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REVIEW ARTICLE
Year : 2012  |  Volume : 2  |  Issue : 3  |  Page : 185-197

Effects of dietary derived antioxidants on the central nervous system


Australasian Research Institute, Sydney Adventist Hospital, Wahroonga, NSW, 2076, Australia, Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia

Date of Web Publication8-Aug-2012

Correspondence Address:
Ross S Grant
185 Fox Valley Rd, Wahroonga, NSW 2076
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.99470

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   Abstract 

Oxidative stress refers to the pathological state in which the production of reactive oxygen and nitrogen species is increased above the body's antioxidant defense and repair capacity. Functional damage, with subsequent cell death, may occur as a consequence of the oxidization of cellular components, such as, proteins, lipids, and nuclear material. Several features of the brain suggest that it is particularly vulnerable to oxidative stress. The brain possesses the highest oxygen metabolic rate of any organ and is continually exposed to excitatory amino acids and neurotransmitters. The brain also contains a high concentration of oxidizable polyunsaturated fatty acids, but has comparatively limited endogenous antioxidant defense mechanisms. Accumulating evidence indicates that dietary-derived antioxidants may mitigate the development of neurodegenerative diseases, with a number of recent studies focusing on the potential therapeutic benefits of supplementation. This review focuses on our current knowledge of how some of these diet-derived antioxidants may exert their neuroprotective effects.

Keywords: Antioxidants, bioavailability, diet, neurodegeneration, oxidative stress


How to cite this article:
Guest JA, Grant RS. Effects of dietary derived antioxidants on the central nervous system. Int J Nutr Pharmacol Neurol Dis 2012;2:185-97

How to cite this URL:
Guest JA, Grant RS. Effects of dietary derived antioxidants on the central nervous system. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Jul 16];2:185-97. Available from: http://www.ijnpnd.com/text.asp?2012/2/3/185/99470


   Introduction Top


Reactive oxygen species (ROS) and reactive nitrogen species (RNS), commonly called free radicals, are produced by the human body in the course of normal metabolism, by a variety of mechanisms. The primary source of ROS is generally agreed to be the leakage of electrons to ground state oxygen from early components of the mitochondrial electron transport chain, resulting in the production of the superoxide radical (O 2•- ) [Figure 1]. [1] Under normal conditions free radicals can be beneficial to the body, being used for a number of physiological functions. Although there is always the potential for damage, this is kept in check by an array of intricately connected antioxidant defense and repair systems. However, under conditions of reduced antioxidant capacity or excess production of ROS, damage to important molecules including lipids, proteins, and DNA can occur, which may ultimately lead to cell death via apoptosis or necrosis.
Figure 1: Neuronal production and mitigation of reactive oxygen and nitrogen species

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The term 'oxidative stress' describes a significant imbalance between the formation of free radicals and the bodies' antioxidant defense and repair systems. It was first defined by Sies, in 1985, as 'an imbalance between oxidants and antioxidants in favor of oxidants.' [2] Accumulating evidence supports the role of oxidative stress in the development of a number of lifestyle diseases, including neurodegenerative disorders, such as, Alzheimer's disease (AD), [3],[4] Parkinson's disease (PD), [5] and amyotrophic lateral sclerosis (ALS). [6] Indeed the brain is particularity vulnerable to oxidative damage, with inadequate antioxidant defenses, to successfully repel an increase in oxidative burden.

Sensitivity of the brain to oxidative stress

A collection of features present in the central nervous system contribute to the brain's vulnerability to oxidative stress: [7]

  1. The brain is one of the most energy-consuming organs and is entirely dependent on aerobic metabolism, utilizing oxygen and glucose to generate Adenosine-5'-triphosphate (ATP). In order to fulfill its high energy needs the brain utilizes approximately 20% of basal oxygen (O 2 ) consumption, despite accounting for only 2% of the bodies' total mass. [8],[9] Consequently a large amount of oxygen is processed per unit of tissue, producing favorable conditions for the production of ROS.
  2. Glutamate is the principal neurotransmitter in the central nervous system. Under normal physiological conditions the concentration of glutamate in the synaptic cleft can reach 1 mM. [10] Higher extracellular levels have been shown to be neurodestructive, through an excitotoxic process. [11],[12] During excitotoxicity, sustained activation of glutamate receptors causes an influx of intracellular Ca 2+ via N0-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and voltage-gated Ca2+ channels. [13],[14],[15] The excessive influx of calcium increases ROS production via different mechanisms, including nitric oxide (NO) synthesis and mitochondrial dysfunction [Figure 1]. [16] Glutamate excitotoxicity has been suggested as a cause of neuronal dysfunction in a number of neurodegenerative diseases. [17],[18]
  3. Excluding glutamate and glycine, a number of neurotransmitters autoxidize. For example serotonin, norepinephrine, dopamine, and its precursor L-3, 4-dihydroxyphenylalanine react with O 2 resulting in the formation of both O 2•- , quinones and semiquinones. This can deplete glutathione (GSH) levels in the surrounding tissue, increasing the vulnerability to an oxidative attack. [19] The autoxidation of dopamine is thought to partially explain the loss of dopaminergic neurons in senescence and in Parkinson's disease. [20]
  4. The average adult brain also contains approximately 60 mg of non-heme iron. [21] Within a healthy brain, the majority of iron is bound to ferritin and some to hemosiderin. [22] However, damage to the brain results in the liberation of iron ions in forms that are able to catalyze free radical reactions via Fenton chemistry. [21] In many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, excess iron is commonly observed in the brain regions associated with cell loss and functional decline. [23],[24] Damage associated with too much free iron is presumably due to the direct relationship between iron and oxidative injury.
  5. Neuronal membranes also contain high concentrations of polyunsaturated fatty acid (PUFA) side chains that are vulnerable to oxidation. [25] Docosahexaenoic acid (DHA), the principal long-chain PUFA in the brain, is particularity vulnerable to oxidation due to the presence and location of its six double bonds. [26] During phases of increased oxidative stress, DHA may be nonenzymatically oxidized into prostaglandin-like A4-, D4-, E4-, F4-, and J4-neuroprostanes. These compounds, formed without cyclooxygenase mediation, trigger the production of additional ROS that are free to oxidize the plasma membranes nearby. [25],[4]
  6. Activation of the brain's resident immunocompetent cells, the microglia, may also contribute to neurodegeneration. Microglia represent 10 to 20% of the total population of glial cells in the adult CNS. [27] They are located in the parenchyma, behind the blood-brain barrier and assist in the removal of cellular debris and foreign neuronal threats. Their activation is controlled by neuronal soluble mediators and cell-to-cell contact. [28] However, once activated, microglia produce a range of ROS, including superoxide and hydrogen peroxide. They also excrete inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interlukin-1 (IL-1), and interlukin-6 (IL-6). These cytokines can magnify ROS production by activating additional microglia and other CNS cells to produce more ROS as well as nitric oxide synthase (iNOS), and subsequently peroxynitrite, increasing the potential for oxidative stress within the brain.


Endogenous antioxidant defense systems within the brain

Fortunately, to help detoxify ROS, powerful antioxidant enzymes exist within all the cells, including neurons. The three main categories of antioxidant enzymes are catalases, superoxide dismutases (SOD), and glutathione peroxidases (GPx). [29] In addition to these well-described antioxidant enzymes, a novel class of peroxide scavengers, termed peroxiredoxins, have recently been isolated, and are thought to be the chief H 2 O 2 removal system within the brain. [30] Together these antioxidant enzymes work to prevent ROS-mediated cellular damage [Figure 1]. However, the antioxidant defense systems in the brain itself appear to be relatively modest. In particular, most regions within the brain, apart from the hypothalamus and substantia nigra, contain comparably low levels of catalase. In addition, any catalase that is present, is located within microperoxisomes and cannot mitigate the H 2 O 2 produced in other subcellular compartments [Figure 1]. [31]

Thus if the production of ROS increases too quickly, the endogenous antioxidant defense system of the brain appears to be easily overwhelmed. In order to maintain tight homeostatic control of ROS and prevent oxidative stress, external supplementation with dietary antioxidants or herbal preparations may prove useful. [32]

Food derived antioxidants within the brain

Accumulating evidence suggests that the dietary intake of antioxidants such as vitamin E, ascorbate, carotenoids, and plant phenols, either through supplementation or the ingestion of various foods, may reduce the risk of some neurodegenerative diseases. Even though their precise mechanism(s) of action are still largely unknown, the neuroprotective effects of these plant-derived phytochemicals are thought to be mediated largely through antioxidant and anti-inflammatory actions.

Vitamin E

Vitamin E is the generic term given to describe a family of eight lipophilic tocotrienols and tocopherols. Of these, α-tocopherol is the most studied, presumably due to its high bioavailability, with the body preferentially absorbing this form.[33] Vitamin E is considered to be one of the principle dietary-derived antioxidants [Table 1], inhibiting lipid peroxidation by scavenging peroxyl radicals more quickly than the rate at which these radicals can react with the membrane proteins or adjacent fatty acid side chains. [34] However, while the antioxidant capacity of vitamin E to scavenge peroxyl radicals and subsequently arrest chain reactions is well-described, [35],[36],[37] the precise action of vitamin E in the CNS remains heavily debated.
Table 1: Dietary sources of antioxidants

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By neutralizing the effects of oxygen and peroxide-free radicals, vitamin E appears to protect the CNS cell membranes from lipid peroxidation. [38],[39],[40] For example, Nishio et al., observed that vitamin E supplementation in young rats significantly reduced the production of F2-isoprostanes, even after hyperoxia. [39] However, data from recent studies suggest that the antioxidant action of vitamin E is not solely responsible for its neuroprotective capacity, with a wide range of molecular actions implicated. For instance, in the brain tissue, vitamin E has been seen to increase the level of glutathione and the activity of various endogenous antioxidant enzymes, including SOD, GPx, and catalase. [40] Using neuronal cells, Crouzin et al., demonstrated that vitamin E can provide protection against oxidative damage via genomic effects, negatively modulating TRPV1 channels and subsequently inhibiting Fe 2+ ion-mediated toxicity and Ca 2+ influx. [41] As reviewed by Singh et al., in 2007, [42] vitamin E can also act as an anti-inflammatory agent. As inflammation is associated with many neurodegenerative diseases [43] and oxidative stress, these anti-inflammatory properties may be an effective arsenal against degenerative changes.

A number of in vivo studies also provide a convincing case for the protective role of vitamin E in the CNS. Low blood concentrations of vitamin E have been linked to poor memory performance and cognitive functioning in the elderly. [44] Likewise reduced levels of vitamin E in the plasma have been associated with vascular dementia and Alzheimer's disease. [45] Supporting these observations are longitudinal studies that report a reduced risk in the development of dementia or cognitive impairment among participants who consume high levels of vitamin E or take vitamin E and C supplements. [46],[47],[48],[49] More convincingly a randomized control trial (RCT) involving Alzheimer's disease patients, found that the consumption of 2000 IU of vitamin E daily for two years significantly reduced the occurrence of primary outcomes, including severe dementia, institutionalization, and death [Table 2]. [50]
Table 2: Effectiveness of antioxidants on cognitive performance in randomized control studies

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In spite of the evidence supporting vitamin E supplementation in the prevention of neurodegeneration a number of studies have not confirmed these findings. [51],[52],[53] For example in an RCT involving participants diagnosed with mild cognitive impairment (MCI), Petersen et al., observed that even early intervention with vitamin E failed to improve cognition [Table 2]. [54] Later in the Women's Health Study, involving 6377 participants, Kang et al., demonstrated that compared to the control, even long-term supplementation with 600 IU of vitamin E per day did not provide cognitive benefits among generally healthy older women [Table 2]. [55]

This inconsistency in the literature may be explained in part by the capacity of vitamin E to also exert pro-oxidant effects. Evidence suggests that the action of vitamin E either as a pro-oxidant or antioxidant is influenced by oxidative conditions. [56],[57] Under extreme oxidative conditions, where the level of free radicals outweighs the concentration of the vitamin, vitamin E has consistently been shown to inhibit oxidative damage. Conversely in mild oxidative conditions, vitamin E can function as a pro-oxidant, increasing oxidation via tocopherol-mediated peroxidation. [58]

It has recently been determined that high-dose vitamin E supplementation is not as safe as previously thought. In 2005, Miller et al., conducted a meta-analysis in which 19 trials were reviewed. [59] Vitamin E doses in excess or equal to 400 IU / day were defined as high. For the 11 high dose trials reviewed (in which nine reported an increased risk of mortality), the risk ratio for all-cause mortality was 1.04 (CI, 1.01 − 1.07; P = 0.035). In comparison the risk ratio for low dosage trials was 0.98 (CI, 0.96 − 1.01; P > 0.2). For doses greater than 150 IU / day, the risk for all-cause mortality was shown to increase in a dose-dependent manner.

In addition to the capacity of vitamin E to exert pro-oxidant effects, long-term supplementation with α-tocopherol has also been shown to decrease the concentration of other tocopherols within the body. For example, in 1986, Baker et al., compared the plasma levels of α and γ-tocopherol;[59] following supplementation with α-tocopherol, the plasma levels rapidly increased reaching a maximum level after three consecutive days of supplementation. After the third day, the plasma α-tocopherol levels plateaued, staying constant for the remaining 25 of the study. The rapid increase in α-tocopherol was paralleled by a rapid decrease in plasma γ-tocopherol, which remained consistently low, until the α-tocopherol consumption ceased. Based on this and other similar findings,[60],[61] studies that solely supplemented with α-tocopherol might not observe an effect, as the increased plasma α-tocopherol may deplete other tocopherols that contribute to the protective action of vitamin E. Clearly further investigation into the efficacy and safe dosage of vitamin E is required before its supplementation can be recommended as a way of reducing the risk of neurodegenerative disease.

Ascorbate

Ascorbate, also called vitamin C, is an essential hydrophilic nutrient required for a variety of biological functions. As humans cannot synthesize ascorbate, due to a defect in the L-gulono-1, 4-lactone oxidase enzyme, it must be dietary-derived [Table 1]. [62] Following consumption, ascorbate is readily absorbed in the gut and is subsequently distributed to all other tissues via the plasma. As reviewed by Rice, ascorbate enters the CNS primarily by active transport at the choroid plexus. [63] From the CSF it diffuses into the brain's extracellular fluid, in which its concentration ranges from 200 to 400 μM. [64],[65],[66] From the extracellular fluid, ascorbate is then taken up into brain cells, including both neurons and glia, where its concentration may increase up to 20-fold. [67]

Even though ascorbate is intracellularly located in all tissues, the high concentrations within the brain and CSF suggest that it is particularly important for CNS homeostasis. As reviewed by Rebec et al., [68] ascorbate has been demonstrated to modulate both glutamate- and dopamine-mediated neurotransmission. Ascorbate is also an essential co-factor for the synthesis of both noradrenaline [69] and many neuropeptides, [70] and has been shown to promote peptide release at physiological concentrations. [71] Ascorbate also promotes myelin formation by enabling the Schwann cells to assemble a basal lamina, [72] and it has been demonstrated to effectively scavenge and mitigate both nitrogen- and oxygen-based radicals. [73]

The antioxidant action of ascorbate is based on its capacity to act as a reducing agent, sacrificially inhibiting the oxidation of other compounds. [74],[75] The oxidation of ascorbate occurs in two steps, initially resulting in the formation of semidehydroascorbate, also called the ascorbyl radical, with further oxidation producing dehydroascorbic acid. [76] Being neither a strong oxidizing nor reducing agent, the poor reactivity of the ascorbyl radical is the key to acorbate's antioxidant action. [74],[75]

Substantial evidence exists in support of the effective antioxidant and free radical scavenging capacity of ascorbate in the CNS. In vitro, ascorbate has been shown to effectively scavenge superoxides; [77] while in brain microsomes, brain slices, and cultured cells, ascorbate has also been demonstrated to prevent the lipid peroxidation provoked by various oxidizing agents. [78],[79] Importantly, the effect of ascorbate appears to be enhanced when used in conjunction with α-tocopherol.[80],[81]

In vivo studies also provide a convincing case for the neuroprotective capacity of ascorbate. Patients suffering from AD have repeatedly been shown to have decreased plasma and CSF ascorbate concentrations, despite sufficient dietary intake. [82],[83] Ascorbate supplementation has been linked to a reduction in the incidence of AD as well as a decline in CSF markers of oxidative stress. [84],[85] For example Quinn et al., has demonstrated that in patients with mild Alzheimer's disease, CSF F2-isoprostane levels are significantly lower in those who consume both α-tocopherol and vitamin C.[85] Substantiating this are results from a randomized, double-blind, placebo-controlled trial conducted by Smith et al., where participants who consumed 500 mg of ascorbic acid per day demonstrated significant improvements in intellectual functioning and cognition compared to the controls [Table 2]. [86]

However, there are occasional studies that have not confirmed these findings. For example from the year 1986 / 1987 through to 2000, Fillenbaum et al., followed a group of representative persons aged 65 - 105 years to determine whether supplementation with vitamins C and / or E delayed the onset of dementia or Alzheimer's disease. They found that neither use of vitamins C and / or E (used by 8% of subjects at baseline) reduced the time to dementia or AD. [87] Importantly this was not a controlled supplementation study; the dietary intakes of individuals was variable and the consistency of compliance was unknown. However, it is relevant to note that ascorbate is also able to function as both an anti- or pro-oxidant (analogous to vitamin E). Most of the later functions involve the reduction of Cu 2+ or Fe 3+ and occur as a consequence of hydroxylation reactions at the active site of dioxygenases. [88] Thus, if free copper or iron ions were available, as might occur in the damaged brain, it is possible for ascorbate to stimulate oxidative damage by reducing Cu 2+ and Fe 3+ ions to the redox active Cu + and Fe 2+ forms, both of which are capable of catalyzing the production of OH from H 2 O 2, through Fenton chemistry.

Carotenoids

Carotenoids are lipid-soluble pigments ranging in color from light yellow to deep red, which are widespread in plant tissue. [89] Based on their chemical structure carotenoids are broadly classified into two groups, hydrocarbons, also termed carotenes, and xanthophylls, their oxygenated derivatives. Using this system, well-described carotenoids such as α-carotene and β-carotene are classified as hydrocarbons, while lutein, lycopene, zeaxanthin, and astaxanthin are described as xanthophylls. [90]

Most carotenoids are derived from a 40-carbon polyene chain that may be associated with oxygenated functional groups and / or terminated by cyclic end groups. The typical blueprint of alteration between single and double bonds in the polyene chain, allows carotenoids to absorb excess energy making them effective antioxidants in vivo. [90] The antioxidant capacity of carotenoids as peroxyl radical scavengers and quenchers of singlet oxygen ( 1 O2 ) and triplet states is described well. [91],[92],[93] Interaction of carotenoids with 1 O2 results in the transfer of energy to the carotenoid molecule forming a triplet excited carotene and ground state oxygen. The excited carotene then returns to the ground state, dispersing its energy into the surrounding solvent. Of the carotenoid class of phytochemicals, open-ringed lycopene is considered the most efficient quencher of singlet oxygen and comprises up to 30% of the total carotenoid content in humans. [94]

As mentioned previously carotenoids are dietary-derived from plants, where they are found in edible flowers, leaves, and fruit [Table 1]. Following consumption the quantity of carotenoids released from the food matrix is highly variable, depending on whether they are dissolved in dietary oil, complexed with other components, such as protein, or present in a crystallized form. [95] In general, it has been estimated that the bioavailability of carotenoids varies from 50% in oils or processed foods to less than 10% in raw vegetables. [96] Upon their release from the food matrix, the absorption of carotenoids into the digestive system follows the same pathway as dietary fat.

In humans, dietary carotenoids aggregate in various tissues including the skin, [97] liver, [98] adipose, [99] breast, [100] prostate, [101] kidney, [98] lung, [98] and brain. [102] Within the brain, at least 16 carotenoids have been identified, including zeaxanthin, alpha-carotene, cis- and trans-betacarotene, lutein, and cis- and trans-lycopene. [102] Even though the exact mechanism of how carotenoids cross the blood brain barrier has yet to be firmly established, their presence within the brain and the documented antioxidant capacity has led to the suggestion that consumption may confer protection against neurodegenerative diseases. Indeed lower plasma levels of carotenoids have been demonstrated in Alzheimer's disease, [45] amyotrophic lateral sclerosis, [103] and vascular dementia patients. [104]

Data from a number of large population studies also support the theory that carotenoids possess neuroprotective properties. In the Physicians Health Study II, 4052 male participants were randomized to consume either 50 mg of β-carotene or a low-dose aspirin placebo every second day for 18 years. From 1997, 1904 additional recruits were also supplemented with either 50 mg of β-carotene or placebo on alternate days for an average of one year. After age 65 years, cognitive testing revealed that while short term β-carotene supplementation did not affect cognitive performance, long-term consumption significantly improved verbal memory and mean global cognitive scores, compared to the placebo [Table 2]. [105]

The precise mechanisms behind these neuroprotective effects have yet to be fully elucidated. Recent studies implicate a wide variety of possible molecular actions. For example using neuroblastoma cells Lee et al., have demonstrated that astaxanthin (ATX) effectively inhibits the formation of NO, while increasing the generation of heme oxygenase-1 (HO-1; Hsp32), an enzyme with anti-inflammatory properties. [106] Chan et al., further observed that pre-treatment of the nerve growth factor differentiated PC12 cells with ATX, and canthaxanthin (CX) prevented the release of TNF-α, IL-1, and IL-6, while also suppressing the activity of caspase-3.[107]

Although lycopene is best known for its powerful antioxidant activity it has also been shown to inhibit the activation of microglia in rats with focal cerebral ischemia and, [108] like ATX, prevent excess formation of NO. [109],[110] Recently, Sandhir et al., observed that consumption of lycopene by rats inhibited lipid peroxidation and significantly reduced 3-nitropropionic acid (3-NP)-stimulated ROS production in the brain tissue. [111] Sandhir et al., also found that lycopene enhanced the activity of the antioxidant enzyme superoxide dismutase (SOD). Together, these studies suggest that the antioxidant capacity of carotenoids is not solely responsible for their neuroprotective properties, and that a wider range of actions, including the modulation of inflammation and upregulation of antioxidant enzymes, are probable. On this basis, and due to the association between oxidative stress and neurodegenerative diseases, it is logical to expect further investigation into carotenoids, which will provide meaningful insights into therapies that may mitigate or prevent neurodegenerative disorders.

Plant phenols

Plant phenols are an ubiquitous group of micronutrients derived from botanical sources. Fruits and vegetables of purple hue, in particular, are known to contain high quantities [Table 1]. Chemically, plant phenols are divided into different classes. Every compound containing a benzene ring with an attached hydroxyl (-OH) group is called a phenol. Monophenols have one aromatic -OH group, diphenols have two, and polyphenols have three or more. Over the past decade plant phenols have become the subject of substantial research interest. One of the key reasons for this interest is the recognition that these compounds possess powerful antioxidant properties. In vitro most phenols inhibit lipid peroxidation by scavenging peroxyl radicals; [112],[113] however, they have also been shown to scavenge OH , nitric dioxide (NO2 ), peroxynitric acid (ONOOH), and hypochlorous acid (HOCl), while the more complex di- and polyphenols also react with O2•- and bind transition metal ions. [114] As plant phenols possess enhanced antioxidant activities it has been proposed that their consumption may confer protection against various diseases associated with oxidative stress, including those that afflict the CNS, such as, Alzheimer's and Parkinson's disease. [115],[116],[117],[118]

Of principal importance is how efficiently plant phenols access the CNS. For plant phenols to protect the brain against neurodegenerative processes they need to cross the blood-brain barrier (BBB). However, few studies have looked at this issue. In 2005 Andres-Lacueva et al., investigated whether different classes of polyphenols could be found in rat brain regions associated with cognitive performance following consumption of a diet supplemented with blue berries. Compared to the control, significantly higher levels of several anthocyanins were found in the cerebellum, cortex, hippocampus, and striatum. [119] Similarly following i.p. administration the phenolic compound resveratrol (3, 4′, 5-trihydroxystilbene), largely found in grapes and berries, was found to rapidly cross the blood−brain barrier and enter the brain tissue in gerbils. [120]

While there is good evidence that a number of plant phenols can cross the BBB, the level found in brain tissue is relativity small. Perfused and exsanguinated animals are considered the gold standard for verifying the quantity of a drug or nutrient that enters the brain. Studies using these methods indicate that plant phenols generally accumulate at concentrations below 1 nmol / g tissue. [121],[122],[123],[124] The small quantities of polyphenols in the brain have led to some scepticism as to whether these phytochemicals can exert sufficient antioxidant effects in the CNS. [125]

A number of animal studies have, however, demonstrated that plant phenols can act as antioxidants in the brain. Ates et al., reported that i.p. administration of 100 mg / kg of resveratrol, immediately after head trauma, significantly reduced malondialdehyde (MDA), NO, and xanthine oxidase levels in the CNS. [126] Similarly Lee et al., observed that i.p. administration of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) (50 mg / kg) 30 minutes before and immediately after ischemia attenuated an increase in brain lipid oxidation (i.e., MDA). [127] While both Ates et al., and Lee et al., found the plant phenol under investigation to function as an antioxidant it is important to note that both were intraperitoneally administered, thereby, passing the first pass metabolism. The benefit of oral ingestion, therefore, remains to be established.

Although numerous in vitro and animal studies document the antioxidant properties of plant phenols, few human in vivo studies have investigated the antioxidant effects of these compounds within the CNS. In 2008, Ryan et al., examined the effects of Pycnogenol, a flavonoid rich blend of procyanidins, extracted from the bark of the French maritime pine, on a range of cognitive and biochemical measures. During a three-month treatment period, 101 elderly participants consumed either 150 mg of Pycnogenol or placebo daily. Pycnogenol supplementation significantly improved memory-based cognition and decreased F2-isoprostanes compared to the control. [128] Conversely, there are a number of reports, whereby, the placing of subjects on flavonoid-poor diets or the consumption of pure phenols or foods rich in flavonoids, has failed to modify parameters of oxidative damage. [129],[130] However, similar to other supplementation studies, these dietary interventions are also generally of a short duration. Their lack of efficacy suggests that the bioavailability of plant phenols may be reduced in whole foods and their effects dose-dependent. Therefore, the low doses obtained from whole foods may require relatively long periods of time to produce measureable change.

In addition to their antioxidant properties plant phenols have also been shown to modulate the activity of an array of cell receptors and enzymes. As a result, plant phenols likely possess a number of other biological actions that are currently poorly understood. Of particular significance is the ability of polyphenols to influence the activity and expression of enzymes required for the production of inflammatory mediators. [131],[132] Luteolin and apigenin suppress IL-6 and TNF-α production, CD40 expression, and phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) in microglial cells. [133] Polyphenols have also been shown to regulate the activity of various endogenous antioxidant enzymes. In mouse striatum, EGCG has been shown to increase the activity of both catalase and SOD. [134] This finding is supported by a previous observation that consumption of a catechin preparation by aged rats decreased the formation of thiobarbiturate reactive substances in the cerebellum and cortex, while increasing midbrain and striatum SOD activity. [135] EGCG has also been shown to modulate amyloid precursor protein (APP) processing [136] and reduce the development of β-amyloid fibrils.[116] Other processes influenced by polyphenols within CNS cells include, the maintenance of calcium homeostasis, [137] the regulation of various cell cycle and survival genes, [138],[139] and activation of the mitogen-activated protein kinase (MAPK) cascade. [140],[141] With the link between oxidative stress and neurodegenerative diseases well-established, further investigation into the potential neuroprotective and antioxidant effects of plant phenols may lead to useful therapies for neurodegenerative disorders.

Pure antioxidant supplementation versus whole foods

The theory that dietary antioxidants prevent neurodegeneration is based on data from epidemiological studies that consistently show that the consumption of fruit and vegetables significantly lowers the risk of developing lifestyle disease's, including dementia [Table 3]. It is, therefore, logical for scientists to attempt to identify the active substances within these whole foods and understand the mechanisms behind their neuroprotective effects.
Table 3: Summary of studies on the affect of fruit and vegetable consumption on cognition

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However, it is not yet known whether supplementation with a pure, single antioxidant has the same health benefits as an antioxidant consumed as part of a whole food or mixture of foods. Although there is evidence suggesting that supplementation may modulate neurodegeneration, studies using purified antioxidants in randomized control trials have produced inconsistent results [Table 2]. Although a number of factors may contribute to this inconsistency, Liu argues that the behavior and / or bioavailability of the pure antioxidant may differ from that of the same molecule consumed as part of a complex whole food matrix. [142]

Bioavailability classically equates to that percentage of the compound of interest reaching the systemic circulation. A number of factors may affect the bioavailability of an antioxidant, including physical properties such as size, relative charge, pKa, and the like, host-related factors such as metabolic capacity (i.e., affecting first pass metabolism), the nature of the food matrix, and the interaction of the antioxidant with other phytochemicals [Figure 2]. [143],[144] These can all significantly influence 'availability' and thus the potential for the antioxidant to confer protection.
Figure 2: Factors potentially affecting antioxidant bioavailability

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The efficiency of vitamin E absorption demonstrates this concept. In a study designed to investigate how the absorption of vitamin E is influenced by the amount of fat in a meal and the food matrix, Jeanes et al., compared the absorption of stable-isotope-labeled vitamin E following meals of varying fat content and source. Jeanes observed that the plasma concentrations of labeled α-tocopherol where higher when ingested with meals containing 17.5 g fat compared to 2.5 g fat. This study also reported increased plasma concentrations of labeled α-tocopherol when consumed in conjunction with a test butter and toast meal, compared to a meal of cereal with full fat milk, despite both meals being of similar caloric value and matched for fat content.[145] These results demonstrate that both the amount of fat and the food matrix influence vitamin E absorption and illustrate how the bioavailability of antioxidants may also be influenced by the 'context' in which it is consumed (e.g., wholefood versus supplement).

Synergistic and/or additive effects of various phytochemicals are likely to occur. Sun et al., characterized the total antioxidant activity of various common fruits. While cranberries had the highest antioxidant activity, combinations of fruits resulted in an even greater antioxidant activity that was both synergistic and additive. [146] It is probable that no single purified antioxidant will be an effective substitute for the complex combination of phytochemicals found in whole fruit and vegetable preparations, in preventing the development of chronic diseases, including those associated with neurodegeneration.


   Conclusion Top


It is now generally acknowledged that oxidative stress plays a key role in the development of a number of lifestyle-associated diseases, including those that afflict the CNS. Although our bodies are equipped with endogenous antioxidant systems to help combat the production of ROS, substantial evidence now supports the view that consumption of dietary antioxidants can make important contributions to the prevention of neurodegeneration. However, consumers need to be educated about the apparently limited health benefits and potential risks of supplementation with isolated antioxidant components. A balanced increase in the consumption of fruits, grains, and vegetables is likely the most effective way by which individuals can improve their antioxidant / anti-inflammatory capacity, modulate inflammatory processes and subsequently reduce their risk of developing neurodegenerative diseases.[157]

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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