Anthocyanins Potentially Contribute to Defense Against Alzheimer's Disease
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molecules Review Anthocyanins Potentially Contribute to Defense against Alzheimer’s Disease Mohammad Afzal *, Amina Redha and Redha AlHasan Biological Sciences Department, Faculty of Science, Kuwait University, Safat-13060, Kuwait; [email protected] (A.R.); [email protected] (R.A.) * Correspondence: [email protected]; Tel.: +1-352-681-7347 Academic Editors: Takanori Tsuda and Wilhelmina Kalt Received: 25 September 2019; Accepted: 5 November 2019; Published: 22 November 2019 Abstract: Anthocyanins (ANTs) are plant pigments that belong to a flavanol class of polyphenols and have diverse pharmacological properties. These compounds are primarily found in fruits and 1 vegetables, with an average daily intake of 180 mgd− of these compounds in the developed world. ANTs are potent antioxidants that might regulate the free radical-mediated generation of amyloid peptides (Abeta-amyloids) in the brain, which causes Alzheimer’s disease (AD). This study presents a literature review of ANTs from different berries and their potential therapeutic value, with particular emphasis on neurodegenerative AD, which owing to oxidative stress. This review also highlights reactive oxygen species (ROS) generation through energy metabolism, nitrogen reactive species, the role of transition metals in generating ROS, and the radical-quenching mechanisms of natural antioxidants, including ANTs. The current status of the bioavailability, solubility, and structure activity relationship of ANTs is discussed herein. Keywords: anthocyanins; antioxidants; transition metals; reactive oxygen species 1. Introduction By definition, berries are small fleshy fruits produced from a single ovary. Berries from eight plant species are considered the healthiest fruit for consumption, namely strawberries, acai berries, grapes, blueberries, goji berries, bilberries, raspberries, and cranberries. Most berries are rich in non-nutritive/nutritive, water-soluble, bioactive flavonoid polyphenols. These include anthocyanidin (sugar-free anthocyanin (ANT)), ANT-3-glycosides, 5-glycosides, diglucosides, acylated ANTs, and enzymatically formed flavanol-ANTs adducts (vitisins). Pyrano-anthocyanins are formed by adding pyruvic acid and acetaldehyde to anthocyanin molecules. In ANTs, glycosylation might occur at positions 30, 40 and 50, as shown in Figure1[ 1]. These molecules have a common flavylium cation structure that generates color. ANTs are present in plant cell vacuoles, and their color is cell-sap pH-dependent [2,3]. Conocarpus lancifolius is a wild plant resistant to biotic and abiotic stress in the desert of Kuwait, and its berries are very rich in various anthocyanins (unpublished work of the authors). There are approximately 17 naturally occurring ANTs, six of which are very common. These include ANT glycosides/diglucosides of cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin (Figure1). These ANTs also contain the six most common sugar residues, namely glucose, rhamnose, galactose, arabinose, xylose, and rutinose [2] (Figure1). To-date, more than 6000 flavonoid polyphenols have been reported [4]. Epidemiological and preclinical studies have shown that the polyphenols of red wine contribute in modulating neurodegenerative diseases, such as Alzheimer’s disease (AD) [5]. One such polyphenol is quercetin-3-O-glucoside (QG), which is a component of many vegetables and fruits, including apples, grapes, black tea, green tea, broccoli, and red onions. It is a potent brain-targeting bioflavonoid that is beneficial in limiting AD. A QG Molecules 2019, 24, 4255; doi:10.3390/molecules24234255 www.mdpi.com/journal/molecules Molecules 2019, 24, 4255 2 of 15 Molecules 2019, 24, x FOR PEER REVIEW 2 of 15 metabolite, quercetin-3-O-glucuronide, accumulates in the brain, significantly reducing Abeta 1–40 andaccumulates Abeta 1–42 in toxicity. the brain, At present,significantly many reducing health supplements Abeta 1–40 and containing Abeta 1–42 quercetin toxicity. are At available present, over themany counter. health Beta-secretase supplements iscontaining a rate limiting quercetin enzyme are available that forms over a the number counter. of Beta-secretase Abeta peptides is a from rate the amyloidlimiting precursor enzyme that protein forms to a yieldnumber Abeta of Abeta 40,Abeta41, peptides from and Abetathe amyloid 25–35. precursor These Abeta protein peptides to yield are involvedAbeta 40, in amyloid-mediatedAbeta41, and Abeta neurodysfunction 25–35. These Abeta [6]. peptides are involved in amyloid-mediated neurodysfunction [6]. 5 R3’ R4’ R5’ R3 R R6 R7 Cyanidin - OH - OH - H - OH - OH - H - OH Delphinidin - OH - OH - OH - OH - OH - H - OH Pelargonidin - H - OH - H - OH - OH - H - OH Malvidin -OCH 3 - OH - OCH3 - OH - OH - H - OH Peonidin -OCH3 - OH - H - OH - OH - H - OH Petunidin -OH - OH - H - OH - OH - H - OCH3 Chrysanthemin -OH - OH - H -O-Glucose - OH - H - OCH3 Cynidin-3-galactoside-OH - OH - H -O-galactose - OH - H - OCH3 Cyanidin-3-arabinoside -OH -O-arabinose - OCH - OH - H - OH - H 3 Figure 1. Naturally occurring substituted cyanidins and anthocyanidins. Figure 1. Naturally occurring substituted cyanidins and anthocyanidins. ToTo date, date, more more than than 650 650 ANTsANTs havehave beenbeen identifiedidentified from fruits fruits and and vegetables vegetables [7]. [7 ].ANT ANT micronutrientsmicronutrients have have many beneficialmany beneficial health eff ects,health including effects, cancer-preventive, including cancer-preventive, immuno-protective, andimmuno-protective, neuroprotective eandffects; neuroprotective moreover, they effects; prevent moreover, cognitive they function prevent impairment,cognitive function alleviate inflamedimpairment, and arduousalleviate joints,inflamed and and attenuate arduous rotundity, joints, and alopecia, attenuate dementia, rotundity, cardiovascular alopecia, dementia, diseases, andcardiovascular obesity [8– diseases,13]. Blackberries and obesity [8–13]. (Rubus Blackberries sp.), mulberries (Rubus sp (Morus.), mulberries alba L.), (Morus and alba elderberries L.), and haveelderberries antimutagenic, have antimicrobial,antimutagenic, anti-inflammatory, antimicrobial, anti-inflammatory, antidiabetic, and anti-neurodegenerativeantidiabetic, and activitiesanti-neurodegenerative [14,15]. These activities activities are [14,15]. associated These with activities their potentare associated antioxidant with actions,their potent which antioxidant help control oxidativeactions, stresswhich (OS) help due tocontrol aging. Theseoxidative ANTs stress inhibit (OS) metallo-proteinases due to aging. 2 andThese 9, which ANTs are associatedinhibit withmetallo-proteinases the metastasis of cancerous2 and 9, cells,which and are cisplatin-induced associated with renalthe metastasis pathophysiology of cancerous [16–19 ].cells, The inand vitro effectcisplatin-induced of ANTs on metabolic renal pathophysiology syndrome-related [16–19]. enzymes The and in anxietyvitro effect has alsoof beenANTs reported on metabolic [20,21 ]. syndrome-relatedBerries are also enzymes rich in and bioflavonoids anxiety has also and been ellagitannins, reported [20,21]. which are naturally found in fruits and vegetables,Berries are particularly also rich in bioflavonoids in the white and core ellagitannins, of citrus fruits. which Bioflavonoids are naturally found and their in fruits glycosides and vegetables, particularly in the white core of citrus fruits. Bioflavonoids and their glycosides are are structurally related to anthocyanidins and ANTs, affecting a wide range of biological systems. structurally related to anthocyanidins and ANTs, affecting a wide range of biological systems. These These molecules are the main antioxidants in plants used to treat allergies, viral infections, arthritis, molecules are the main antioxidants in plants used to treat allergies, viral infections, arthritis, and and anti-inflammatory conditions, including hemorrhoids. anti-inflammatory conditions, including hemorrhoids. Molecules 2019, 24, 4255 3 of 15 MoleculesQuercetin 2019, 24 (Figure, x FOR 2PEER) is a REVIEW polyphenolic bioflavonoid that is highly concentrated in red wine,3 grapes,of 15 broccoli, citrus, and red and yellow onions. In human breast cancer cell lines, quercetin is an agonist Quercetin (Figure 2) is a polyphenolic bioflavonoid that is highly concentrated in red wine, of the G protein-coupled α,β-estrogen receptors, which is activated by 17β-estradiol, in addition grapes, broccoli, citrus, and red and yellow onions. In human breast cancer cell lines, quercetin is an to regulating different genes and modulating learning and memory [22,23]. In rats, quercetin does agonist of the G protein-coupled α,β-estrogen receptors, which is activated by 17β-estradiol, in not undergo phase I metabolism; however, in phase II metabolism, it produces many conjugated addition to regulating different genes and modulating learning and memory[22,23]. In rats, metabolites, with five of its hydroxyl groups glucuronidated by UDP-glucuronosyl transferase. quercetin does not undergo phase I metabolism; however, in phase II metabolism, it produces many Quercetin-3-conjugatedO -glucosidesmetabolites, (Q-3-G)with five exhibit of its estrogenic-likehydroxyl groups behavior glucuronidated with non-specific by UDP-glucuronosyl proteins kinase inhibitortransferase. activities, Quercetin-3- and theyO-glucosides promote estrogenic (Q-3-G) exhibit receptors estrogenic-like [22,24]. Quercetin, behavior its with 3-O -glucosidenon-specific and its metaboliteproteins kinase quercetin-3- inhibitorO activities,-glucuronide