Polyphenols and Neurodegenerative Diseases

 2011/2012 Pedro Manuel Marques de Freitas Polyphenols and Neurodegenerative Diseases Março, 2012   Pedro Manuel Marques de Freitas Polyphenols and Neurodegenerative Diseases Mestrado Integrado em Medicina Área: Bioquímica Trabalho efetuado sob a Orientação de: Doutora Maria da Conceição Costa Pinho Calhao Trabalho organizado de acordo com as normas da revista: Nutrional Neuroscience Março, 2012               3           4   Polyphenols and Neurodegenerative Diseases Pedro Freitas From: Department of Biochemistry, Faculty of Medicine, Porto University, Porto, Portugal. Correspondence: Pedro Manuel Marques de Freitas Department of Biochemistry, Faculty of Medicine, Porto University Al. Prof. Hernâni Monteiro 4200-319 Porto, Portugal Phone: +351225513624 Fax: +351225513624 E-mail: [email protected] Word count: 6334 Number of tables/figures: 3 5   Abstract With the expansion of the aged population, the prevalence of age-associated disorders like Alzheimer’s and Parkinson’s disease is growing, as well as the economic burden of its care and treatment. In this light, the preventive and therapeutic benefits of dietary polyphenols may directly improve human life and healthcare costs. Polyphenols display the capacity to protect neurons against oxidative stress, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognition. The anti-aging and neuroprotective aptitude of these dietary-derived phytochemicals counteract the environment in which neurodegenerative diseases arise. And while the mechanisms by which these effects occur are yet to be fully understood, it is evident that further investigation may yield a potential use for polyphenols as nutritional and pharmacological interventions against specific age-associated diseases. The focus of this review is aimed at presenting the classification, bioavailability and metabolism of polyphenols, as well as the mechanisms of action underlying their neuroprotective features. Keywords: Alzheimer, diet, inflammation, Parkinson, polyphenols. 6   Introduction Ageing is a highly complex process marked by succeeding events that promote alterations in the normal functioning of an individual organism over time.1 The overall decline in function of entire organs or systems with subsequent vulnerability to oxidative and inflammatory insults, is known to play a key role in both ageing and the complex etiology of certain age-associated diseases such as Alzheimer’s and Parkinson’s disease. The aim of this article is to give an overview on the dynamic capacity of polyphenols to protect the central nervous system, by exerting antioxidant activities, suppressing neuroinflammation, and improving cognitive function. Polyphenols: classification, bioavailability and metabolism Polyphenols (i.e. several hydroxyl groups on aromatic rings) are secondary metabolites of plants, that were initially identified as the plant’s defensive response against stress from ultraviolet radiation, pathogens, and physical damage.2 They also contribute to their pigmentation, and are responsible for the astringency and bitterness of plant derived food and beverage.3 About 10,000 phenolic compounds of plant origin have been characterized, ranging from simple molecules to highly polymerized compounds. They can be broadly divided 7   into two categories, flavonoids and non-flavonoid polyphenols, depending on the number of phenol rings and the chemical groups that bind these rings to one anothor (Table 1).4 Flavonoids comprise the largest and most important single group of polyphenols. They are found ubiquitously in plants and dietary sources include fruits, vegetables, cereals, tea, wine and fruit juices.5 Flavonoids consist of two aromatic carbon rings, benzopyran (A and C rings) and benzene (B ring), and may be divided into six subgroups based on the degree of oxidation of the C-ring, the hydroxylation pattern of the ring structure and the substitution of the 3-position.5 The main dietary groups of flavonoids are (1) flavonols (e.g. kaempferol, quercetin), which are found in onions, leeks, and broccoli; (2) flavones (e.g. apigenin, luteolin), which are found in parsley and celery; (3) isoflavones (e.g. daidzein, genistein), which are mainly found in soy and soy products; (4) flavonones (e.g. hesperetin, naringenin), which are mainly found in citrus fruit and tomatoes; (5) flavan-3-ols (e.g. catechin, epicatechin, epigallocatechin, epigallocatechin gallate), which are abundant in green tea, red wine, and chocolate; and (6) anthocyanidins (e.g. pelargonidin, cyanidin, malvidin), whose sources include red wine and berry fruits.6 Among the non-flavonoid polyphenols there are 4 distinct groups: (1) phenolic acids (e.g. caffeic acid, gallic acid); (2) lignans (e.g. secoisolariciresinol); (3) stilbenes (e.g. resveratrol); and (4) curcuminoids (e.g. curcumin). Two classes of phenolic acids can be distinguished: derivatives of benzoic acid and derivatives of cinnamic acid. The benzoic acid content of edible plants is generally very low, with the exception of certain red fruits, black radish, onions and tea leaves (gallic acid). The cinnamic acids are more common and consist chiefly of p-coumaric, caffeic, 8   ferulic and sinapic acids . Blueberries, kiwis, plums, cherries and apples possess the highest content of cinnamic acids, being caffeic acid the most abundant phenolic acid.5 Lignans are formed of 2 phenylpropane units. The richest dietary source is linseed, which contains secoisolariciresinol and low quantities of matairesinol. Lentils, triticale, wheat, garlic, asparagus, carrots, pears and prunes are minor sources of lignans.5 Stilbenes are molecules of two phenolic rings connected by an ethene molecule. Resveratrol is the main stilbene and can be found in grapes, red wine, berries, pistachios and peanuts. There are two isomeric forms of resveratrol, cis-resveratrol and the most biologically active trans-resveratrol (trans-3,4,5-trihydroxystilbene).7 Curcuminoids are major chemical components of turmeric, a commonly used spice derived from the rhizome of the plant Curcuma longa, used to give specific flavor and yellow color to Indian curries and in food preservation. Curcumins in turmeric include curcumin I (77%), demethoxycurcumin (curcumin II, 17%), and bisdemethoxycurcumin (curcumin III, 3%).8 Bioavailability of polyphenols varies widely from one compound to another, so it is important to realize that the polyphenols that are most common in the human diet are not necessarily the most active within the body. Chemical structure, which determines their rate and extent of intestinal absorption is the main factor responsible for their biological activities. Other variables, such as intestinal absorption, excretion of glucuronides toward the intestinal lumen, metabolism by the microflora, intestinal and hepatic metabolism, plasma kinetics, the nature of circulating metabolites, binding to albumin, cellular uptake, intracellular metabolism, accumulation in tissues, and biliary and urinary excretion are also very important, and should be integrated when determining polyphenols bioavailability and be considered in bioactivity research.5 9   synaptic plasticity.67 Intracellular Aβ may target cytoplasmic signaling pathways and impair mitochondrial function.68 Aβ-mediated ROS production is also linked to increased inflammatory responses, including increased production of cytokines, nitric oxide, and eicosanoids.69-71 PD is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of dopaminergic neurons in the substancia nigra pars compacta, and it affects approximately 1% of the population over the age of 50.54,72 Clinical manifestations of PD include motor impairment involving resting tremor, a slowing of physical movement (bradykinesia), postural instability, gait difficulty, and rigidity. The most probable origin of the etiology of dopaminergic neuronal demise is a combination of genetic susceptibilities and environmental factors, including heavy metals and herbicides.73-74 Oxidative stress has been widely believed to be an important pathogenetic mechanism of neuronal apoptosis in PD.75 The majority of PD cases are sporadic (90 – 95%), while familial cases account for 5 – 10% of PD.76 One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein.77-78 The toxic effects of α-synuclein include impaired endoplasmic reticulum, Golgi fragmentation, sequestration of anti-apoptotic proteins into aggregates, and the formation of pores on cellular membranes.79 The onset of PD is accompanied by the dramatic depletion of levels of glutathione in substancia nigra , resulting in a selective decrease in mitochondrial complex I activity (a major hallmark of PD) and a marked reduction in overall mitochondrial function.80 The harm to mitochondrial 16   complex I causes α-synuclein aggregation, which contributes to the death of dopamine neurons, leading to a dopamine deficit in the striatum. The features of enhanced oxidative stress linked with PD are supported by postmortem studies, and by studies demonstrating the capacity of oxidative stress to induce nigral cell degeneration.81 In addition, other important factors, involving inflammation, toxic action of nitric oxide, defects in protein clearance, and mitochondrial dysfunction all contribute to the etiology of PD.82 Iron content alterations have been described in the brains of PD and AD patients, which may be caused to a large extent, by endogenous dysregulation of iron uptake, transport, distribution , and storage.83-86 Iron is one of the most essential transition metals involved in the formation of ROS, owing to its interaction with hydrogen peroxide through Fenton chemistry and generation of the aggressively reactive hydroxyl radical. Accumulation of iron, specifically in the substancia nigra pars compacta, is one cardinal feature of PD, and is considered to be a major contributor to OS.87 Analysis of AD brains indicates iron accumulation within specific brain regions, displaying selective vulnerability to neurodegeneration, such as the hippocampus and cerebral cortex.88-89 Damage to brain cells in Parkinson’s, Alzheimer’s and other neurodegenerative diseases seems to result from the combination of a number of damaging factors including excessive inflammation and increased levels of iron, both of which lead to increased free radical production, exhaust the brain’s supply of protective antioxidants and trigger the production of certain proteins, such as Aβ. 17   Polyphenols display neuroprotective effects One of the most important aspects of current polyphenol research is the focus on the neuroprotective capacity that is a characteristic feature of this broad family of compounds. There is increased interest in uncovering efficient antioxidants to reduce the risk of AD, PD, and other neurodegenerative disorders, since current therapeutic approaches are merely symptomatic, without any disease-modifying activity. Because many diseases of ageing can be directly linked to repeated oxidative stress and chronic inflamation,90 therapies that can diminish such effects have become an important tool in seeking more effective treatments for diseases such as Alzheimer’s and Parkinson’s.53,91 Continuing research highlights the dynamic capacity of polyphenols to protect against age-associated disorders through a variety of important mechanisms. The chemical antioxidant activity of polyphenols is correlated with the number of hydroxyl groups present on the aromatic A and B rings, and with the presence of a C2-C3 double bond, the most active ones containing between 3 and 6 hydroxyl groups.52 The antioxidant mechanism is based on the donation of a hydrogen and the formation of a phenoxyl radical that undergoes stabilization either by release of a further hydrogen, or by reaction with another radical.3 In general, polyphenols have the capacity to chelate metal ions and to quench free radical species.53 The ability of flavones and flavan-3-ol polyphenols to chelate redox-active transition metal ions, such as iron or copper, depends on the presence of their carboxylic and hydroxylic groups and may contribute to their antioxidant activity, because it prevents metals from catalyzing free radical formation.54 18   Green tea is an extremely popular drink in eastern countries, and green tea polyphenols known as catechins, are natural plant flavonoids found in the tea leaves. The major tea catechins include, epicatechin (EC), epigallocatechin (EGC), EC gallate (ECG), and EGC gallate (EGCG).92 Other compounds in green tea are the flavonols (quercetin, kaempferol, and rutin), caffeine, phenolic acids, and theanine.93 Catechins are especially concentrated in green tea, which account for 30 – 40% of the dry weight of the leaves.94-95 All four tea catechins have been demonstrated to be potent antioxidants, resulting from their direct oxygen and nitrogen species scavenging properties, induction of endogenous antioxidant enzymes, and the capacity to bind and chelate excess of divalent metals, such as iron and copper.96-97 The rank order of antioxidant abilities of green tea components is EGCG>ECG>EGC>EC.98 Catechins are well absorbed after oral administration, and are biotransformed in the liver to their conjugated metabolites, i.e., glucuronidated, methylated, sulfated derivatives.1 By simply drinking green tea, polyphenols can cross the BBB and have neuroprotective effects.99 Nutritional studies demonstrated that a consumption of green tea could have a beneficial role in reducing the risk of PD.100 The mechanisms underlying this beneficial role were the capacity of EGCG to act as an iron chelator,101 and increase the activity of two major antioxidant enzymes, superoxide dismutase and catalase, further helping to decrease free radical damage.102 EGCG has also been shown to competitively inhibit the uptake by the presynaptic or vesicular transporters of metabolites from the neurotoxin MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).103 This competition could protect dopaminergic neurons against MPTP induced injury.104 In AD, EGCG has been reported to interfere with an early step in the amyloid formation cascade by binding directly to the natively unfolded α-synuclein and Aβ 19   pollypeptides, thus inhibiting their fibrilogenesis and redirecting them into an alternative “off pathway” before they become toxic.105 EGCG has recently been found to convert large, mature α-synuclein and Aβ fibrils into smaller, amorphous non-toxic protein aggregates.106 In addition, EGCG exerts neuroprotection by modulating intracellular signaling pathways such as MAPK,107 PKC,108-110 and PI-3K/Akt111 which will be discussed later in this review, and inhibit the activation of nuclear factor kappaB112 (NF-κB) and pro-apoptotic pathways.113 Several studies using dietary supplements with either spinach, strawberries, or blueberries extracts have been reported to reduce some neurological deficits in aged animals (Morris water maze performance).114-118 In addition, blueberries supplementation was also effective in reversing cognitive declines in object recognition.119 Catechin, epicatechin, and anthocyanidins are the main polyphenols present in blueberries, and there is a significant positive correlation between their serum content and postprandial antioxidant status.120 Aged rats with blueberries supplemented diet had significantly lower levels of NF-κB than aged control diet rats,119 revealing that the neuroprotection conceded might involve more than the blueberries extract antioxidant actions. Blueberries extract supplementation could also reduce the volume of infarction in the cerebral cortex, and increase the post-stroke locomotor activity induced by isquemia/reperfusion,118 as well has protect against neuronal loss in the CA1 and CA2 regions of the hippocampus after cerebral isquemia.121 Additionally, blueberries supplemented APP/PS1 mice exhibited greater levels of hippocampal extracellular signal regulated kinase (ERK), as well as striatal and hippocampal PKCα, when compared with transgenic mice maintained on a control diet.122 Resveratrol is the main non-flavonoid polyphenol found in grapes and red wine, and it has been reported to possess antioxidant, anti-inflammatory, antimutagenic, and 20   anticarcinogenic effects,123-124 as well as a beneficial effect against AD pathology by promoting anti-amyloidogenic mechanisms.100 Several epidemiological studies indicate that a moderate consumption of wine is associated with a lower incidence of AD.125-127 Resveratrol not only possesses the capacity to directly scavenge free radical species, but also regulates the cytotoxic effects of Aβ oligomers and fibrils via phosphorylation of PKC, which activates the transmembrane protein α-secretase.128-129 α-secretase catalyzes the formation of a soluble, non-amyloidogenic (non-plaque forming) protein from APP , and thus does not allow for the formation of neuritic plaques. Modulation of NF-κB activity, or NF-κB/SIRT1 pathway could also be implicated in the neuroprotective effect of resveratrol, since activation of SIRT1 by resveratrol inhibits NF-κB signaling by promoting deacetylation of lys310 of RelA/p65130, thereby protecting cells against the Aβ peptide.131-132 Genistein, the most active component of soy isoflavone, is a phytoestrogen that is capable of crossing the BBB,133 manifesting potent antioxidative properties,134-135 and neuroprotective activity.59 Genistein has been shown to protect neurons form Aβinduced damages largely via a estrogen receptor mediated pathway, as well as by its antioxidative properties.59 Curcumin has been used for centuries in Asia as a food additive and a traditional herbal medicine, and it has been revealed that besides its potent antioxidative, and antiinflammatory properties, it also exhibits anti-amyloidogenic effects.136 Epidemiological studies have raised the possibility that the properties of this molecule are responsible for the significantly reduced (4.4 fold) prevalence of AD in India compared to the United States of America.137 These observations could be explained by the ability of curcumin to reduce IL-1β,138 a proinflammatory cytokine, inhibit β-secretase and Aβ aggregation,7,139 and bind to the redox-active metals iron and copper.140 The 21   neuroprotective effects of curcumin relevant to PD are likely to be associated with its antioxidant and anti-inflammatory properties.141-142 Acute oral administration of curcumin results in poor bioavailability due to its rapid conversion to glucuronides, suggesting that very small doses of curcumin are necessary for its neuroprotective effect.2 In addition, it is worth noting that excessive application of curcumin may produce pro-oxidative effects.143 The flavonoid-rich ginkgo biloba has been used for 5000 years in traditional Chinese medicine. EGb 761 is a standardized extract of ginkgo biloba, whose flavonoid content is composed of quercetin, kaempferol, and isorhamnetin. Several studies have highlighted the potential of EGb 761 and its constituents to prevent lipid oxidation,144 and to act as antioxidants and free radical scavengenrs.145-146 Ginkgo biloba also exerts a combination of anti-amyloidogenic, and anti-apoptotic effects particularly in connection with age related dementias and AD.147-149 EGb 761 is able to inhibit Aβ fibrils formation due to its iron chelating properties,147,150 and is able to rescue primary hippocampal neurons and PC12 cells against the toxicity of the Aβ peptide.150-151 Polyphenols improve memory With ageing, neuronal populations and synaptic connections are lost over time, resulting in diminished efficiency in the processing and storage of sensory information, however, emerging evidence suggests that polyphenols are able to induce improvements in memory acquisition, consolidation, storage, and retrieval. There is strong evidence that flavonoid intake is associated with better cognitive evolution, i.e. the preservation of cognitive performance with ageing.152 Furthermore, flavonoids found in fruits and 22   fruit juices (most notably flavan-3-ols, flavanones, and anthocyanins) have the capacity to improve memory.30,153-155 A number of animal intervention studies, using diets containing between 1 and 2% (w/w) freeze-dried fruit/fruit juice, have indicated that grape, pomegranate, strawberry, and blueberry, as well as pure flavonoids (epicatechin and quercetin), are capable of affecting several aspects of memory and learning, notably rapid156 and slow157-160 memory acquisition, short-term working memory,153,161-164 longterm reference memory ,165 reversal learning,156,161 and memory retention/retrieval.166 For example, fruits such as strawberry, blueberry, and blackberry (all rich in anthocyanidins and flavan-3-ols) have been shown to be beneficial in retarding functional, age-related central nervous system and cognitive behavioral deficits.157,167-168 There is also extensive evidence that blueberries are effective at reversing age-related deficits in spatial working memory.153,163,165,168-173 The ability of polyphenols to reverse age-related declines in memory, relies on their potential to interact with the cellular and molecular architecture of the brain responsible for memory. In general, the short-term storage of both implicit and explicit memory involves functional changes in the strength of pre-existing synaptic connections, whilst their long term storage requires the synthesis of new protein and the growth of new connections.5 The capacity of polyphenols to interact with, and effectively modify the pathways within neurons and synapses leading to changes in the efficiency of de novo protein synthesis, will allow for the likelihood to affect the process of memory.5 Long-term potentiation (LTP) is widely considered to be one of the major mechanisms by which the brain learns and maintains memories.174-175 It refers to a persistent increase in the chemical strength of a synapse, and is known to contribute to “synaptic plasticity” or the increased strength of the connection between two neurons, a process thought to underlie memory.176-177 Various signaling pathways have been linked 23   with the control of de novo protein synthesis in the context of LTP, synaptic plasticity and memory: (1) cAMP-dependent protein kinase (protein kinase A);178 (2) protein kinase B (PKBAkt);179 (3) PKC;180 (4) calcium-calmodulin kinase (CaMK);181 and (5) ERK.182-183 All five pathways converge to signal to the cAMP-response element-binding protein (CREB), a transcription factor which binds to the promoter regions of many genes associated with synapse re-modeling, synaptic plasticity and memory (Figure 1).185-185 The importance of CREB activation in the induction of long-lasting changes in synaptic plasticity and memory is highlighted by studies which show that disruption of CREB activity specifically blocks the formation of long-term memory,186 whereas agents that increase the amount or activity of CREB accelerate the process.187 Furthermore, CREB is known to be a critical transcription factor linking the actions of neurotrophins, such as BDNF, to neuronal survival, differentiation, and synaptic function.188-189 BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system. It’s secretion from neurons is under activity dependent control and is crucial for the formation of appropriate synaptic connections during development, and for learning and memory in adults.190 Decreases in BDNF and pro-BDNF have been reported in AD,191-192 and the importance of pro-BDNF has been emphasized by the finding that a polymorphism that replaces valine for methionine at position 66 of the pro-domain is associated with memory defects and abnormal hippocampal function in humans.193 Ultimately, CREB activation and neurotrophyn synthesis are able to induce synaptic plasticity, and represents a vital stage in converting brief afferent signals into long lasting memory.5 The increase in synaptic receptor, and neuronal spine density and morphology are hallmarks of synaptic plasticity ,194-195 and constitute integral events in LTP.5 24   Flavonoids through the interactions within MAPK pathways, such as the ERK pathway are believed to influence memory,196 since ERK is associated with prosurvival and pro-neurotrophin signaling through the activation of CREB.197-199 Fisetin, a flavonoid found in strawberries, has been shown to improve LTP and to enhance object recognition in mice by a mechanism dependent on the activation of ERK and CREB.200 Similarly, the flavan-3-ol (-)epicatechin induces both ERK ½ and CREB activation in cortical neurons and subsequently increases CREB regulated gene expression,201 whilst nanomolar concentrations of quercetin are effective at enhancing CREB activation.202 The citrus flavanone hesperetin is also capable of activating ERK ½ signaling in cortical neurons,203 and EGCG is capable of restoring both PKC and ERK ½ activities in 6hidroxydopamine treated and serum deprived neurons.109,204 These effects on the ERK pathway are highly concentration-dependent, with high affinity receptor agonist-like actions at low concentrations, and direct enzyme inhibition at high concentrations.205-206 In addition, the finding that anthocyanidins and flavan-3-ols appear in the hippocampus following blueberry supplementation may indicate that changes in memory are linked directly to flavonoids and their action on the ERK-CREB-BDNF pathway.207 Another mechanism that may exert beneficial effects on memory consists on the ability of flavonoids to activate the Akt/PKB pathway, which also has the potential to activate CREB. Hesperetin can activate the Akt/PKB pathway, as well as inhibit proapoptotic proteins such as ASK1, Bad, caspase-9, and caspase-3 in cortical neurons.203 Flavonoid-induced activation of CREB and enhancement of BDNF expression in neurons will ultimately lead to the activation of PI3 kinase/Akt signaling pathway via the binding of BDNF to preor post-synaptic TrkB receptors.208 These events trigger the activation of the mTOR pathway and the increased translation of specific mRNA subpopulations,209 including the activity-regulated cytoskeletal-associated protein 25   References 1. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, et al. Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One. 2004;6:e5846. 2. Ferguson LR. Role of plant polyphenols in genomic stability. Mutations Research. 2001;475:89-111. 3. Roosi L, Mazzitelli S, Arciello M, Capo CR, Rotilio G. 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