aging brain. The present review highlights recent advances in our understanding of the role for microglia in maintaining brain homeostasis and cognitive functioning in aging. Moreover, we propose an integrated, mechanistic model that postulates an individual’s resiliency to cognitive decline afforded by MLFs might be mediated by the mitigation of aberrant microglia activation in aging, and subsequent suppression of neuroinflammation.
Chapter
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Neurodegenerative disorders have become one of the most serious threats to global civilization in recent years. According to present data and future projections, the number of dementia cases will dramatically rise from 13.5 million cases in 2000 to 21.2 million in 2025 and 36.7 million in 2050. Medical advancements have increased human life expectancy and led to a rise in neurodegenerative disorders, which pose a growing social and economic burden. Unfortunately, the onset or advancement of these diseases cannot be stopped or slowed down by existing medication or therapy. Subsequently, there is an immediate need to develop alternative strategies that can prevent, delay, and even cure neurodegeneration. Recent research to understand the relationship between a healthy lifestyle, nutrition, and diseases indicates that nutritional interventions could be a possible and effective way to protect against age-related neurodegenerative disorders. Emerging evidence has revealed that dietary consumption of flavonoids significantly improves human memory and neuro-cognitive capabilities and inhibits or slows down the neuronal aging process and associated neurodegenerative diseases, including Alzheimer’s disease. Flavonoids exert their beneficial effect via their ability to inhibit neuronal apoptosis, enhance neuronal function, and induce neuronal regeneration. Flavonoids induce neuronal proliferation and survival by stimulating various cellular signaling processes; it also reduces oxidative stress and promotes long-term potentiation in the brain’s hippocampal region. All these neuroprotective actions of flavonoids thus impede the development and progression of neurodegeneration. They could be a promising medical armamentarium to fight against the development and progression of age-related neurodegenerative disorders.
Chapter
Everybody eats, and what we eat – or do not – affects the brain and mind. There is significant general, applied, academic, and industry interest about nutrition and the brain, yet there is much misinformation and no single reliable guide. Diet Impacts on Brain and Mind provides a comprehensive account of this emerging multi-disciplinary science, exploring the acute and chronic impacts of human diet on the brain and mind. It has a primarily human focus and is broad in scope, covering wide-ranging topics like brain development, whole diets, specific nutrients, research methodology, and food as a drug. It is written in an accessible format and is of interest to undergraduate and graduate students studying nutritional neuroscience and related disciplines, healthcare professionals with an applied interest, industry researchers seeking topic overviews, and interested general readers.
Article
Alcohol‐induced aggression and related violence is a serious and common social problem globally. Alcohol use is increasingly found in the form of alcoholic herbal mixtures (AHM) with indiscriminate and unregulated alcohol content. This study investigated the effects of AHM on aggressive‐like, neurocognitive impairment and brain biochemical alteration in mice. Thirty‐two male resident mice were paired housed with female mice for 21 days in four groups (n = 8). Resident mice were treated orally with normal saline, AHM, ethanol and AHM + ethanol daily for 14 days. Aggressive‐like behaviour was scored based on the latency and frequency of attacks by the resident mouse on the intruder. Neurocognitive impairment was determined using the Y‐maze test (YMT) and novel object recognition test (NORT). Acetylcholinesterase, glutamic acid decarboxylase (GAD), pro‐inflammatory and oxidative stress parameters were determined in the prefrontal cortex (PFC). Neuronal morphology, cytochrome c (Cyt‐c) and nuclear factor‐kappa B (NF‐ĸB) expressions were determined. AHM and in combination with ethanol showed an increased index of aggression typified by frequency of attack and reduced latency to attack when compared to normal saline‐treated animals. Co‐administration of AHM and ethanol significantly reduced cognitive correct alternation (%) and discrimination index in the YMT and NORT, respectively. AHM and ethanol increased acetylcholinesterase, Pro‐inflammatory cytokines and oxidative stress parameters while they reduced GAD. There were significantly reduced neuronal counts and increased expression of Cyt‐c and NF‐ĸB, respectively Alcoholic herbal mixture increased aggressiveness and caused neurocognitive impairment via increased oxido‐inflammatory stress in the prefrontal cortex.
Article
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The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract and collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota’s ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment.
Chapter
O livro enfatiza fatores que regem a vida humana do início ao fim e que podem ser muito diferentes entre indivíduos e populações: 1) caracteres genéticos herdados diretamente de nossos pais e indiretamente de nossos ancestrais, os quais permanecem relativamente estáveis ao longo da vida; 2) fatores ambientais (alimentação, condição e estilo de vida) até certo ponto controláveis, sendo a alimentação o mais importante. A primeira parte do livro trata da definição e da conceituação do processo de envelhecimento e seus efeitos na saúde. Seguem-se a apresentação e a discussão de mecanismos que promovem degradação molecular e celular responsáveis por distúrbios metabólicos que podem resultar em doenças crônico-degenerativas. A maior parte do texto é dedicada à apresentação de alimentos e compostos bioativos que agem combatendo o envelhecimento precoce e retardando doenças da idade. Por fim, faz-se uma discussão sobre conceitos de dietas saudáveis com sugestões para pesquisas, visando melhorar o perfil alimentar do brasileiro.
Chapter
Age-related cognitive decline is emerging as one of the greatest health challenges of the twenty-first century. With the projected trends in population ageing and population growth, the prevalence of cognitive decline and risk of dementia is constantly increasing since cognitive impairment results from the physiological process of brain aging. Cognitive decline is characterized by a decline in memory and other cognitive processes, changes in health behaviours and impaired their everyday functional abilities. Currently, available treatments for cognitive impairment are of limited value, with none slowing the progression or attenuating cognitive decline in the elderly. Recently, studies are focusing on potential benefits of various pharmacological treatments for optimizing the quality of life of elderly. Therefore, this chapter will focus on the role of antioxidants, emphasising on the increasing evidence that cognitive decline is accompanied by elevated oxidative stress.
Chapter
The area of research on the health benefits of berries, their bioactive compounds and their related metabolites has exploded in the last 20 years resulting in new knowledge in the understanding of their metabolism, molecular mode of action as well as their clinical significance in promoting health and preventing chronic disease. Berries and Berry Bioactive Compounds in Promoting Health, reviews state-of-the-art research findings on this exponentially growing area. This comprehensive book brings together international experts in their corresponding fields with cutting-edge reviews. Exploring the effects and mechanisms of action of berry bioactive compounds and their metabolites on different body systems and chronic diseases, including their role on gut microbiota and eventual effect on health is the focus of this book. Unique topics covered, include the chemistry and analytical methods of detection of berry bioactive compounds, bioavailability, metabolism and factors that affect them including individual variability, their interaction with the gut microbiome, and their role and mechanism(s) of action on chronic diseases such as cardiovascular disease, diabetes mellitus, metabolic syndrome and obesity-induced inflammation, and cancer as well as neuroprotection and wound healing. It will be of benefit to scientists conducting research in the area of berries and their bioactive compounds on health and disease and for health care professionals, nutritionists, dietitians and clinical researchers, nutraceutical and natural food product developers (industry) and food regulators.
Article
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The current scientific community is facing a daunting challenge to unravel reliable natural compounds with realistic potential to treat neurological disorders such as Alzheimer’s disease (AD). The reported compounds/drugs mostly synthetic deemed the reliability and therapeutic potential largely due to their complexity and off-target issues. The natural products from nutraceutical compounds emerge as viable preventive therapeutics to fill the huge gap in treating neurological disorders. Considering that Alzheimer’s disease is a multifactorial disease, natural compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs so far used to treat Alzheimer’s disease. A wide range of plant extracts and phytochemicals reported to possess the therapeutic potential to Alzheimer’s disease includes curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and other phytochemicals such as huperzine A, limonoids, and azaphilones. Reported targets of these natural compounds include inhibition of acetylcholinesterase, amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc. We tenaciously aimed to review the in-depth potential of natural products and their therapeutic applications against Alzheimer’s disease, with a special focus on a diversity of medicinal plants and phytocompounds and their mechanism of action against Alzheimer’s disease pathologies. We strongly believe that the medicinal plants and phytoconstituents alone or in combination with other compounds would be effective treatments against Alzheimer’s disease with lesser side effects as compared to currently available treatments.
Article
Objective: To determine the synergistic effects of nutrition, specifically adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and physical activity on cognition and brain outcomes in a cross-sectional healthy aging cohort. Methods: A total of 132 adults (age range 52-91; Clinical Dementia Rating = 0) from the UCSF Brain Aging Project completed a 15-item MIND diet food frequency questionnaire and an 11-item self-report measure of weekly physical activity (Physical Activity Scale [PASE]). Cognitive outcomes included executive functioning, episodic memory, and language. Neuroimaging outcomes consisted of total grey matter volume and total white matter volume, adjusted for total intracranial volumes. All regression interaction models adjusted for age, sex, education, and a composite vascular burden score. Results: There was a significant interaction between PASE and MIND on executive functioning and total grey matter volume. Low levels of both related to disproportionately poorer cognitive and brain structural outcomes. Increasing levels of either, but not both, PASE or MIND related to better executive functioning and gray matter outcomes. For memory, language, and total white matter volume, the interaction between PASE and MIND showed the same directionality but did not reach statistical significance. Conclusions: Higher levels of physical activity associated with better executive functioning and gray matter volume, particularly when diet was poor. Similarly, higher levels of MIND diet adherence were associated with better brain and cognitive outcomes when physical activity was low. However, highest levels of physical activity and MIND diet together did not necessarily lead to disproportionately better cognitive and brain volume outcomes.
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Intracellular amyloid β (Aβ) oligomers are key therapeutic targets because they are strongly cytotoxic and play crucial roles in the cognitive function in Alzheimer’s disease (AD). Anthocyanins, polyphenolic flavonoids with antioxidant and neuroprotective properties, are potential therapeutic candidates for AD. Here, we investigated the effects of anthocyanin-enriched extracts from fruits of mulberry (Morus alba Linn.) in Thailand against the neurotoxicity of Aβ oligomers. Using the monitoring system for Aβ aggregation, we revealed that the extract induced the dissociation of Aβ in cultured HEK293T cells. To investigate the effects on cognitive function, we orally administered the extract to Aβ-GFP transgenic mice (Aβ-GFP Tg), a mouse model that expresses Aβ oligomers inside neurons, and performed the novel object recognition test and passive avoidance test. Aβ-GFP Tg usually showed deficits in novel object recognition memory and reference memory compared to non-Tg, but administration of the extract improved both compared to vehicle-treated Aβ-GFP Tg. Aβ-GFP Tg exhibited lower superoxide dismutase (SOD) activity than non-Tg. However, after the administration of the extract, the SOD activity was restored. These results suggest that Thai mulberry fruit extract ameliorate cytotoxicity induced by the intracellular Aβ oligomers and may be an effective therapeutic or preventive candidate for AD.
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Background: Motor and cognitive decline as part of the normal aging process is linked to alterations in synaptic plasticity and reduction of adult neurogenesis in the dorsal striatum. Neuroinflammation, particularly in the form of microglial activation, is suggested to contribute to these age-associated changes. Objective and methods: To explore the molecular basis of alterations in striatal function during aging we analyzed RNA-Seq data for 117 postmortem human dorsal caudate samples and 97 putamen samples acquired through GTEx. Results: Increased expression of neuroinflammatory transcripts including TREM2, MHC II molecules HLA-DMB, HLA-DQA2, HLA-DPA1, HLA-DPB1, HLA-DMA and HLA-DRA, complement genes C1QA, C1QB, CIQC and C3AR1, and MHCI molecules HLA-B and HLA-F was identified. We also identified down-regulation of transcripts involved in neurogenesis, synaptogenesis, and synaptic pruning, including DCX, CX3CL1, and CD200, and the canonical WNTs WNT7A, WNT7B, and WNT8A. The canonical WNT signaling pathway has previously been shown to mediate adult neurogenesis and synapse formation and growth. Recent findings also highlight the link between WNT/β-catenin signaling and inflammation pathways. Conclusions: These findings suggest that age-dependent attenuation of canonical WNT signaling plays a pivotal role in regulating striatal plasticity during aging. Dysregulation of WNT/β-catenin signaling via astrocyte-microglial interactions is suggested to be a novel mechanism that drives the decline of striatal neurogenesis and altered synaptic connectivity and plasticity, leading to a subsequent decrease in motor and cognitive performance with age. These findings may aid in the development of therapies targeting WNT/β-catenin signaling to combat cognitive and motor impairments associated with aging.
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Bacteria carrying New Delhi metallo-β-lactamase-1 (New Delhi metallo-β-lactamase, NDM-1) resistance gene is a new type of "superbug", which can hydrolyze almost all β-lactam antibiotics, rapidly spread among the same species and even spread among different species. NDM-1 belongs to the class B1 broad-spectrum enzyme of β-lactamase. The two positively charged zinc ions in the active center have electrostatic interaction with the hydroxyl ions in them to seize the hydrogen atom near the water molecule to form a bridging ring water molecule, which strengthens its nucleophilicity and attacks the carbonyl group on the lactam ring; thus, catalyzing the hydrolysis of β-lactam antibiotics. Since NDM-1 has an open active site and unique electrostatic structure, it essentially provides a wider range of substrate specificity. Due to its flexible hydrolysis mechanism and more and more variants also aggravate the threat of drug-resistant bacteria infection, there is still no effective inhibitor in clinic, which is a serious threat to human health and public health safety. The electron-rich substituents of NDM-1 inhibitors coordinate with two positively charged zinc ions in the active center of the enzyme through ion-dipole interaction to produce NDM-1 inhibitory activity. In this review, the research progress of NDM-1 enzyme and its inhibitors in the past 5 years was reviewed. The crystal structure, active center structure, surrounding important amino acid residues, newly discovered inhibitors and their action mechanism are classified and summarized in detail, which can be used as a reference for the development of effective drugs against drug-resistant bacteria targeting NDM-1.
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BACKGROUND: Growing evidence suggests that hyperglycemia could be harmful for cognitive function. That insulin (INS) has a neuro-modulatory role is supported by various findings, but its effect on microglia, the innate immune cells in the brain, is largely unknown. Blueberries have been shown to reduce neuro-inflammation. OBJECTIVE: We hypothesized that high glucose stimulated an inflammation in microglia and that BB and INS were able to reduce it and both might act through GLUT-1 transporter. METHODS: We examined the effects of low (5 mM), medium (25 mM), or high (50 mM) glucose, stimulated or not with lipopolysaccharide (LPS; 100 nM) with either BB extract (2 mg/ml) and/or INS, on inflammatory responses in a microglia cell line. Nitric oxide (NO) production and the expression levels of iNOS, TNF-α, NOX4 and glucose transporter protein-1 (GLUT1) were assessed. RESULTS: We observed that treatment with BB, similarly to INS treatments, reduced the high glucose concentration-induced response on oxidative stress and inflammation, and that this protective effect is more important with LPS added to glucose media. Interestingly, both BB and INS attenuated the LPS-induced inflammatory response on GLUT1. CONCLUSION: Increasing glucose concentration triggers inflammation by microglia. BB as well as INS protected microglia from high glucose levels, by reducing inflammation and altering glucose transport in microglia. These preliminary data compared for the first time BB to Insulin on microglia. Blueberries are promising dietary intervention to prevent diabetic neuropathy. Our preliminary results suggest a possible new mechanism involving GLUT-1 by which BB has insulin-like effects.
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In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdU-immunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D 28K , microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 ± 17% ( p < 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls.
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Emerging evidence from our lab indicate that fruits and vegetables, in particular blueberry (BB) extracts, are able to ameliorate age-related declines in neuronal and cognitive function, common in disorders such as Alzheimer disease. The current study examined if the beneficial effects were also discernable with supplementation of BB extracts, in an already well balanced diet. Indeed, following an 8 week supplementation regime, age-related declines in several behavioral parameters such as balance, coordination, working memory and reference memory were still protected against. Similarly, BB extracts also potentiated oxotremorine enhancement of K+-evoked release of dopamine from striatal slices. Decline in the dopaminergic system have been shown to have a profound effect on cognitive functions. The improvement in dopamine release may have been due in part to the observed increase in striatal vitamin C levels. Although assessment of serum transaminase levels in BB supplemented animals appeared to suggest improved liver function, this was not thought to be the reason for the elevated vitamin C levels. The underlying mechanism for this is unclear. Together these findings highlight the diverse in vivo actions of dietary polyphenolics, a number of which may be important against age-related declines in certain brain functions. Furthermore they are to be able to mediate protective effects despite the diet containing sufficient concentrations of antioxidants.
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Two experiments sought to elicit distractor suppression in older adults (aged 62–78 yrs). Exp 1 used a procedure that increased suppression in younger adults (aged 17–25 yrs), thus creating a more sensitive measure of suppression in older adults. To compensate for older adults' slowed processing, Exp 2 used a longer stimulus exposure duration. Neither experiment produced suppression in older adults; both experiments, however, included trial types that elicited parallel facilitatory effects for both age groups. Older adults thus seemed to process distractors but failed to engage inhibitory mechanisms in their rejection of distracting stimuli. Finally, both experiments tested the relationships among suppression, interference, and everyday cognitive failure. Neither experiment suggested relationships between reaction time (RT) effects and self-reported cognitive lapses. Results are discussed within L. Hasher and R. T. Zacks's (1988) attentional framework. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three-month-old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double-labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory. © 1999 John Wiley & Sons, Inc. J Neurobiol 39: 569–578, 1999
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Two experiments compared the performance of older and younger adults on a task assessing suppression (or negative priming) for location of distractors. A 3rd experiment compared the 2 age groups on suppression for location and identity of distractors such that location was irrelevant to selection and response. Older and younger adults showed location suppression across all experiments. In Experiment 3, identity suppression was found for younger but not older adults. In addition, younger adults revealed an additive effect for suppression of identity and location. Consistent evidence of inhibition of return was not found for either age group. The findings are discussed in terms of the Hasher and Zacks (1988) theory of reduced inhibitory efficiency in the elderly and in terms of neurophysiological evidence that inhibition of identity and location may function separately within the 2 cortical visual systems.
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The hippocampus is one of the few areas of the rodent brain that continues to produce neurons postnatally. Neurogenesis reportedly persists in rats up to 11 months of age. Using bromodeoxyuridine (BrdU) labeling, the present study confirms that in the adult rat brain, neuronal progenitor cells divide at the border between the hilus and the granule cell layer (GCL). In adult rats, the progeny of these cells migrate into the GCL and express the neuronal markers NeuN and calbindin-D28k. However, neurogenesis was drastically reduced in aged rats. Six-to 27-month-old Fischer rats were injected intraperitoneally with BrdU to detect newborn cells in vivo and to follow their fate in the dentate gyrus. When killed 4-6 weeks after BrdU labeling, 12- to 27-month-old rats exhibited a significant decline in the density of BrdU-positive cells in the granule cell layer compared with 6-month-old controls. Decreased neurogenesis in aging rats was accompanied by reduced immunoreactivity for poly-sialylated neural cell adhesion molecule, a molecule that is involved in migration and process elongation of developing neurons. When animals were killed immediately (12 hr) after BrdU injection, significantly fewer labeled cells were observed in the GCL and adjacent subgranular zone of aged rats, indicative of a decrease in mitotic activity of neuronal precursor cells. The reduced proliferation was not attributable to a general aged-related metabolic impairment, because the density of BrdU-positive cells was not altered in other brain regions with known mitotic activity (e.g., hilus and lateral ventricle wall). The decline in neurogenesis that occurs throughout the lifespan of an animal can thus be related to a decreasing proliferation of granule cell precursors.
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Previous studies have shown that the orbital and medial prefrontal cortex (OMPFC) is extensively connected with medial temporal and cingulate limbic structures. In this study, the organization of these projections was defined in relation to architectonic areas within the OMPFC. All of the limbic structures were substantially connected with the following posterior and medial orbital areas: the posteromedial, medial, intermediate, and lateral agranular insular areas (Iapm, Iam, Iai, and Ial, respectively) and areas 11m, 13a, 13b, 14c, and 14r. In contrast, lateral orbital areas 12o, 12m, and [12] and medial wall areas 24a, b and 32 were primarily connected with the amygdala, the temporal pole, and the cingulate cortex. Data were not obtained on the poateroventral medial wall. Three distinct projections were recognized from the basal amygdaloid nucleus: (1) The dorsal part projected to area 121; (2) the ventromedial part projected to most areas in the posterior and medial orbital cortex except for areas Iai, 12o, 13a, and 14c; and (3) the ventrolateral part projected to orbital areas 12o, Iai, 13a, 14c, and to the medial wall areas. The accessory basal and lateral amygdaloid nuclei projected most strongly to areas in the posterior and medial orbital cortex. The medial, anterior cortical, and central amygdaloid nuclei and the periamygdaloid cortex were connected with the posterior orbital areas. The projection from the hippocampus originated from the rostral subiculum and terminated in the medial orbital areas. The same region was reciprocally connected with the anterornedial nucleus of the thalamus, which received input from the rostral subiculum. The parahippocampal cortical areas (including the temporal polar, entorhinal, perirhinal, and posterior parahippocampal cortices) were primarily connected with posterior and medial orbital areas, with some projections to the dorsal parr of the medial wall. The rostral cingulate cortex sent fibers to the medial wall, to the medial orbital areas, and to lateral areas 12o, 12r, and Iai. The posterior cingulate gyrus, including the caudomedial lobule, was especially strongly connected with area 11 m. © 1995 Wiley‐Liss, Inc.
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The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The two-phase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that serial transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on serial transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbic-cortical-striatal networks.
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We demonstrate here that under physiological conditions neurogenesis continues to occur in the dentate gyrus of senescent mice and can be stimulated by living in an enriched environment. Neurogenesis was investigated by confocal microscopy of three-channel immunofluorescent staining for the proliferation marker bromodeoxyuridine (BrdU) and neuronal and glial markers. Quantification was performed with unbiased stereological counting techniques. Neurogenesis decreased with increasing age. Stimulation of adult and aged mice by switching from standard housing to an enriched environment with opportunities for social interaction, exploration, and physical activity for 68 d resulted in an increased survival of labeled cells. Phenotypic analysis revealed that, in enriched living animals, relatively more cells differentiated into neurons, resulting in a threefold net increase of BrdU-labeled neurons in 20-month-old mice (105 vs 32 cells) and a more than twofold increase in 8-month-old mice (684 vs 285 cells) compared with littermates living under standard laboratory conditions. Corresponding absolute numbers of BrdU-positive astrocytes and BrdU-positive cells that did not show colabeling for neuronal or glial markers were not influenced. The effect on the relative distribution of phenotypes can be interpreted as a survival-promoting effect that is selective for neurons. Proliferation of progenitor cells appeared unaffected by environmental stimulation.
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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.
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Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. However, the molecular mechanisms underlying long-term spatial memory are poorly understood. In this study, we show that mitogen-activated protein kinase (MAPK, also called ERK) is activated in the dorsal, but not the ventral, hippocampus of rats after training in a spatial memory task, the Morris water maze. The activation was expressed as enhanced phosphorylation of MAPK in the pyramidal neurons of the CA1/CA2 subfield. In contrast, no increase in the percentage of phospho-MAPK-positive cells was detected in either the CA3 subfield or the dentate gyrus. The enhanced phosphorylation was observed only after multiple training trials but not after a single trial or after multiple trials in which the location of the target platform was randomly changed between each trial. Inhibition of the MAPK/ERK cascade in dorsal hippocampi did not impair acquisition, but blocked the formation of long-term spatial memory. In contrast, intrahippocampal infusion of SB203580, a specific inhibitor of the stress-activated MAPK (p38 MAPK), did not interfere with memory storage. These results demonstrate a MAPK-mediated cellular event in the CA1/CA2 subfields of the dorsal hippocampus that is critical for long-term spatial memory.
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Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress that may be ameliorated by antioxidants. Our previous study had shown that rats given dietary supplements of fruit and vegetable extracts with high antioxidant activity for 8 months beginning at 6 months of age retarded age-related declines in neuronal and cognitive function. The present study showed that such supplements (strawberry, spinach, or blueberry at 14.8, 9.1, or 18.6 gm of dried aqueous extract per kilogram of diet, respectively) fed for 8 weeks to 19-month-old Fischer 344 rats were also effective in reversing age-related deficits in several neuronal and behavioral parameters including: oxotremorine enhancement of K(+)-evoked release of dopamine from striatal slices, carbachol-stimulated GTPase activity, striatal Ca(45) buffering in striatal synaptosomes, motor behavioral performance on the rod walking and accelerod tasks, and Morris water maze performance. These findings suggest that, in addition to their known beneficial effects on cancer and heart disease, phytochemicals present in antioxidant-rich foods may be beneficial in reversing the course of neuronal and behavioral aging.
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In primates, prefrontal, inferior temporal, and posterior parietal cortex are important for cognitive function. It is shown that in adult macaques, new neurons are added to these three neocortical association areas, but not to a primary sensory area (striate cortex). The new neurons appeared to originate in the subventricular zone and to migrate through the white matter to the neocortex, where they extended axons. These new neurons, which are continually added in adulthood, may play a role in the functions of association neocortex.
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Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.
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Mitogen-activated protein kinases (MAPKs) play important roles in cell proliferation, differentiation, and apoptosis. Important functional roles for MAPKs in postmitotic cells have recently been suggested. In the present study, we investigated the effect of aging on the brain ERK (extracellular signal-regulated kinase) and p38 MAPK signaling pathways of Fischer 344 rats. The results show that basal tyrosine-phosphorylated ERK1/ERK2 in cortex of 24-month-old rats was reduced by 36%-59%, compared to 6- and 12-month-old rats (p<.05, 24- vs. 12- or 6-month-old rats). Similarly, the phosphotransferase activities of ERK and p38 MAPK, measured by in vitro immunocomplex kinase assays using myelin basic protein (MBP) as substrate, were shown to be reduced approximately 50% and 59% respectively, in the cerebrocortex of 24-month-old rats (p<.01, 24- vs. 12- or 6-month-old rats). The reductions in basal ERK and p38 MAPK activities are not due to altered protein levels of these kinases as assessed by Western analysis. Immunohistochemically, no age-related differences in ERK expression and cellular distribution were observed However, cytosolic ERK tended to aggregate in brain neurons of aged rats. In contrast brain tyrosine-phosphorylated PLCgamma1 did not change with age. Activation of ERK in response to EGF or PMA was also reduced in cortical brain slices of 24-month-old rats. These results demonstrate an age-associated selective impairment in the MAPK signaling pathways. Moreover, lifelong caloric restriction completely prevented the age-related decrease in basal brain ERK activity and diminished the age-related reduction of p38 MAPK activity. Taken together, these data indicate that ERK and p38 MAPK signaling pathways are impaired in the aged brain and that lifelong caloric restriction modulates these defects in brain intracellular signaling pathways.
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In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdU-immunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D(28K), microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 +/- 17% (p < 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls.
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Tyrosine nitration is a widely used marker of peroxynitrite (ONOO−) produced from the reaction of nitric oxide with superoxide. Pfeiffer and Mayer (Pfeiffer, S., and Mayer, B. (1998) J. Biol. Chem. 273, 27280–27285) reported that superoxide produced from hypoxanthine plus xanthine oxidase in combination with nitric oxide produced from spermine NONOate did not nitrate tyrosine at neutral pH. They suggested that nitric oxide and superoxide at neutral pH form a less reactive intermediate distinct from preformed alkaline peroxynitrite that does not nitrate tyrosine. Using a stopped-flow spectrophotometer to rapidly mix potassium superoxide with nitric oxide at pH 7.4, we report that an intermediate spectrally and kinetically identical to preformed alkalinecis-peroxynitrite was formed in 100% yield. Furthermore, this intermediate nitrated tyrosine in the same yield and at the same rate as preformed peroxynitrite. Equivalent concentrations of nitric oxide under aerobic conditions in the absence of superoxide did not produce detectable concentrations of nitrotyrosine. Carbon dioxide increased the efficiency of nitration by nitric oxide plus superoxide to the same extent as peroxynitrite. In experiments using xanthine oxidase as a source of superoxide, tyrosine nitration was substantially inhibited by urate formed from hypoxanthine oxidation, which was sufficient to account for the lack of tyrosine nitration previously reported. We conclude that peroxynitrite formed from the reaction of nitric oxide with superoxide at physiological pH remains an important species responsible for tyrosine nitration in vivo.
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The vertebrate brain continues to produce new neurons throughout life. In the rat hippocampus, several thousand are produced each day, many of which die within weeks. Associative learning can enhance their survival; however, until now it was unknown whether new neurons are involved in memory formation. Here we show that a substantial reduction in the number of newly generated neurons in the adult rat impairs hippocampal-dependent trace conditioning, a task in which an animal must associate stimuli that are separated in time. A similar reduction did not affect learning when the same stimuli are not separated in time, a task that is hippocampal-independent. The reduction in neurogenesis did not induce death of mature hippocampal neurons or permanently alter neurophysiological properties of the CA1 region, such as long-term potentiation. Moreover, recovery of cell production was associated with the ability to acquire trace memories. These results indicate that newly generated neurons in the adult are not only affected by the formation of a hippocampal-dependent memory, but also participate in it.
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Fibroblast growth factor-2 (FGF-2) promotes proliferation of neuroprogenitor cells in culture and is up-regulated within brain after injury. Using mice genetically deficient in FGF-2 (FGF-2(-/-) mice), we addressed the importance of endogenously generated FGF-2 on neurogenesis within the hippocampus, a structure involved in spatial, declarative, and contextual memory, after seizures or ischemic injury. BrdUrd incorporation was used to mark dividing neuroprogenitor cells and NeuN expression to monitor their differentiation into neurons. In the wild-type strain, hippocampal FGF-2 increased after either kainic acid injection or middle cerebral artery occlusion, and the numbers of BrdUrd/NeuN-positive cells significantly increased on days 9 and 16 as compared with the controls. In FGF-2(-/-) mice, BrdUrd labeling was attenuated after kainic acid or middle cerebral artery occlusion, as was the number of neural cells colabeled with both BrdUrd and NeuN. After FGF-2(-/-) mice were injected intraventricularly with a herpes simplex virus-1 amplicon vector carrying FGF-2 gene, the number of BrdUrd-labeled cells increased significantly to values equivalent to wild-type littermates after kainate seizures. These results indicate that endogenously synthesized FGF-2 is necessary and sufficient to stimulate proliferation and differentiation of neuroprogenitor cells in the adult hippocampus after brain insult.
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Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of protein kinases and phosphorylation of their downstream effectors plays a major role. Recent findings in our laboratory have shown a requirement for the mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to test the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperitoneally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatial learning, we administered SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platform compared with vehicle-treated controls and also failed to use a selective search strategy during subsequent probe trials in which the platform was removed. These impairments cannot be attributed to nonspecific effects of the drug during the training phase; no deficit was seen in the visible platform task, and injection of SL327 following training produced no effect on the performance of these mice in the hidden platform task. These findings indicate that the MAPK cascade is required for spatial and contextual learning in mice.
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Long-term potentiation (LTP) of synaptic activity is by far the most popular and widely researched model of synaptic plastic changes that might occur during learning. Numerous recent reports, however, have not found a correlation between the inducibility of LTP in the hippocampus and the ability of animals to learn hippocampus-dependent tasks. For example, some experiments with gene deletion (knockout) mice strains have shown that in some strains LTP is not inducible in the dentate gyrus, in area CA3, or CA1, but the animals are still able to learn spatial tasks. This apparent mismatch has rejuvenated the discussion concerning whether LTP is a good model for mechanisms that underlie memory formation in the nervous system. This review analyzes the conditions under which LTP is induced or learning takes place and suggests reasons for the mismatches that can occur and what we can learn from them. High-frequency stimulation protocols and in vitro assays cannot be seen to resemble natural firing patterns or conditions found in the brain. More physiological experimental conditions, especially in vivo recording in awake animals, could lead the way to the development of improved models of learning mechanisms that better correlate with learning abilities of animals. J. Neurosci. Res. 58:62–75, 1999. © 1999 Wiley-Liss, Inc.
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The syndrome associated with lack of growth hormone (GH) in adults can be reversed by treatment with recombinant human GH (rhGH) with apparently beneficial clinical effects. This syndrome is strikingly similar to the characteristics of normal older adults which are known as the somatopause. GH secretion and insulin-like growth factor I levels are reduced in healthy older people and it has been suggested that the somatopause is an age-related GH deficiency state.This review describes the physiological control of GH secretion in adults and seeks an explanation for the age-related decline, considering the impact of other factors such as nutrition and mobility, and particularly whether exercise offers a physiological approach to changing both the GH decline and the somatopause. The benefits and side-effects of treatment with rhGH for normal older people or older patients facing catabolic stresses are reviewed together with alternative approaches to stimulate GH such as GH-releasing hormone and the new pharmaceutical GH secretagogues.
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A stereological method for obtaining estimates of the total number of neurons in five major subdivisions of the rat hippocampus is described. The new method, the optical fractionator, combines two recent developments in stereology: a three-dimensional probe for counting neuronal nuclei, the optical disector, and a systematic uniform sampling scheme, the fractionator. The optical disector results in unbiased estimates of neuron number, i.e., estimates that are free of assumptions about neuron size and shape, are unaffected by lost caps and overprojection, and approach the true number of neurons in an unlimited manner as the number of samples is increased. The fractionator involves sampling a known fraction of a structural component. In the case of neuron number, a zero dimensional quantity, it provides estimates that are unaffected by shrinkage before, during, and after processing of the tissue. Because the fractionator involves systematic sampling, it also results in highly efficient estimates. Typically only 100-200 neurons must be counted in an animal to obtain a precision that is compatible with experimental studies. The methodology is compared with those used in earlier works involving estimates of neuron number in the rat hippocampus and a number of new stereological methods that have particular relevance to the quantitative study of the structure of the nervous system are briefly described in an appendix.
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The purpose of the present investigation was to examine the topographical organization of efferent projections from the cytoarchitectonic divisions of the mPFC (the medial precentral, dorsal anterior cingulate and prelimbic cortices). We also sought to determine whether the efferents from different regions within the prelimbic division were organized topographically. Anterograde transport of Phaseolus vulgaris leucoagglutinin was used to examined the efferent projections from restricted injection sites within the mPFC. Major targets of the prelimbic area were found to include prefrontal, cingulate, and perirhinal cortical structures, the dorsomedial and ventral striatum, basal forebrain nuclei, basolateral amygdala, lateral hypothalamus, mediodorsal, midline and intralaminar thalamic nuclei, periaqueductal gray region, ventral midbrain tegmentum, laterodorsal tegmental nucleus, and raphe nuclei. Previously unreported projections of the prelimbic region were also observed, including efferents to the anterior olfactory nucleus, the piriform cortex, and the pedunculopontine tegmental‐cuneiform region. A topographical organization governed the efferent projections from the prelimbic area, such that the position of terminal fields within target structures was determined by the rostrocaudal, dorsoventral, and mediolateral placement of the injection sites. Efferent projections from the medial precentral and dorsal anterior cingulate divisions (dorsomedial PFC) were organized in a similar topographical fashion and produced a pattern of anterograde labeling different from that seen with prelimbic injection sites. Target structures innervated primarily by the dorsomedial PFC included certain neocortical fields (the motor, somatosensory, and visual cortices), the dorsolateral striatum, superior colliculus, deep mesencephalic nucleus, and the pontine and medullary reticular formation. Previously unreported projections to the paraoculomotor central gray area and the mesencephalic trigeminal nucleus were observed following dorsomedial PFC injections. These results indicate that the efferent projections of the mPFC are topographically organized within and across the cytoarchitectonic divisions of the medial wall cortex. The significance of topographically organized and restricted projections of the rat mPFC is discussed in light of behavioral and physiological studies indicating functional heterogeneity of this region.
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Long-term potentiation (LTP) in the dentate gyrus of the anaesthetized rat is associated with a persistent increase in the concentration of glutamate in the extracellular compartment. At the in vitro level, this is mirrored by an increase in the ability of slices or synaptosomes from potentiated tissue to release glutamate in response to a depolarizing stimulus. In both cases, the activity-induced enhancement of glutamate release is dependent on the activation of the NMDA receptor. A similar increase in glutamate release in vitro is observed in the dentate gyrus prepared from rats trained in a variety of learning tasks, including classical conditioning and the Morris water maze. These results are consistent with the hypothesis that similar presynaptic mechanisms are engaged in LTP and learning.
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New evidence indicates that neural activity regulates the expression of trophic factors in the brain but regulation of these molecules by select aspects of behaviour remains solely a fascinating possibility. We report that following training in the Morris water maze, a spatial memory task, the hippocampus and cerebellum of learning rats exhibited an increase in basic fibroblast growth factor messenger RNA. Basic fibroblast growth factor messenger RNA levels were higher during the learning of the task and decreased once asymptotic performance was reached, suggesting an involvement of basic fibroblast growth factor in learning/memory. An active control group, which exercised for the same time as the learning group but the spatial learning component of the task was minimized, exhibited a minor increase in basic fibroblast growth factor messenger RNA. The intensification of the physical activity component of the task by massed or intensive training resulted in greater increases in basic fibroblast growth factor messenger RNA for both learning and yoked groups, but levels of basic fibroblast growth factor messenger RNA in the learning group remained higher than yoked only in the cerebellum. Changes in basic fibroblast growth factor were accompanied by an increase in astrocyte density in the hippocampus in agreement with described roles of basic fibroblast growth factor in astrocyte proliferation/reactivity. Results suggest that learning potentiates the effects of physical activity on trophic factor induction in select brain regions. Trophic factor involvement in behaviour may provide a molecular basis for the enhanced cognitive function associated with active lifestyles, and guide development of strategies to improve rehabilitation and successful ageing.
Article
New neurons are continuously born in the dentate gyrus of the adult mouse hippocampus, and regulation of adult neurogenesis is influenced by both genetic and environmental determinants. Mice of the 129/SvJ strain have significantly less hippocampal neurogenesis than other inbred mouse strains [1] and do not perform well in learning tasks. Here, the impact of environmental stimuli on brain plasticity during adulthood of 129/SvJ mice was studied using 'enriched environments' where mice receive complex inanimate and social stimulation [2,3]. In contrast to our earlier reports on mice of the C57BL/6 strain - which are competent in learning tasks and in which environmental stimulation did not influence cell proliferation [4,5] - environmentally stimulated 129/SvJ mice were found to have twice as many proliferating cells in the dentate gyrus compared with mice in standard housing. Environmental stimulation fostered the survival of newborn cells in 129/SvJ mice; this effect had also been seen in C57BL/6 mice. Phenotypic analysis of the surviving cells revealed that environmental stimulation resulted in 67% more new neurons. In combination with our earlier results, these data indicate a differential impact of inheritable traits on the environmental regulation of adult hippocampal neurogenesis. In addition, we observed behavioral changes in environmentally stimulated 129/SvJ mice.