Κυριακή 28 Ιουλίου 2019

Dietary carotenoids are thought to provide health benefits in decreasing the risk of disease, particularly certain cancers and eye disease. The carotenoids that have been most studied in this regard are beta-carotene, lycopene, lutein, and zeaxanthin. In part, the beneficial effects of carotenoids are thought to be due to their role as antioxidants. beta-Carotene may have added benefits due its ability to be converted to vitamin A. Furthermore, lutein and zeaxanthin may be protective in eye disease because they absorb damaging blue light that enters the eye. Food sources of these compounds include a variety of fruits and vegetables, although the primary sources of lycopene are tomato and tomato products. Additionally, egg yolk is a highly bioavailable source of lutein and zeaxanthin. These carotenoids are available in supplement form. However, intervention trials with large doses of beta-carotene found an adverse effect on the incidence of lung cancer in smokers and workers exposed to asbestos. Until the efficacy and safety of taking supplements containing these nutrients can be determined, current dietary recommendations of diets high in fruits and vegetables are advised.

Representative food-derived carotenoids and their structures.
https://www.hindawi.com/journals/omcl/2018/4120458/tab1/

α-Carotene Banana, butternut, carrot, pumpkin
β-Carotene Apricots, banana, broccoli, cantaloupe, carrot, dairy products, honeydew, kale, mango, nectarine, peach, pumpkin, spinach, sweet potato, tomato
Crocetin Gardenia fruit, saffron stigma
Crocin Gardenia fruit, saffron stigma
β-Cryptoxanthin Apple, broccoli, celery, chili, crustaceans, grape, green beans, papaya, pea, peach, peppers, salmonid fish, squashes, tangerine
Lutein Apple, basil, broccoli, celery, crustaceans, cucumber, dairy products, grapes, green pepper, kale, kiwi, maize, parsley, pea, pumpkin, salmonid fish, spinach, squash
Lycopene Grapefruit, guava, tomato, watermelon
Zeaxanthin Basil, crustaceans, cucumber, dairy products, honeydew, kale, maize, mango, orange, parsley, salmonid fish, spinach
Marine
Astaxanthin Crustaceans, algae, salmonid fish
Fucoxanthin Brown seaweeds

Bioactivities of representative food-derived carotenoids and their implications in neurodegenerative diseases.

CarotenoidBioactivityReferenceImplication in NDReference

α-CaroteneAntioxidant[631]AD: human[130]
PD: human[137138]
β-CaroteneAntioxidant[63031]AD: human[130134135]
PD: rodent[137138]
ALS: cell[113]
CrocetinAntioxidant[35]AD: cell[121125]
Antineuroinflammation[54]
CrocinAntioxidant[34]AD: rodent[115]
Antineuroinflammation[57]Cell[114]
Autophagy[71]PD: rodent[117118]
Drosophila[119]
Cell[116]
β-CryptoxanthinAntioxidant[636]AD: human[130]
LuteinAntioxidant[631]AD: human[130133]
Antineuroinflammation[495153]PD: rodent[167]
Autophagy[6870]HD: rodent[168]
LycopeneAntioxidant[631]AD: human[130133]
Antineuroinflammation[6466]Rodent[368991]
Autophagy[7274]C. elegans[104]
Cell[100102]
PD: human[138]
Rodent[9295]
Cell[103]
HD: rodent[9699]
ZeaxanthinAntioxidant[631]AD: human[132133]
Marine
AstaxanthinAntioxidant[63133]AD: human[134]
Antineuroinflammation[585962]Cell[107108]
Autophagy[7576]PD: rodent[110]
Cell[109112]
ALS: cell[113]
FucoxanthinAntioxidant[16]AD: rodent[106]
Antineuroinflammation[63]Cell[105]
Autophagy[77]




Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 4120458, 13 pages
https://doi.org/10.1155/2018/4120458
Review Article
Recent Advances in Studies on the Therapeutic Potential of Dietary Carotenoids in Neurodegenerative Diseases
Kyoung Sang Cho,1 Myeongcheol Shin,1 Sunhong Kim,2,3 and Sung Bae Lee4
1Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea
2Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
3Department of Bioscience, University of Science and Technology, Daejeon 34113, Republic of Korea
4Department of Brain and Cognitive Sciences, DGIST, Daegu 42988, Republic of Korea

Correspondence should be addressed to Sunhong Kim; sunhong@kribb.re.kr and Sung Bae Lee; sblee@dgist.ac.kr

Received 22 November 2017; Revised 22 February 2018; Accepted 13 March 2018; Published 16 April 2018

Academic Editor: Julio B. Daleprane

Copyright © 2018 Kyoung Sang Cho et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Carotenoids, symmetrical tetraterpenes with a linear C40 hydrocarbon backbone, are natural pigment molecules produced by plants, algae, and fungi. Carotenoids have important functions in the organisms (including animals) that obtain them from food. Due to their characteristic structure, carotenoids have bioactive properties, such as antioxidant, anti-inflammatory, and autophagy-modulatory activities. Given the protective function of carotenoids, their levels in the human body have been significantly associated with the treatment and prevention of various diseases, including neurodegenerative diseases. In this paper, we review the latest studies on the effects of carotenoids on neurodegenerative diseases in humans. Furthermore, animal and cellular model studies on the beneficial effects of carotenoids on neurodegeneration are also reviewed. Finally, we discuss the possible mechanisms and limitations of carotenoids in the treatment and prevention of neurological diseases.

1. Introduction
Carotenoids are natural pigments present in various organisms, such as plants, animals, and microorganisms. For example, the orange color of carrots and the red color of tomatoes are due to their carotenoid components [1]. Plant, algae, and fungi produce >600 different types of carotenoids. Animals obtain carotenoids from food since they cannot synthesize them. As pigment molecules, carotenoids play a role in the process of photosynthesis, either in photoprotection or light collection [2]. Carotenoids confer photoprotection by dissipating light energy that is not used directly for photosynthesis, and they contribute to photosynthesis through light collection, during which they pass light through to the chloroplast [2]. Carotenoids also act as antioxidants that reduce reactive by-products, such as reactive oxygen species (ROS), during photosynthesis [3]. As a result, carotenoids protect the photosynthetic apparatus from oxidative damage. In addition, carotenoids play various other roles in nature, including the development and oxidative stress signaling in plants, sex-related coloration patterns, and as a precursor for vitamin A in many species [3, 4].

Carotenoids, also known as tetraterpenoids, are C40 hydrocarbons that have isoprenoids as building units (Table 1). The C40 carbon skeleton of carotenoids is produced by the linkage of two C20 geranylgeranyl diphosphate molecules; all of the carotenoid variants are derived from the skeleton [4]. Carotenoids can be divided into two groups according to their polarity: xanthophylls (polar carotenoids such as astaxanthin, β-cryptoxanthin, lutein, and zeaxanthin) and carotene (nonpolar carotenoids such as α-carotene, β-carotene, and lycopene) [5]. The distinctive structural feature of carotenoids is the long, alternating double and single bond system, which is associated with light absorption and oxidation [4].


Table 1: Representative food-derived carotenoids and their structures.
The major sources of carotenoids in the human diet are fruits and vegetables, which have various colors, such as green, red, orange, and yellow [6]. Humans consume approximately 40 carotenoids from common fruits and vegetables (Table 1) [7]. Dark green vegetables, such as broccoli, coriander, kale, and spinach, contain a large number of chloroplasts, in which most carotenoids exist; therefore, they possess high concentrations of carotenoids [8]. As chloroplasts generally contain the most consistent carotenoid composition [9], the distribution of carotenoids is similar among different plant species in this group [7]. On the other hand, in red-, orange-, or yellow-colored fruits and vegetables, carotenoids are mainly accumulated in chromoplasts, which are usually converted from chloroplasts during ripening [10]. As chromoplasts in different plant species contain various carotenoids, the carotenoid distribution in this group is diverse [6]. Some seafood and animal foods also contain carotenoids. Animals cannot synthesize carotenoids; instead, they ingest carotenoids through foods and accumulate these molecules in their bodies. As a result, some animal foods contain carotenoids. For example, high concentrations of lutein and zeaxanthin accumulate in egg yolks [11]. Milk and dairy products, salmonid fish, and crustaceans also provide various carotenoids [12]. The main carotenoid in bovine milk is β-carotene [13], whereas the major carotenoids in salmonid fish and crustaceans are astaxanthin and canthaxanthin [12, 14, 15]. In addition, some edible brown seaweeds contain fucoxanthin as a major carotenoid [16, 17].

Carotenoids are differentially distributed in various organs of the human body. Interestingly, xanthophylls account for 66–77% of the total carotenoids in the frontal and occipital lobes of the human brain [18], whereas less than 40% of the total carotenoids in most tissues and plasma are reported to be xanthophylls [19–21]. It was reported that the human brain contains sixteen carotenoids, with the major carotenoids being anhydrolutein, α-carotene, α-cryptoxanthin, cis- and trans-β-carotene, β-cryptoxanthin, lutein, cis- and trans-lycopene, and zeaxanthin [18]. Given their property of protecting tissues from oxidative stress and their localization in the brain, the role of carotenoids in preventing or treating oxidative stress-associated diseases, including neurodegenerative diseases, is of interest.

As carotenoids have various physiological activities, such as antioxidant activity, the amount of carotenoid in the human body is important for health. Therefore, the intake of carotenoids through the diet is associated with the prevention and treatment of various diseases, including age-related macular degeneration [22], cancer [23, 24], cardiovascular diseases [25], and neurodegenerative diseases [5]. In the present paper, we review the latest studies that show the effects of dietary carotenoids on neurodegenerative diseases, and discuss the prospect of the use of carotenoids in the prevention and treatment of these diseases.

2. Bioactivities of Carotenoids
As stated above, most carotenoids have a symmetrical tetraterpene structure with a linear C40 hydrocarbon backbone (Table 1). These highly unsaturated fatty chains are susceptible to modifications, such as cis-trans isomerization or cyclization, and result in the characteristic coloration induced by light absorption. Owing to their highly lipophilic structures, carotenoids are found in the lipid membrane. Nonpolar carotenes reside in the inner part of the membrane, whereas polar xanthophylls are located across the bilayer, tilted ~40° from the axis normal to the membrane plane [26, 27]. Inserted carotenoids may affect the physical properties of the lipid bilayer; however, their exact function in the membrane remains unclear besides in their prevention of the oxidative damage of lipids [27]. Significant evidence has shown that carotenoids can reduce oxidative damage by scavenging ROS and exert anti-inflammatory effects in vivo (Table 2) [28].


Table 2: Bioactivities of representative food-derived carotenoids and their implications in neurodegenerative diseases.
2.1. Antioxidant Activity
Carotenoids have been demonstrated to be one of the most potent natural singlet oxygen scavengers, with a fast quenching rate () [29]. They can effectively neutralize ROS and other free radicals to provide protection against oxidation in both photosynthetic and nonphotosynthetic organisms [6, 16, 29–37]. However, each carotenoid shows different antioxidant activities, owing to the presence of functional groups with increasing polarities as well as the number of conjugated double bonds [31]. The antioxidant property of carotenoids has inspired many epidemiological and clinical studies that have investigated if these pigment molecules are able to prevent various ROS-mediated disorders such as cancer, inflammation, retinal degeneration, and neurodegeneration. In the case of cancer, many studies have shown that carotenoid consumption is correlated with a reduced risk of several types of cancer; however, other studies have shown that the cancer-preventive effects of carotenoids are negligible or even that they are carcinogenic [38, 39].

Lutein is a xanthophyll and the most abundant carotenoid in the human retina and brain [18, 40]. The Age-Related Eye Disease Study (AREDS) showed that a formulation consisting of vitamins C, E, β-carotene, and zinc is beneficial for the prevention of age-related macular degeneration (AMD) [41]. In a second study, although primary analysis from the AREDS2 did not reveal a benefit of daily supplementation with lutein/zeaxanthin on AMD progression [42], secondary exploratory analyses suggested that lutein/zeaxanthin were helpful in reducing this risk [43]. In addition, given that increased oxidative stress and inflammation are observed in age-related macular degeneration [44], lutein supplementation may improve visual function through antioxidant activity.

In addition to their antioxidant activities, carotenoids can protect cells from the oxidative stress induced by some stressors via activation of endogenous antioxidant enzymatic activities and a reduction in DNA damage. Crocetin, a pharmacologically active metabolite of Crocus sativus L., exerts cardioprotective effects by increasing superoxide dismutase (SOD) and glutathione peroxidase activities in cardiac hypertrophy induced by norepinephrine in rats [35]. Crocin, another component of Crocus sativus L., has also been shown to increase SOD activity to prevent the death of PC-12 cells during serum/glucose deprivation [34]. Recent studies have demonstrated that marine carotenoids such as astaxanthin and fucoxanthin also display antioxidant properties by activating the antioxidant network, including SOD and catalase [45, 46]. In addition, β-cryptoxanthin protects human cells from H2O2-induced damage by stimulating the repair of damage caused by DNA oxidation as well as by its antioxidant activity [36]. Lycopene and β-carotene also provide protection against DNA damage at low concentrations [32]. However, opposite effects have been shown at higher concentrations in cells with oxidative damage [32].

2.2. Antineuroinflammation
Neuroinflammation is a local response of the nervous system during neurodegeneration, trauma, and autoimmune disorders. A variety of cell types, including astrocytes, microglia, vascular cells, neutrophils, and macrophages, are involved in neuroinflammation [47]. Growing evidence suggests that neuroinflammation is one of the pathological features of many neurodegenerative disorders and autoimmune diseases, such as multiple sclerosis [44, 47, 48]. In the last decade, some carotenoids have been shown to have antineuroinflammatory effects in vivo. Among the polar xanthophylls, the ability of lutein to suppress inflammation has been demonstrated in murine retinal cells [49–51] and in a clinical trial studying retinal health in preterm infants [52]. In addition, it has been shown that lutein reduces lipid peroxidation and proinflammatory cytokine release by suppressing the activation of the nuclear factor-κB (NF-κB) pathway in the presence of a variety of oxidative stressors [53–56]. It has also been demonstrated that crocin and crocetin are able to suppress the production of proinflammatory cytokines and nitric oxide by lipopolysaccharide, interferon γ, and β-amyloid (Aβ) stimulation in microglial cells [57]. Astaxanthin, a member of the xanthophyll family that confers the pink color in flamingos, has an anti-inflammatory effect and antioxidant activity similar to other carotenoids [58, 59]. Furthermore, astaxanthin has also been found to reduce hippocampal and retinal inflammation in streptozotocin-induced diabetic rats, alleviating cognitive deficits, retinal oxidative stress, and depression [60–62]. Fucoxanthin, another member of the marine xanthophylls, exerts anti-inflammatory effects against various stimuli through Akt, NF-κB, and mitogen-activated protein kinase pathways [63].

Lycopene, one of the carotenes present in large amounts in tomatoes, has been demonstrated to reduce neuroinflammatory phenotypes, depression-like behaviors, and inflammation-induced cognitive function defects in murine models [64–66]. As a whole, cellular and animal models have revealed that carotenoids are potent anti-inflammatory agents in the nervous system and act through the suppression of inflammation pathways.

2.3. Modulation of Autophagy
Autophagy, a catabolic process necessary for the cleanup of damaged organelles, protein complexes, and even single proteins, as well as for the recycling of nutritional building blocks, has been implicated in numerous disorders and conditions such as aging, cancer, and neurodegeneration. A growing amount of evidence strongly suggests that autophagy removes misfolded or aggregated proteins, the main features of most neurodegenerative diseases, for example, tau fibrils in Alzheimer’s disease (AD) and Lewy bodies in Parkinson’s disease (PD) [67]. Recent studies have shown that some carotenoids are able to modulate autophagy in cellular and animal models. It has been recently demonstrated that lutein attenuates cobalt chloride-induced autophagy via the mTOR pathway in rat Müller cells [68], whereas it induces autophagy through the upregulation of Beclin-1 in retinal pigment epithelial cells [69, 70]. Crocin has also been shown to have a paradoxical effect on autophagy. The induction of autophagy by crocin occurs during hypoxia, and the inhibition of autophagy by crocin occurs during reperfusion [71]. Lycopene has also been shown to be involved in autophagy [72–74]. Astaxanthin has been found to attenuate autophagy in hepatic cells [75, 76]. In a model of murine traumatic brain injury, fucoxanthin has the ability to protect neuronal cells from death through the activation of autophagy and the nuclear factor erythroid 2-related factor pathway [77]. The modulation of autophagy by carotenoids remains a controversial topic, and the precise molecular mechanism of this modulation remains unclear.

3. Beneficial Effects of Carotenoids on Neurodegenerative Diseases
3.1. Neurodegenerative Diseases
Neurodegenerative diseases are neuronal disorders that feature a progressive loss of neurons and are associated with protein aggregates [78]. The major neurodegenerative diseases include AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), all of which have disease-specific causative factors and pathological features. For examples, senile plaques with Aβ aggregates and fibrillary tangles with hyperphosphorylated tau are hallmarks of AD [79]. Similarly, aggregation of α-synuclein, huntingtin, and TAR DNA-binding protein 43 is associated with PD, HD, and ALS, respectively [80–82].

Although these neurodegenerative diseases have different causative factors, they share common features that might be closely related to the onset and progress of disease by the induction of neuronal cell death. One of the shared features is oxidative stress due to elevated ROS production during disease progression [78]. ROS are reactive chemicals with oxygen that can attack and damage the macromolecules, such as lipids, DNA, and proteins, of living cells [83]. In neuronal cells of patients with neurodegenerative diseases, ROS levels are increased by various cellular events, including mitochondrial insults and release of redox metals that interact with oxygen [84, 85], which result in neuronal cell death [85]. In addition, the pathological environment of neurodegenerative diseases, such as the increase in protein aggregates, results in sustained inflammation due to microglia activation [86]. Although the inducers of inflammation vary among different diseases, chronic inflammation is induced in neurons through largely common mechanisms [87]. Once neuroinflammation is chronically activated, cytokines and chemokines are released by long-standing activated microglia and oxidative stress is increased, which may be detrimental to neurons [88].

Given that oxidative damage and increased neuroinflammation are critically related with the pathogenesis of and late-onset massive neuronal loss in neurodegenerative diseases, the neuroprotective effect of carotenoids has been of specific interest in the search for effective treatments for these diseases. To provide an update on the latest advances in this field, we have reviewed the papers published in recent years in the following paragraphs.

3.2. Animal and Cellular Model Studies on the Beneficial Effects of Carotenoids on Neurodegenerative Diseases
Controlled animal model or cell culture studies allow for the accurate assessment of the sole influence of carotenoid administration on neurodegenerative diseases that human studies do not. Indeed, numerous experimental studies have recently highlighted the beneficial effects of carotenoids on neurodegenerative diseases (Table 2). Notably, most of these recent experimental studies have focused on either AD or PD.

In the case of well-studied lycopene, administration of lycopene in murine models of AD leads to the attenuation of mitochondrial oxidative damage [89] and inhibition of NF-κB activity and related expression of proinflammatory cytokines in the brain [64], which together may contribute to the suppression of Aβ formation [90] and improvement of memory retention [64, 89]. In a recent study that used a tau transgenic mouse model for AD, dietary lycopene supplementation was shown to improve cognitive performance [91]. Similarly, in the context of PD, lycopene-rich tomato powder intake successfully prevented the decline in striatal dopamine levels and degeneration of nigral dopaminergic neurons in rodent models of PD [92, 93]. Consistently, in more recent studies, administration of lycopene was shown to protect against rotenone-induced oxidative stress, neurobehavioral impairments [94], and depletion of dopamine and its metabolites by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [95]. Moreover, the effect of lycopene was also experimentally assessed in vivo in the context of HD. Administration of lycopene alone [96–98], in combination with epigallocatechin-3-gallate [96], or with quercetin and poloxamer 188 [99] showed protective effects against HD-like symptoms induced by 3-nitropropionic acid in rodent models. Consistent with the results obtained from animal model studies, lycopene treatment was also recently shown to be very effective in attenuating neuropathic phenotypes in cultured cell models of AD [100–102] and PD [103]. Interestingly, the beneficial effects of lycopene were also confirmed in a study using a Caenorhabditis elegans model for AD [104].

In addition to lycopene, other dietary carotenoids such as fucoxanthin, astaxanthin, crocin, and crocetin have recently begun to be investigated experimentally for their potential beneficial effects. The beneficial effect of fucoxanthin was recently assessed in the context of AD [105, 106]. Moreover, astaxanthin has been shown to protect neurons in the context of various neurodegenerative diseases, including AD [107, 108], PD [109–112], and ALS [113]. Similarly, crocin was recently shown to be beneficial in both AD [114, 115] and PD [116–119]. Other recent studies on crocetin also support the beneficial effects of carotenoids on AD [120–122]. Of note, Tiribuzi et al. [122] used monocytes derived from patients with AD for analysis, and concluded that trans-crocetin improved the clearance of Aβ in vitro through the involvement of cathepsin B.

3.3. Human Studies on the Beneficial Effects of Carotenoids on Neurodegenerative Diseases
Consistent with the results obtained from animal and cell culture model studies showing the beneficial effects of carotenoid treatment on neurodegenerative diseases, a number of epidemiological studies have also linked the consumption of a carotenoid-rich diet with a decreased risk of neurodegenerative diseases in humans (Table 2) [123–126].

The epidemiological correlation between disease risk and carotenoid intake (or its level in the blood) is evident in various neurodegenerative diseases (Table 2). In the case of AD, the most investigated neurodegenerative disease, several studies have reported lower concentrations of carotenoids such as β-carotene, lutein, and vitamin A in the blood plasma of AD patients than in control subjects [127–129]. A very recent case-control study showed that the concentration of six major carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein, lycopene, and zeaxanthin) in serum was significantly lower in patients with AD than in cognitively normal control subjects [130]. The results of a study comparing the levels of plasma carotenoids between patients with AD and normal subjects suggested that maintaining a high level of lutein in relation to plasma lipids can reduce the risk of AD [131]. Consistently, Nolan et al. [132] concluded that the serum concentrations of lutein, zeaxanthin, and meso-zeaxanthin were significantly lower in AD patients than in control subjects. Similarly, high concentrations of lutein, lycopene, and zeaxanthin in the serum were associated with a lower risk of death from AD [133].

In addition to blood carotenoid levels, carotenoid intake has also been epidemiologically associated with a reduced risk of AD and decreased rates of cognitive decline [123–125]. Additional studies have suggested that there are potential beneficial effects of providing carotenoid supplementation to patients with AD [126]. Kiko et al. [134] and de Oliveira et al. [135] reported that the supply of antioxidant supplements, including astaxanthin and a vitamin complex containing α-tocopherol, ascorbic acid, and β-carotene, reduced Aβ contents in red blood cells and ROS generation in the cells of AD patients, respectively. Moreover, a potentially related result was also recently published in an elderly Chinese population, and showed carotenoids to be one of the most highly protective factors against mild cognitive impairment in a cross-sectional study based on a 33-item food frequency questionnaire collected from 2892 elderly subjects [136]. However, the sole influence of carotenoid consumption on the risk or progression of AD has not yet been clearly established in humans.

Unlike in AD, there have been inconsistencies on the association between carotenoid intake and the reduced risk of PD until very recently. Although a number of epidemiological studies have proposed a possible association between increased intake of both provitamin A and nonprovitamin A carotenoid species and the reduced risk of PD, the risk reduction was small and did not always reach statistical significance [6]. To clarify the inconsistencies observed in human studies, a recent systematic review that analyzed pooled data from relevant papers published between 1990 and 2013 raised the possibility that both α- and β-carotene levels might be inversely proportional to PD risk [137]. Following this systematic study, a very recent paper by Kim et al. [138] reported that the serum levels of some carotenoids (α-carotene, β-carotene, and lycopene) were significantly lower in PD patients, and that these carotenoids were inversely correlated with clinical variables representing disease progression. On the contrary, another study reported that the consumption of vitamin E and carotenoids was not associated with the risk of PD [139]. Thus, more studies are required to draw a solid conclusion on the relationship between carotenoid intake and PD risk reduction.

In the case of ALS, Fitzgerald et al. [140] analyzed pooled results from five published cohort studies on the association between carotenoids and ALS, and suggested that the ingestion of carotenoid-rich foods can prevent or delay the onset of ALS. Consistently, a recent paper published in JAMA Neurology [141] reported that a greater intake of antioxidant nutrients and foods high in carotenoids seems to be associated with more beneficial effects in ALS around the time of diagnosis. Lastly, in the case of HD, there have been no epidemiological studies on carotenoids published in recent years, unlike for the other representative neurodegenerative diseases described above.

Unlike animal model studies, the human studies conducted thus far have focused on the statistical assessment of the epidemiological correlation between the risk of disease and carotenoid intake (or its level in the blood), rather than clinical trials directly measuring the beneficial effects of carotenoid supplementation on the treatment of disease symptoms. However, as can be expected from the in vivo and in vitro bioactivities of carotenoids, a number of studies have shown that various carotenoids have beneficial effects on neurodegenerative diseases.

3.4. Possible Molecular Mechanisms of the Effects of Carotenoids on Neurodegenerative Diseases
Extensive studies suggest that carotenoids may inhibit the onset of neurodegenerative diseases through a variety of mechanisms. The effects of carotenoids have already been studied in different cellular contexts [28, 126, 142, 143] that may have the same working mechanisms as in neurodegenerative diseases. In the case of AD, it has been shown that, through ROS quenching, upregulation of antioxidant enzyme systems, hypocholesterolemic properties, antineuroinflammatory effects, antiamyloid aggregation activity, and regulation of amyloid oligomer-induced signaling, carotenoids may ameliorate mitochondrial dysfunction, oxidative stress, sustained neuroinflammation, impaired lipid metabolism, Aβ aggregation, and Aβ neurotoxicity, all of which are critically associated with the pathogenesis of AD [63, 105, 106, 144]. In neurodegenerative disease states, the various mechanisms of action of carotenoids are likely to occur simultaneously. For example, administration of lycopene resulted in the concomitant reduction of Aβ-induced mitochondrial dysfunction, inflammatory cytokine mediators, and caspase-3 activity in a rat model of AD [64]. Furthermore, astaxanthin treatment reduced Aβ-induced damage in a cultured cell model through several mechanisms including downregulation of apoptotic factors, inhibition of inflammatory cytokine mediating action, and simultaneous reduction of ROS [106].

How can a single substance exhibit these various effects? The functional diversity may be due to the strong antioxidant properties of carotenoids that regulate ROS, key regulators of various biological activities. ROS induces functional modification of macromolecules, including lipids, DNA, and proteins, in the aging brains and brains of patients with neurodegenerative diseases [78]. These modifications may affect cellular processes by altering gene expression and signal transduction [145]. For example, the oxidation of PTEN, a lipid phosphatase and suppressor of PI3-kinase pathway, via oxidative stress results in the activation of the NF-κB pathway via IκB kinase (IKK) activation [54]. Since NF-κB regulates the expression of many genes, including oxidative stress-responsive and inflammation-related genes [146], a sustained increase in ROS in the brains of patients with neurodegenerative diseases may lead to an inflammatory response. Therefore, powerful antioxidants, such as carotenoids, can lower the level of ROS to mitigate cellular damage and simultaneously inhibit inflammatory responses by lowering the activity of NF-κB. Indeed, recent studies have shown that various carotenoids suppress inflammation via inhibition of NF-κB activity [56, 63, 147–152]. Given that oxidative stress and neuroinflammation are crucial to the onset and progress of various neurodegenerative diseases, it is expected that similar working mechanisms may be commonly applied to other neurodegenerative diseases.

In addition to these well-characterized cellular mechanisms of carotenoid functions, the recently proposed carotenoid-mediated regulation of autophagy described above also has a strong potential for protecting neurons in neurodegenerative disease conditions through the reduction of toxic disease proteins conferring neuronal toxicity. However, the role of autophagy in the effects of carotenoids on neurodegenerative diseases remains unclear. Further studies are needed to determine the role that carotenoid-regulated autophagy plays in neuroprotection.

4. Conclusion
In this article, we reviewed the recent updates on the beneficial effects of dietary carotenoids on neurodegenerative diseases. An increasing number of papers have demonstrated that dietary carotenoids protect neurons in the context of neurodegenerative diseases through several mechanisms, such as ROS quenching, upregulation of antioxidant enzyme systems, and antineuroinflammatory effects. Indeed, the number of research papers studying the link between carotenoids and neurodegenerative diseases has steadily increased to date. Notably, animal and cell culture model studies have recently begun to be actively conducted, and these model studies strongly support the hypothesis that carotenoid intake may have therapeutic potential in either preventing or ameliorating various neurodegenerative diseases. AD and PD have been more thoroughly studied in this regard than other types of rare neurodegenerative diseases (e.g., ALS and HD). In the rodent models of these diseases, administration of certain types of carotenoids, including lycopene, successfully attenuated not only cellular-level phenotypes such as mitochondrial oxidative damage and increased neuroinflammation, but also organism-level phenotypes such as memory impairment and locomotive defects. Of note, the beneficial effects of dietary carotenoids such as astaxanthin, crocin, crocetin, and fucoxanthin on neurodegenerative diseases have been recently studied in animal model systems, broadening our understanding of the association between carotenoid uptake and neurodegenerative diseases.

Although many of the studies presented in this paper demonstrate the beneficial effects of carotenoids as food nutrients on neurodegenerative diseases, some aspects of the carotenoid effect need to be clarified for medical use beyond food nutrients. First, the results of many studies have lacked an accurate analysis of the mechanisms by which carotenoids exert neuroprotective effects. The strong antioxidant properties of carotenoids can explain the neuroprotective effects of carotenoids in that one of the characteristic pathologies in neurodegenerative diseases is increased oxidative stress. However, the mechanisms by which carotenoids inhibit neuroinflammation and activate autophagy have not been thoroughly studied. In addition, many cell studies have shown that some carotenoids regulate the expression of antioxidant and inflammatory proteins, and it is interesting to note how they regulate gene expression. Second, clinical application studies in human patients are required. The causal relationship of the carotenoid effect in human patients can only be clarified by studies of this type. It may also be possible to infer the correlation between carotenoid intake and the onset of disease through comparative studies of races that eat different foods. Finally, in terms of the complexity in the pathogenic mechanisms underlying these diseases, it seems likely that simply increasing the dietary intake of carotenoids may exert only limited protective effects to neurons. For this reason, we expect that future studies determining other neuroprotective reagents/treatments that confer synergistic effects in combination with carotenoids in neurodegenerative diseases will be essential in finding effective treatments.

Abbreviations
Aβ: β-Amyloid
AD: Alzheimer’s disease
ALS: Amyotrophic lateral sclerosis
HD: Huntington’s disease
PD: Parkinson’s disease
ROS: Reactive oxygen species.
Disclosure
Sunhong Kim and Sung Bae Lee are cocorresponding authors.

Conflicts of Interest
The authors declare that they have no conflicts of interest.

Acknowledgments
This paper was supported by Konkuk University in 2016.

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Naturally occurring carotenoids

  • Hydrocarbons
  • Alcohols
  • Glycosides
    • Oscillaxanthin 2,2'-Bis(β-L-rhamnopyranosyloxy)-3,4,3',4'-tetradehydro-1,2,1',2'-tetrahydro-γ,γ-carotene-1,1'-diol
    • Phleixanthophyll 1'-(β-D-Glucopyranosyloxy)-3',4'-didehydro-1',2'-dihydro-β,γ-caroten-2'-ol
  • Ethers
    • Rhodovibrin 1'-Methoxy-3',4'-didehydro-1,2,1',2'-tetrahydro-γ,γ-caroten-1-ol
    • Spheroidene 1-Methoxy-3,4-didehydro-1,2,7',8'-tetrahydro-γ,γ-carotene
  • Epoxides
  • Aldehydes
  • Acids and acid esters
  • Ketones
  • Esters of alcohols
    • Astacein 3,3'-Bispalmitoyloxy-2,3,2',3'-tetradehydro-β,β-carotene-4,4'-dione or 3,3'-dihydroxy-2,3,2',3'-tetradehydro-β,β-carotene-4,4'-dione dipalmitate
    • Fucoxanthin 3'-Acetoxy-5,6-epoxy-3,5'-dihydroxy-6',7'-didehydro-5,6,7,8,5',6'-hexahydro-β,β-caroten-8-one
    • Isofucoxanthin 3'-Acetoxy-3,5,5'-trihydroxy-6',7'-didehydro-5,8,5',6'-tetrahydro-β,β-caroten-8-one
    • Physalien
    • Zeaxanthin (3R,3'R)-3,3'-Bispalmitoyloxy-β,β-carotene or (3R,3'R)-β,β-carotene-3,3'-diol
    • Siphonein 3,3'-Dihydroxy-19-lauroyloxy-7,8-dihydro-β,ε-caroten-8-one or 3,19,3'-trihydroxy-7,8-dihydro-β,ε-caroten-8-one 19-laurate
  • Apocarotenoids
    • β-Apo-2'-carotenal 3',4'-Didehydro-2'-apo-b-caroten-2'-al
    • Apo-2-lycopenal
    • Apo-6'-lycopenal 6'-Apo-y-caroten-6'-al
    • Azafrinaldehyde 5,6-Dihydroxy-5,6-dihydro-10'-apo-β-caroten-10'-al
    • Bixin 6'-Methyl hydrogen 9'-cis-6,6'-diapocarotene-6,6'-dioate
    • Citranaxanthin 5',6'-Dihydro-5'-apo-β-caroten-6'-one or 5',6'-dihydro-5'-apo-18'-nor-β-caroten-6'-one or 6'-methyl-6'-apo-β-caroten-6'-one
    • Crocetin 8,8'-Diapo-8,8'-carotenedioic acid
    • Crocetinsemialdehyde 8'-Oxo-8,8'-diapo-8-carotenoic acid
    • Crocin Digentiobiosyl 8,8'-diapo-8,8'-carotenedioate
    • Hopkinsiaxanthin 3-Hydroxy-7,8-didehydro-7',8'-dihydro-7'-apo-b-carotene-4,8'-dione or 3-hydroxy-8'-methyl-7,8-didehydro-8'-apo-b-carotene-4,8'-dione
    • Methyl apo-6'-lycopenoate Methyl 6'-apo-y-caroten-6'-oate
    • Paracentrone 3,5-Dihydroxy-6,7-didehydro-5,6,7',8'-tetrahydro-7'-apo-b-caroten-8'-one or 3,5-dihydroxy-8'-methyl-6,7-didehydro-5,6-dihydro-8'-apo-b-caroten-8'-one
    • Sintaxanthin 7',8'-Dihydro-7'-apo-b-caroten-8'-one or 8'-methyl-8'-apo-b-caroten-8'-one
  • Nor- and seco-carotenoids
    • Actinioerythrin 3,3'-Bisacyloxy-2,2'-dinor-b,b-carotene-4,4'-dione
    • β-Carotenone 5,6:5',6'-Diseco-b,b-carotene-5,6,5',6'-tetrone
    • Peridinin 3'-Acetoxy-5,6-epoxy-3,5'-dihydroxy-6',7'-didehydro-5,6,5',6'-tetrahydro-12',13',20'-trinor-b,b-caroten-19,11-olide
    • Pyrrhoxanthininol 5,6-epoxy-3,3'-dihydroxy-7',8'-didehydro-5,6-dihydro-12',13',20'-trinor-b,b-caroten-19,11-olide
    • Semi-α-carotenone 5,6-Seco-b,e-carotene-5,6-dione
    • Semi-β-carotenone 5,6-seco-b,b-carotene-5,6-dione or 5',6'-seco-b,b-carotene-5',6'-dione
    • Triphasiaxanthin 3-Hydroxysemi-b-carotenone 3'-Hydroxy-5,6-seco-b,b-carotene-5,6-dione or 3-hydroxy-5',6'-seco-b,b-carotene-5',6'-dione
  • Retro-carotenoids and retro-apo-carotenoids
    • Eschscholtzxanthin 4',5'-Didehydro-4,5'-retro-b,b-carotene-3,3'-diol
    • Eschscholtzxanthone 3'-Hydroxy-4',5'-didehydro-4,5'-retro-b,b-caroten-3-one
    • Rhodoxanthin 4',5'-Didehydro-4,5'-retro-b,b-carotene-3,3'-dione
    • Tangeraxanthin 3-Hydroxy-5'-methyl-4,5'-retro-5'-apo-b-caroten-5'-one or 3-hydroxy-4,5'-retro-5'-apo-b-caroten-5'-one
  • Higher carotenoids
    • Nonaprenoxanthin 2-(4-Hydroxy-3-methyl-2-butenyl)-7',8',11',12'-tetrahydro-e,y-carotene
    • Decaprenoxanthin 2,2'-Bis(4-hydroxy-3-methyl-2-butenyl)-e,e-carotene
    • C.p. 450 2-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-2'-(3-methyl-2-butenyl)-b,b-carotene
    • C.p. 473 2'-(4-Hydroxy-3-methyl-2-butenyl)-2-(3-methyl-2-butenyl)-3',4'-didehydro-l',2'-dihydro-b,y-caroten-1'-ol
    • Bacterioruberin 2,2'-Bis(3-hydroxy-3-methylbutyl)-3,4,3',4'-tetradehydro-1,2,1',2'-tetrahydro-y,y-carotene-1,1'-dio

Some carotenoids are produced by bacteria to protect themselves from oxidative immune attack. The golden pigment that gives some strains of Staphylococcus aureus their name (aureus = golden) is a carotenoid called staphyloxanthin. This carotenoid is a virulence factor with an antioxidant action that helps the microbe evade death by reactive oxygen species used by the host immune system.[34]

Foods

Beta-carotene, found in pumpkinssweet potatocarrots and winter squash, is responsible for their orange-yellow colors.[1]Dried carrots have the highest amount of carotene of any food per 100 gram serving, measured in retinol activity equivalents (provitamin A equivalents).[17] Vietnamese gac fruit contains the highest known concentration of the carotenoid lycopene.[18]Although green, kalespinachcollard greens, and turnip greens contain substantial amounts of beta-carotene.[1] The diet of flamingos is rich in carotenoids, imparting the orange-colored feathers of these birds.[19]

Physiological effects

Reviews of epidemiological studies seeking correlations between carotenoid consumption in food and clinical outcomes have come to various conclusions:
  • A 2016 review looking at correlations between diets rich in fruit and vegetables (some of which are high in carotenoids) and lung cancer found a protective effect up to 400 g/day.[20]
  • A 2015 review found that foods high in carotenoids appear to be protective against head and neck cancers.[21]
  • Another 2015 review looking at whether caretenoids can prevent prostate cancer found that while several studies found correlations between diets rich in carotenoids appeared to have a protective effect, evidence is lacking to determine whether this is due to carotenoids per se.[22]
  • A 2014 review found no correlation between consumption of foods high in carotenoids and vitamin A and the risk of getting Parkinson's disease.[23]
  • Another 2014 review found no conflicting results in studies of dietary consumption of carotenoids and the risk of getting breast cancer.[24]
Carotenoids are also important components of the dark brown pigment melanin, which is found in hair, skin, and eyes. Melanin absorbs high-energy light and protects these organs from intracellular damage.
  • Several studies have observed positive effects of high-carotenoid diets on the texture, clarity, color, strength, and elasticity of skin.[25][26][27]
  • A 1994 study noted that high carotenoid diets helped reduce symptoms of eyestrain (dry eye, headaches, and blurred vision) and improve night vision.[28][29]
Humans and other animals are mostly incapable of synthesizing carotenoids, and must obtain them through their diet. Carotenoids are a common and often ornamental feature in animals. For example, the pink color of salmon, and the red coloring of cooked lobsters and scales of the yellow morph of common wall lizardsare due to carotenoids.[30][citation needed] It has been proposed that carotenoids are used in ornamental traits (for extreme examples see puffin birds) because, given their physiological and chemical properties, they can be used as visible indicators of individual health, and hence are used by animals when selecting potential mates.[31]



Foods. 2015 Dec; 4(4): 698–701. Published online 2015 Dec 10. doi: 10.3390/foods4040698 PMCID: PMC5224555 PMID: 28231232 Dietary Carotenoids and the Nervous System Billy R. Hammond, Jr. Author information Article notes Copyright and License information Disclaimer Department of Psychology, University of Georgia, Athens, GA 30602, USA; E-Mail: ude.agu@dnommahb; Tel.: 706-542-4812 Received 2015 Nov 30; Accepted 2015 Dec 7. This article has been cited by other articles in PMC. This issue of Foods is focused on the general topic of carotenoids within the nervous system. The focus is on the effects of the xanthophylls on the central nervous system (CNS), reflecting the majority of work in this area. This field of study is relatively new, despite knowing that carotenoids could be found, even within the brain itself, for nearly 40 years. The first report was in 1976 and described a patient taking high-dose beta-carotene as a treatment for erythropoietic protoporphyria. This patient had clearly detectable concentrations of beta-carotene within whole sections of the cerebrum [1]. The next notable contribution was by Cutler (1984) [2], who measured total carotenoids in the brain tissues of a variety of species (including humans), and argued that higher brain concentrations were linked to increased longevity when considered across species (a link between carotenoids and increased lifespan has also been argued within species ranging from drosophilia to human; [3,4]). The first study that really quantified carotenoid within brain with any real specificity, however, was conducted by Craft et al. (2004) [5]. The Craft study analyzed carotenoid content in five elderly brains (dissecting various brain sections and distinguishing between gray and white matter) and found a seeming preference for xanthophylls in the human brain. This certainly made sense in that only two (of the 20 or so carotenoids circulating within blood) dietary carotenoids, lutein (L) and zeaxanthin (Z), are typically found in retina, and, there, they achieve millimolar concentrations (the highest accumulation of carotenoids in the body). The retina is central nervous system tissue and is widely regarded as “an approachable part of the brain” [6]. Not only are L and Z in ocular tissue at high amounts, their exclusive presence makes it clear that they are concentrated via some active mechanism. The brain, like the retina, appears to accumulate xanthophylls not simply through passive diffusion but actively. If this is so, then the implication is that these carotenoids have a role to play in the actual function of the brain itself. As research has progressed, it has become clear that the carotenoids within the CNS do not play a singular role but appear to have a multitude of functions. Lutein, for instance, the dominant carotenoid in brain, has been described as a “work-horse molecule” [7]. The body often takes advantage of commonly available materials to serve a host of functions. For example, serotonin helps regulate not only gastrointestinal function and wound healing, but also dreaming, moods, and memory. Similarly, lutein appears to serve a surprising diversity of functions. One category, that the xanthophylls, in general, likely play within the CNS, appears to be simply prophylactic. The brain is largely fat and, of course, is very metabolically active and, hence, highly oxygenated. Carotenoids are known to inhibit lipid peroxidation. The brain is also clearly subject to inflammation, and carotenoids are known to be potent anti-inflammatory agents [8]. In addition to protection, however, the xanthophylls may serve other functions in brain tissue that range from epigenetic regulation to cellular communication [9,10]. On this front, the empirical work has outpaced basic research on mechanisms. We have some fairly convincing evidence that the xanthophylls influence the function of the central nervous system: Results ranging from temporal processing speed to cognition [11,12,13]. At present, however, we have very little understanding of how exactly the pigments achieve these changes. It is perhaps surprising that it has taken us this long to study how foods, and the components of which they are composed, influence critically important tissues like the brain. Disciplines like psychology and nutrition have rarely interacted in the past. Although “we are what we eat” may be an oft-quoted axiom, it rarely translates into actual study. This appears to be changing. In 2005, Hammond and Wooten [14] found that macular xanthophylls were correlated with temporal processing speed, a measure known to be determined largely at the level of the visual cortex. As the authors noted, L and Z are “…providing some functional improvement unrelated to protection. L, for instance, in model systems…, has been shown to improve gap junction communication, which could improve cell to-cell communication within the nervous system. Thus, increasing L and Z intake could theoretically improve signaling efficiency throughout the visual system.” In 2008, Johnson et al. [11] directly tested this idea and conducted a classic clinical trial (randomized, double-blind, placebo-controlled) on the efficacy of L, Z, and DHA on cognitive function of elderly women. That study found a statistically significant influence of these compounds on functions like verbal fluency and memory. The next pivotal studies in this area also emerged from the Jean Mayer Human Nutrition Research Center on Aging at Tufts University and were presented as conference abstracts in 2011 [15,16]This work confirmed Craft’s original finding of the predominance of xanthophylls in human brain and extended the work in a variety of ways: e.g., to infants and centenarians (the former helping to motivate the addition of xanthophylls to infant formula; the latter in collaboration with the Centenarian project at the University of Georgia). Since 2011, the number of researchers studying the role of xanthophylls in brain function continues to increase (see, for example, [12,13]). As is often the case with highly applied science, the number of sponsors in this area has increased concomitantly (certainly suggesting more research to come). Thus far, research on how nutrition in general and xanthophylls specifically influence the central nervous system has been highly productive; so much so that it serves as an influential model for an emerging discipline which could be loosely described as nutritional neuroscience. This volume contains papers from many of the leaders in this inchoate area and covers topics ranging from eye to brain. Go to: Conflicts of Interest The author declares no conflict of interest. Go to: References 1. Mathews-Roth M.M., Abraham A.A., Gabuzda T.G. Beta-carotene content of certain organs from two patients receiving high doses of beta-carotene. Clin. Chem. 1976;22:922–924. [PubMed] [Google Scholar] 2. Cutler R.G. Carotenoids and retinol: Their possible importance in determining longevity of primate species. Proc. Natl. Acad. Sci. USA. 1984;81:7627–7631. doi: 10.1073/pnas.81.23.7627. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 3. 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