ABSTRACT
On exploratory class missions, astronauts will be exposed to a range of heavy particles which vary in linear energy transfer (LET). Previous research has shown a direct relationship between particle LET and cognitive performance such that, as particle LET decreases the dose needed to affect cognitive performance also decreases. Because a significant portion of the total dose experienced by astronauts may be expected to come from exposure to low LET 4He particles, it would be important to establish the threshold dose of 4He particles that can produce changes in cognitive performance. The results indicated that changes in neuronal function and cognitive performance could be observed following both head-only and whole-body exposures to 4He particles at doses as low as 0.01-0.025 cGy. These results, therefore, suggest the possibility that astronauts on exploratory class missions may be at a greater risk for HZE-induced deficits than previously anticipated.
Subject(s)
Behavior, Animal/radiation effects , Cognition/physiology , Head/radiation effects , Helium/administration & dosage , Neurons/physiology , Whole-Body Irradiation/methods , Animals , Cognition/radiation effects , Male , Neurons/radiation effects , Rats , Rats, Sprague-DawleyABSTRACT
Daily supplementation of blueberries (BBs) reverses age-related deficits in behavior in aged rats. However, it is unknown whether BB is more beneficial to one subset of the population dependent on baseline cognitive performance and inflammatory status. To examine the effect of individual differences on the efficacy of BB, aged rats (17 months old) were assessed for cognition in the radial arm water maze (RAWM) and divided into good, average, and poor performers based on navigation errors. Half of the rats in each cognitive group were then fed a control or a 2% BB diet for 8 weeks before retesting. Serum samples were collected, pre-diet and post-diet, to assess inflammation. Latency in the radial arm water maze was significantly reduced in the BB-fed poor performers (p < .05) and preserved in the BB-fed good performers. The control-fed good performers committed more working and reference memory errors in the post-test than pretest (p < .05), whereas the BB-fed good performers showed no change. An in vitro study using the serum showed that BB supplementation attenuated lipopolysaccharide (LPS)-induced nitrite and tumor necrosis factor-alpha, and cognitive performance was associated with innate anti-inflammatory capability. Therefore, consumption of BB may reverse some age-related deficits in cognition, as well as preserve function among those with intact cognitive ability.
Subject(s)
Aging , Anti-Inflammatory Agents , Antioxidants , Blueberry Plants , Cognition , Diet Therapy/methods , Aging/immunology , Aging/psychology , Animals , Anti-Inflammatory Agents/immunology , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Behavior, Animal , Cognition/drug effects , Cognition/physiology , Maze Learning , Neuroimmunomodulation/drug effects , Neuroimmunomodulation/physiology , Plants, Medicinal , Rats , Treatment Outcome , Tumor Necrosis Factor-alpha/bloodABSTRACT
Diets supplemented with walnuts have shown to protect brain against oxidative and inflammatory cytotoxicity and promote protective cellular and cognitive function. The current study was undertaken to test the hypothesize that whole walnut extract (WNE) inhibits lipopolysaccharide (LPS)-induced microglial activation by regulating calmodulin (CaM) expression through [Ca2+]i. To test this hypothesis, we used an in vitro model the highly aggressively proliferating immortalized cells, a rat microglial cell line, treated with various concentrations of WNEs. Treatment with WNE (1.5%, 3%, or 6%) induced a slow rise in intracellular calcium in a concentration- and time-dependent manner, and this rise became exaggerated when cells were depolarized with potassium chloride (100 mmol/L). Cells treated with WNE (1%, 3%, or 6%) upregulated CaM protein levels, with 1 hour posttreatment being the peak time, regardless of WNE concentration. Interestingly, this WNE-induced upregulation of CaM was blocked by pretreatment with thapsigargin. Additionally, treatment with WNE (1%, 3%, or 6%) 1 hour prior to LPS treatment was found to be effective in preventing LPS-induced upregulation of inducible nitric oxide synthase expression, upregulation of ionized Ca2+-binding adaptor-1, and downregulation of CaM. These findings suggest that bioactive compounds in walnut are capable of modulating microglial activation through regulation of intracellular calcium and CaM expression. Nutritional interventions using walnuts may be effective in the amelioration of chronic inflammation and neurodegeneration.
Subject(s)
Brain/drug effects , Calcium/metabolism , Calmodulin/metabolism , Juglans , Microglia/drug effects , Nuts , Plant Extracts/pharmacology , Animals , Brain/cytology , Brain/metabolism , Calcium-Binding Proteins/metabolism , Cell Line , Enzyme Inhibitors/pharmacology , Lipopolysaccharides , Microfilament Proteins/metabolism , Microglia/metabolism , Nitric Oxide Synthase Type II/metabolism , Potassium Chloride/pharmacology , Rats , Thapsigargin/pharmacology , Up-RegulationABSTRACT
Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plasticity, brain homeostasis, and maintenance in the central nervous system and is a crucial factor in preserving the cognitive function and repair of damaged brain cells affected by aging and brain disorders. Intrinsic factors such as aging, neuroinflammation, oxidative stress, and brain injury, as well as lifestyle factors such as high-fat and high-sugar diets and alcohol and opioid addiction, negatively affect adult neurogenesis. Conversely, many dietary components such as curcumin, resveratrol, blueberry polyphenols, sulforaphane, salvionic acid, polyunsaturated fatty acids (PUFAs), and diets enriched with polyphenols and PUFAs, as well as caloric restriction, physical exercise, and learning, have been shown to induce neurogenesis in adult brains. Although many of the underlying mechanisms by which nutrients and dietary factors affect adult neurogenesis have yet to be determined, nutritional approaches provide promising prospects to stimulate adult neurogenesis and combat neurodegenerative diseases and cognitive decline. In this review, we summarize the evidence supporting the role of nutritional factors in modifying adult neurogenesis and their potential to preserve cognitive function during aging.
Subject(s)
Aging/physiology , Cognition/physiology , Neurogenesis/physiology , Nutritional Physiological Phenomena/physiology , Adult , Aged , Brain/physiology , Cognitive Dysfunction/physiopathology , Female , Hippocampus/physiology , Humans , Male , Middle Aged , Neurodegenerative Diseases/physiopathologyABSTRACT
The protective effects of anthocyanin-rich blueberries (BB) on brain health are well documented and are particularly important under conditions of high oxidative stress, which can lead to "accelerated aging." One such scenario is exposure to space radiation, consisting of high-energy and -charge particles (HZE), which are known to cause cognitive dysfunction and deleterious neurochemical alterations. We recently tested the behavioral and neurochemical effects of acute exposure to HZE particles such as 56Fe, within 24-48h after exposure, and found that radiation primarily affects memory and not learning. Importantly, we observed that specific brain regions failed to upregulate antioxidant and anti-inflammatory mechanisms in response to this insult. To further examine these endogenous response mechanisms, we have supplemented young rats with diets rich in BB, which are known to contain high amounts of antioxidant-phytochemicals, prior to irradiation. Exposure to 56Fe caused significant neurochemical changes in hippocampus and frontal cortex, the two critical regions of the brain involved in cognitive function. BB supplementation significantly attenuated protein carbonylation, which was significantly increased by exposure to 56Fe in the hippocampus and frontal cortex. Moreover, BB supplementation significantly reduced radiation-induced elevations in NADPH-oxidoreductase-2 (NOX2) and cyclooxygenase-2 (COX-2), and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus and frontal cortex. Overall results indicate that 56Fe particles may induce their toxic effects on hippocampus and frontal cortex by reactive oxygen species (ROS) overload, which can cause alterations in the neuronal environment, eventually leading to hippocampal neuronal death and subsequent impairment of cognitive function. Blueberry supplementation provides an effective preventative measure to reduce the ROS load on the CNS in an event of acute HZE exposure.
Subject(s)
Anthocyanins/administration & dosage , Behavior, Animal/drug effects , Blueberry Plants/chemistry , Iron Radioisotopes/adverse effects , Memory/drug effects , Neuroprotective Agents/administration & dosage , Oxidative Stress/drug effects , Animals , Antioxidants/administration & dosage , Behavior, Animal/radiation effects , Cosmic Radiation/adverse effects , Diet , Frontal Lobe/drug effects , Frontal Lobe/radiation effects , Hippocampus/drug effects , Hippocampus/radiation effects , Learning/drug effects , Learning/radiation effects , Male , Memory/radiation effects , Oxidative Stress/radiation effects , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: Açaí (Euterpe spp.), an exotic palm fruit, has recently emerged as a promising source of natural antioxidants with wide pharmacological and nutritional value. In this study, two different species of açaí pulp extracts, naturally grown in two distinct regions of the Amazon, namely, Euterpe oleracea Mart. (habitat: Brazilian floodplains of the Amazon) and Euterpe precatoria Mart. (habitat: Bolivian Amazon), were studied for their effects on brain health and cognition. METHODS: Neurochemical analyses were performed in critical brain regions associated with memory and cognition of 19-month-old açaí-fed rats, in whom the cognitive benefits of açaí had been established. RESULTS: Results indicated significant reductions (P< 0.05) in prooxidant NADPH-oxidoreductase-2 (NOX2) and proinflammatory transcription factor NF-κB in açaí-fed rats. Measurement of Nrf2 expression, a transcription factor for antioxidant enzymes, and a possible link between oxidative stress, neuroinflammation and autophagy mechanisms, indicated significant overexpression (P<0.005) in the hippocampus and frontal cortex of the açaí-fed rats. Furthermore, significant activation of endogenous antioxidant enzymes GST and SOD were also observed in the açaí-fed animals when compared to control. Analysis of autophagy markers such as p62, phospho-mTOR, beclin1 and MAP1B-LC3 revealed differential expression in frontal cortex and hippocampus, mostly indicating an upregulation in the açaí-fed rats. DISCUSSION: In general, results were more profound for EP than EO in hippocampus as well as frontal cortex. Therefore, an açaí-enriched diet could possibly modulate Nrf2, which is known to modulate the intracellular redox status, thereby regulating the ubiquitin-proteosomal pathway, ultimately affecting cognitive function in the aging brain.
Subject(s)
Diet , Euterpe , Frontal Lobe/drug effects , Hippocampus/drug effects , NF-E2-Related Factor 2/drug effects , Plant Extracts/administration & dosage , Animals , Antioxidants/analysis , Autophagy/drug effects , Cognition/drug effects , Frontal Lobe/chemistry , Frontal Lobe/metabolism , Fruit/chemistry , Hippocampus/chemistry , Hippocampus/metabolism , Inflammation/prevention & control , Male , Memory/drug effects , NADPH Oxidase 2/analysis , NADPH Oxidase 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/physiology , NF-kappa B/analysis , NF-kappa B/antagonists & inhibitors , Oxidation-Reduction , Oxidative Stress/drug effects , Phytotherapy , Rats , Rats, Inbred F344 , Species SpecificityABSTRACT
The shift in equilibrium towards excess reactive oxygen or nitrogen species production from innate antioxidant defenses in brain is a critical factor in the declining neural function and cognitive deficit accompanying age. Previous studies from our laboratory have reported that walnuts, rich in polyphenols, antioxidants, and omega fatty acids such as alpha-linolenic acid and linoleic acid, improve the age-associated declines in cognition and neural function in rats. Possible mechanisms of action of these effects include enhancing protective signaling, altering membrane microstructures, decreasing inflammation, and preventing accumulation of polyubiquitinated protein aggregates in critical regions of the brain. In the current study, we investigated whether the serum collected from aged animals fed with walnut diets (0, 6, and 9%, w/w) would enhance protection on stressed BV-2 microglia in vitro. In the growth medium, fetal bovine serum was substituted with the serum collected from 22-month-old rats fed per protocol for 12 weeks. Walnut diet serum (6 and 9%) significantly attenuated lipopolysaccharide-induced nitrite release compared to untreated control cells and those treated with serum from rats fed 0% walnut diets. The results also indicated a significant reduction in pro-inflammatory tumor necrosis factor-alpha, cyclooxygenase-2, and inducible nitric oxide synthase. These results suggest antioxidant and anti-inflammatory protection or enhancement of membrane-associated functions in brain cells by walnut serum metabolites.
Subject(s)
Aging/blood , Brain/metabolism , Diet , Juglans , Microglia/metabolism , Neuroprotection , Nuts , Animals , Brain/drug effects , Brain/growth & development , Brain/immunology , Cell Line , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Lipopolysaccharides/toxicity , Male , Mice , Microglia/drug effects , Microglia/immunology , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , Oxidative Stress/drug effects , Random Allocation , Rats, Inbred F344 , Serum/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVES: The present study was carried out to determine if lyophilized açaí fruit pulp (genus, Euterpe), rich in polyphenols and other bioactive antioxidant and anti-inflammatory phytochemicals, is efficacious in reversing age-related cognitive deficits in aged rats. METHODS: The diets of 19-month-old Fischer 344 rats were supplemented for 8 weeks with 2% Euterpe oleracea (EO), Euterpe precatoria (EP), or a control diet. Rats were tested in the Morris water maze and then blood serum from the rats was used to assess inflammatory responses of BV-2 microglial cells. RESULTS: After 8 weeks of dietary supplementation with 2% EO or EP, rats demonstrated improved working memory in the Morris water maze, relative to controls; however, only the EO diet improved reference memory. BV-2 microglial cells treated with blood serum collected from EO-fed rats produced less nitric oxide (NO) than control-fed rats. Serum from both EO- and EP-fed rats reduced tumor necrosis factor-alpha (TNF-α). There is a relationship between performance in the water maze and the production of NO and TNF-α by serum-treated BV-2 cells, such that serum from rats with better performance was more protective against inflammatory signaling. DISCUSSION: Protection of memory during aging by supplementation of lyophilized açaí fruit pulp added to the diet may result from its ability to influence antioxidant and anti-inflammatory signaling.
Subject(s)
Cognition/drug effects , Euterpe/chemistry , Microglia/drug effects , Phytotherapy , Plant Preparations/pharmacology , Polyphenols/pharmacology , Animals , Antioxidants/pharmacology , Cells, Cultured , Diet , Dietary Supplements , Male , Maze Learning/drug effects , Memory/drug effects , Microglia/cytology , Nitric Oxide/blood , Rats , Rats, Inbred F344 , Tumor Necrosis Factor-alpha/bloodABSTRACT
Population aging is leading to an increase in the incidence of age-related cognitive dysfunction and, with it, the health care burden of caring for older adults. Epidemiological studies have shown that consumption of fruits, nuts, and vegetables is positively associated with cognitive ability; however, these foods, which contain a variety of neuroprotective phytochemicals, are widely under-consumed. Surprisingly few studies have investigated the effects of individual plant foods on cognitive health but recent clinical trials have shown that dietary supplementation with individual foods, or switching to a diet rich in several of these foods, can improve cognitive ability. While additional research is needed, increasing fruit, nut, and vegetable intake may be an effective strategy to prevent or delay the onset of cognitive dysfunction during aging.
Subject(s)
Cognition Disorders/prevention & control , Cognition , Cognitive Aging , Diet, Healthy , Fruit , Healthy Aging , Nuts , Vegetables , Age Factors , Cognition Disorders/psychology , Humans , Protective Factors , Risk FactorsABSTRACT
High consumption of fruits and vegetables has been associated with reduced risk of debilitating diseases and improved cognition in aged populations. These beneficial effects have been attributed to the phytochemicals found in fruits and vegetables, which have previously been shown to be anti-inflammatory and modulate autophagy. Tart cherries contain a variety of potentially beneficial phytochemicals; however, little research has been done to investigate the effects of tart cherry on the aging brain. Therefore, the purpose of this study was to determine if tart cherry supplementation can improve cognitive and motor function of aged rats via modulation of inflammation and autophagy in the brain. Thirty 19-month-old male Fischer 344 rats were weight-matched and assigned to receive either a control diet or a diet supplemented with 2 % Montmorency tart cherry. After 6 weeks on the diet, rats were given a battery of behavioral tests to assess for strength, stamina, balance, and coordination, as well as learning and working memory. Although no significant effects were observed on tests of motor performance, tart cherry improved working memory of aged rats. Following behavioral testing, the hippocampus was collected for western/densitometric analysis of inflammatory (GFAP, NOX-2, and COX-2) and autophagy (phosphorylated mTOR, Beclin 1, and p62/SQSTM) markers. Tart cherry supplementation significantly reduced inflammatory markers and improved autophagy function. Daily consumption of tart cherry reduced age-associated inflammation and promoted protein/cellular homeostasis in the hippocampus, along with improvements in working memory. Therefore, addition of tart cherry to the diet may promote healthy aging and/or delay the onset of neurodegenerative diseases.
Subject(s)
Aging , Autophagy , Dietary Supplements , Encephalitis/diet therapy , Hippocampus/physiology , Memory, Short-Term , Prunus avium/chemistry , Animals , Behavior Rating Scale , Biomarkers/analysis , Cognition , Male , Maze Learning , Motor Activity , Powders , Rats , Rats, Inbred F344 , Time FactorsABSTRACT
Advanced glycation end products (AGEs) are naturally occurring macromolecules that are formed in vivo by the non-enzymatic modification of proteins, lipids, or nucleic acids by sugar, even in the absence of hyperglycemia. In the diet, AGEs are found in animal products, and additional AGEs are produced when those foods are cooked at high temperatures. Studies have linked AGEs to various age-related physiological changes, including wrinkles, diabetic complications, and neurodegenerative disease, including Alzheimer's disease. Dietary berry fruits have been shown to reduce the severity or slow the progression of many physiological changes and disease pathologies that accompany aging. Emerging evidence has shown that the phytochemicals found in berry fruits exhibit anti-glycative activity. In this review, we briefly summarize the current evidence supporting the neuroprotective anti-glycative activity of berry fruits and their potential to preserve cognitive function during aging.
Subject(s)
Aging , Brain/physiology , Diet , Fruit/metabolism , Alzheimer Disease/prevention & control , Animals , Fruit/chemistry , Glycation End Products, Advanced/antagonists & inhibitors , Humans , Neurodegenerative Diseases/prevention & control , Neuroprotective Agents/chemistryABSTRACT
Although it has been shown that exposure to HZE particles disrupts cognitive performance when tested 2-4 weeks after irradiation, it has not been determined whether exposure to HZE particles acutely affects cognitive performance, i.e., within 4-48 h after exposure. The current experiments were designed to determine the acute effects of exposure to HZE particles ((16)O and (56)Fe) on cognitive performance and whether exposure to HZE particles affected learning or memory, as well as to understand the relationship between acute changes in the levels of NOX2 (a measure of oxidative stress) and COX2 (a measure of neuroinflammation) in specific brain regions and cognitive performance. The results of these studies indicate that the acute effects of radiation exposure on cognitive performance are on memory, not learning. Further, the acute effects of exposure to HZE particles on oxidative stress and neuroinflammation and their relationship to cognitive performance indicate that, although the effects of exposure to both (56)Fe and (16)O are widespread, only changes in specific regions of the brain may be related to changes in cognitive function.
Subject(s)
Cosmic Radiation/adverse effects , Iron Radioisotopes , Learning/radiation effects , Memory/radiation effects , Oxygen Radioisotopes , Animals , Dose-Response Relationship, Radiation , Humans , Learning/physiology , Male , Memory/physiology , Oxidative Stress/radiation effects , RatsABSTRACT
Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 4'-trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and anti-inflammatory signaling and behavioral outcomes.
Subject(s)
Brain/drug effects , Cognition Disorders/drug therapy , Stilbenes/administration & dosage , Aging/drug effects , Aging/metabolism , Aging/psychology , Animals , Antioxidants/administration & dosage , Antioxidants/metabolism , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Brain/metabolism , Cognition Disorders/metabolism , Cognition Disorders/psychology , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/psychology , Resveratrol , Social Behavior Disorders/drug therapy , Social Behavior Disorders/metabolism , Social Behavior Disorders/psychology , Stilbenes/metabolism , Treatment OutcomeABSTRACT
Particles of high energy and charge (HZE particles), which are abundant outside the magnetic field of the Earth, have been shown to disrupt the functioning of neuronal communication in critical regions of the brain. Previous studies with HZE particles, have shown that irradiation produces enhanced indices of oxidative stress and inflammation as well as altered neuronal function that are similar to those seen in aging. Feeding animals antioxidant-rich berry diets, specifically blueberries and strawberries, countered the deleterious effects of irradiation by reducing oxidative stress and inflammation, thereby improving neuronal signaling. In the current study, we examined the effects of exposure to (56)Fe particles in critical regions of brain involved in cognitive function, both 36h and 30 days post irradiation. We also studied the effects of antioxidant-rich berry diets, specifically a 2% blueberry or strawberry diet, fed for 8 weeks prior to radiation as well as 30 days post irradiation. (56)Fe exposure caused significant differential, neurochemical changes in critical regions of the brain, such as hippocampus, striatum, frontal cortex, and cerebellum, through increased inflammation, and increased oxidative stress protein markers. (56)Fe exposure altered the autophagy markers, and antioxidant-rich berry diets significantly reduced the accumulation of p62 in hippocampus, a scaffold protein that co-localizes with ubiquitinated protein at the 30 days post irradiation time-point. Exposure to (56)Fe particles increased the accumulation of disease-related proteins such as PHF-tau in the hippocampus of animals fed the control diet, but not in the irradiated animals fed the blueberry diet. These results indicate the potential protective effects of antioxidant-rich berry diets on neuronal functioning following exposure to HZE particles.
Subject(s)
Blueberry Plants , Brain/radiation effects , Cosmic Radiation/adverse effects , Diet , Fragaria , Iron/adverse effects , Neurons/radiation effects , Animals , Antioxidants/administration & dosage , Antioxidants/metabolism , Apoptosis Regulatory Proteins/metabolism , Autophagy/physiology , Autophagy/radiation effects , Beclin-1 , Brain/physiopathology , Membrane Glycoproteins/metabolism , NADPH Oxidase 2 , NADPH Oxidases/metabolism , Neuroimmunomodulation/physiology , Neuroimmunomodulation/radiation effects , Neurons/physiology , Neuroprotective Agents/administration & dosage , Oxidative Stress/physiology , Oxidative Stress/radiation effects , Peptides/metabolism , Random Allocation , Rats , TOR Serine-Threonine Kinases/metabolism , tau Proteins/metabolismABSTRACT
OBJECTIVES: Oxidative damage to lipids, proteins, and nucleic acids in the brain often causes progressive neuronal degeneration and death that are the focal traits of chronic and acute pathologies, including those involving cognitive decline. The aim of this study was to investigate the specific effects of both Euterpe oleracea and Euterpe precatoria açaí fruit pulp on restoring stressor-induced calcium dysregulation, stunted growth of basal dendrites, and autophagy inhibition using embryonic hippocampal and HT22 hippocampal neurons. METHODS: Water-soluble whole fruit pulp extracts from two açaí species were applied to rat primary neurons and HT22 hippocampal neurons with varied time and concentrations. Recovery of neurons from dopamine-induced Ca(2+) dysregulation was measured by live cell imaging using fluorescent microscopy. The effect of açaí fruit pulp extracts on neurons following chemically-induced autophagy inhibition was measured using both immunofluorescence and immunohistochemical techniques. RESULTS: It has been postulated that at least part of the loss of cognitive function in aging may depend on a dysregulation in calcium ion (Ca(2+)) homeostasis and a loss of autophagy function in the brain, which affects numerous signaling pathways and alters protein homeostasis. In the present study, polyphenol-rich fruit pulp extracts from two species of açaí, Euterpe precatoria and Euterpe oleracea, when applied to rat hippocampal primary neuronal cells (E18), caused a significant (P < 0.05) recovery of depolarized brain cells from dopamine-induced Ca(2+) influx. Autophagy, a protein homeostasis mechanism in brain, when blocked by known inhibitors such as bafilomycin A1 or wortmannin, caused a significant reduction in the growth of primary basal dendrites in rodent primary hippocampal neurons and significant accumulation of polyubiquitinated proteins in mouse HT22 hippocampal neurons in culture. However, pretreatment with açaí extracts up to 1 mg/mL significantly increased the length of basal dendrites and attenuated the inhibitor-induced autophagy dysfunction. Açaí extracts activated the phosphorylation of mammalian target of rapamycin, increased the turnover of autophagosomes and MAP1 B LC3-II, and decreased accumulation of LC3-ubiquitin binding P62/SQSTM1. CONCLUSION: Although the polyphenol profile of Euterpe precatoria showed substantially higher concentrations of major flavonoids han Euterpe oleracea, the relative effects were essentially similar for both species. The study adds to growing evidence that supports the putative health effects of açaí fruit species on brain cells.
Subject(s)
Autophagy/drug effects , Brain/drug effects , Calcium/metabolism , Cognition Disorders/metabolism , Euterpe/chemistry , Oxidative Stress/physiology , Polyphenols/pharmacology , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Brain/cytology , Brain/metabolism , Cell Line , Cognition Disorders/drug therapy , Dendrites/drug effects , Dopamine , Flavonoids/analysis , Flavonoids/pharmacology , Flavonoids/therapeutic use , Fruit/chemistry , Homeostasis , Mice , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Polyphenols/therapeutic use , Proteins/metabolism , Rats, Sprague-Dawley , Signal Transduction , Species SpecificityABSTRACT
Because of the combination of population growth and population aging, increases in the incidence of chronic neurodegenerative disorders have become a societal concern, both in terms of decreased quality of life and increased financial burden. Clinical manifestation of many of these disorders takes years, with the initiation of mild cognitive symptoms leading to behavioral problems, dementia and loss of motor functions, the need for assisted living, and eventual death. Lifestyle factors greatly affect the progression of cognitive decline, with high-risk behaviors including unhealthy diet, lack of exercise, smoking, and exposure to environmental toxins leading to enhanced oxidative stress and inflammation. Although there exists an urgent need to develop effective treatments for age-related cognitive decline and neurodegenerative disease, prevention strategies have been underdeveloped. Primary prevention in many of these neurodegenerative diseases could be achieved earlier in life by consuming a healthy diet, rich in antioxidant and anti-inflammatory phytochemicals, which offers one of the most effective and least expensive ways to address the crisis. English walnuts (Juglans regia L.) are rich in numerous phytochemicals, including high amounts of polyunsaturated fatty acids, and offer potential benefits to brain health. Polyphenolic compounds found in walnuts not only reduce the oxidant and inflammatory load on brain cells but also improve interneuronal signaling, increase neurogenesis, and enhance sequestration of insoluble toxic protein aggregates. Evidence for the beneficial effects of consuming a walnut-rich diet is reviewed in this article.
Subject(s)
Aging , Brain Diseases/prevention & control , Brain/physiology , Juglans , Neurodegenerative Diseases/prevention & control , Aged , Brain Diseases/diet therapy , Brain Diseases/metabolism , Humans , Neurodegenerative Diseases/diet therapy , Neurodegenerative Diseases/metabolismABSTRACT
An increase in the aggregation of misfolded/damaged polyubiquitinated proteins has been the hallmark of many age-related neurodegenerative diseases. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased oxidative and inflammatory stresses. Walnuts, rich in omega fatty acids, have been shown to improve memory, cognition and neuronal effects related to oxidative stress (OS) and inflammation (INF) in animals and human trials. The current study found that feeding 19-month-old rats with a 6% or 9% walnut diet significantly reduced the aggregation of polyubiquitinated proteins and activated autophagy, a neuronal housekeeping function, in the striatum and hippocampus. Walnut-fed animals exhibited up-regulation of autophagy through inhibiting phosphorylation of mTOR, up-regulating ATG7 and Beclin 1, and turnover of MAP1BLC3 proteins. The clearance of polyubiquitinated protein aggregates such as p62/SQSTM1 was more profound in hippocampus, a critical region in the brain involved in memory and cognitive performance, than striatum. The clearance of ubiquitinated aggregates was in tandem with significant reductions in OS/INF, as indicated by the levels of P38-MAP kinase and phosphorylations of nuclear factor kappa B and cyclic AMP response element binding protein. The results demonstrate the effectiveness of a walnut-supplemented diet in activating the autophagy function in brain beyond its traditionally known antioxidant and anti-inflammatory benefits.
Subject(s)
Brain/drug effects , Diet , Juglans , Nuts , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Autophagy/drug effects , Autophagy-Related Protein 7 , Beclin-1 , Brain/metabolism , Cognition/drug effects , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Fatty Acids, Unsaturated/administration & dosage , Hippocampus/drug effects , Hippocampus/metabolism , Inflammation/prevention & control , Male , Memory/drug effects , NF-kappa B/genetics , NF-kappa B/metabolism , Oxidative Stress/drug effects , Phosphorylation/drug effects , Rats , Rats, Inbred F344 , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Ubiquitin-Activating Enzymes/genetics , Ubiquitin-Activating Enzymes/metabolism , Ubiquitinated Proteins/genetics , Ubiquitinated Proteins/metabolism , Up-Regulation , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismSubject(s)
Aging , Brain/metabolism , Cognitive Dysfunction/prevention & control , Diet , Fruit , Memory Disorders/prevention & control , Neurons/metabolism , Animals , Antioxidants/administration & dosage , Antioxidants/therapeutic use , Brain/growth & development , Fruit/chemistry , Health Promotion , Humans , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/therapeutic use , Oxidative StressABSTRACT
Parkinson's disease (PD) is characterized pathologically by the formation of ubiquitin and α-synuclein (α-syn)-containing inclusions (Lewy bodies), dystrophic dopamine (DA) terminals, and degeneration of midbrain DA neurons. The precise molecular mechanisms underlying these pathological features remain elusive. Accumulating evidence has implicated dysfunctional autophagy, the cell self-digestion and neuroprotective pathway, as one of the pathogenic systems contributing to the development of idiopathic PD. Here we characterize autophagy-deficient mouse models and provide in vivo evidence for the potential role that impaired autophagy plays in pathogenesis associated with PD. Cell-specific deletion of essential autophagy gene Atg7 in midbrain DA neurons causes delayed neurodegeneration, accompanied by late-onset locomotor deficits. In contrast, Atg7-deficient DA neurons in the midbrain exhibit early dendritic and axonal dystrophy, reduced striatal dopamine content, and the formation of somatic and dendritic ubiquitinated inclusions in DA neurons. Furthermore, whole-brain-specific loss of Atg7 leads to presynaptic accumulation of α-syn and LRRK2 proteins, which are encoded by two autosomal dominantly inherited PD-related genes. Our results suggest that disrupted autophagy may be associated with enhanced levels of endogenous α-syn and LRRK2 proteins in vivo. Our findings implicate dysfunctional autophagy as one of the failing cellular mechanisms involved in the pathogenesis of idiopathic PD.
Subject(s)
Autophagy/physiology , Dopaminergic Neurons/pathology , Ephrin-B1/metabolism , Nerve Degeneration/pathology , Presynaptic Terminals/metabolism , alpha-Synuclein/metabolism , Animals , Autophagy/genetics , Autophagy-Related Protein 5 , Autophagy-Related Protein 7 , Brain/pathology , Cells, Cultured , Chromatography, High Pressure Liquid/methods , Dendrites/pathology , Disease Models, Animal , Dopamine/metabolism , Embryo, Mammalian , Fibroblasts/metabolism , Gene Expression Regulation/genetics , Inclusion Bodies/genetics , Inclusion Bodies/pathology , Intermediate Filament Proteins/genetics , Intermediate Filament Proteins/metabolism , Mice , Mice, Transgenic , Microtubule-Associated Proteins/deficiency , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Motor Activity/genetics , Movement Disorders/genetics , Nerve Degeneration/etiology , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nestin , Presynaptic Terminals/pathology , Presynaptic Terminals/ultrastructure , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism , Ubiquitin/metabolismABSTRACT
Age-related diseases of the brain compromise memory, learning, and movement and are directly linked with increases in oxidative stress and inflammation. Previous research has shown that supplementation with berries can modulate signaling in primary hippocampal neurons or BV-2 mouse microglial cells. Because of their high polyphenolic content, fruit pulp fractions of açai ( Euterpe oleracea Mart.) were explored for their protective effect on BV-2 mouse microglial cells. Freeze-dried açai pulp was fractionated using solvents with different polarities and analyzed using HPLC for major anthocyanins and other phenolics. Fractions extracted using methanol (MEOH) and ethanol (ETOH) were particularly rich in anthocyanins such as cyanidin, delphinidin, malvidin, pelargonidin, and peonidin, whereas the fraction extracted using acetone (ACE) was rich in other phenolics such as catechin, ferulic acid, quercetin, resveratrol, and synergic and vanillic acids. Studies were conducted to investigate the mitigating effects of açai pulp extracts on lipopolysaccharide (LPS, 100 ng/mL) induced oxidative stress and inflammation; treatment of BV-2 cells with acai fractions resulted in significant (p < 0.05) decreases in nitrite production, accompanied by a reduction in inducible nitric oxide synthase (iNOS) expression. The inhibition pattern was emulated with the ferulic acid content among the fractions. The protection of microglial cells by açai pulp extracts, particularly that of MEOH, ETOH, and ACE fractions, was also accompanied by a significant concentration-dependent reduction in cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (p38-MAPK), tumor necrosis factor-α (TNFα), and nuclear factor κB (NF-κB). The current study offers valuable insights into the protective effects of açai pulp fractions on brain cells, which could have implications for improved cognitive and motor functions.