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Cognitive and neuroprotective effects of chlorogenic acid Erin Heitman, Donald K. Ingram
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Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, USA
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Objectives: The aim of this review was to provide an overview of studies conducted to determine the effects of chlorogenic acid (CGA) on cognition and neurological health. Methods: A literature search was conducted using PubMed and various search terms including chlorogenic acid, CGA, CA, memory, neuroscience, cognition, nutrition, antioxidant, pharmacokinetics, neuroprotection, and neurodegeneration. Results: Many studies have linked CGA consumption to a wide range of health benefits, including neuroprotection, cardioprotection, weight loss, chemopreventive properties, anti-inflammatory activity, decreased blood pressure, decreased diet-induced insulin resistance, decreased blood pressure, anxiolytic effects, and antihyperalgesic effects. Pre-clinical and clinical studies both provide evidence that CGA supplementation could protect against neurological degeneration and the resulting diseases associated with oxidative stress in the brain; however, no formal, well-controlled studies have been performed to date. Discussion: Recent research suggests that dietary consumption of CGA could produce a wide range of health benefits and physiological effects. There is also mounting evidence that the consumption of polyphenols, including CGA, in the diet could reduce the risk of developing neurodegenerative conditions. Further studies should be conducted with a focus on the effects of CGA on cognition and the nervous system and employing well-designed clinical studies. Keywords: Chlorogenic acid, Antioxidant, Cognition, Memory, Neuroprotection, Neurodegeneration, Alzheimer’s disease, Parkinson’s disease
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As a polyphenol with wide distribution in the human diet, chlorogenic acid (CGA) is gaining increased research attention regarding a wide range of health benefits, a list of which is presented in Table 1. CGAs comprise a family of esters formed between specific trans-cinnamic acids and quinic acid.1 Typically the only CGA commercially available is 5O-caffeoylquinic acid, the molecular structure of which is shown in Fig. 1.1 Ito et al. 2 noted that this form of CGA can pass the blood–brain barrier (BBB) as a metabolite or in its pure form to act directly on the central nervous system (CNS). CGA is also a compound found in a wide variety of food and beverages commonly consumed by humans including fruits, vegetables, olive oil, spices, wine, and coffee.1 Fruit sources include apples,1,17 cherries,18,19 plums,20 berries,21 apricots,22 and Correspondence to: Donald K. Ingram, Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, LSU System, 6400 Perkins Road, Baton Rouge, LA 70808, USA. Email: [email protected]
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1476830514Y.0000000146
tomatoes,23,24 while a common vegetable source is potatoes.1,25,26 CGA is also found in beverages including tea,1,27,28 coffee,28,29 and wine.1 Caffeinated and decaffeinated coffees both contain high amounts of CGA,14 and caffeinated coffee contains more CGA (7–9%) than caffeine (1%).29 A single cup of coffee contains between 70 and 350 mg of CGA, so coffee drinkers could obtain up to 1 g of CGA a day.1 In coffee-consuming populations, CGA is likely one of the major polyphenols in the diet.20 Table 2 provides examples of various food and beverage sources with high contents of CGA. Because CGA is present in a variety of food and beverages consumed daily, research is accelerating to ascertain its nutritional benefits and physiological effects. Antioxidant properties of CGA have been demonstrated in numerous studies including abilities to induce cardioprotective effects,8 anti-tumor activity,12 and even neuroprotective effects.5–7 The neuroprotective effects of CGA have been postulated to stem primarily from its activity as an antioxidant
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Table 1. Purported health benefits of CGA Health benefit
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Weight loss Neuroprotection Cardioprotection Chemopreventive properties Anti-inflammatory activity Decreased diet-induced insulin resistance Decreased blood pressure Anxiolytic effects Antihyperalgesic effects
3,4 5–7 8,9 10–12 13 14 8 15 16
Numerous epidemiological studies have shown strong correlations between the consumption of polyphenols in the diet and reduced risk of developing neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases.36,37 There is mounting evidence that coffee consumption, high in CGA, appears to be neuroprotective and can attenuate cognitive decline.5,14,29,38,39 In this review, we will consider a wide range of basic and clinical studies pertaining to the potential for the CGA to benefit cognition and reduce risk of neurodegeneration.
In vitro studies
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Figure 1. Chemical structure of CGA (5-O-caffeoylquinic acid).15
A recent study by Kim et al. 40 investigated the protective effect of CGA on oxidative damage to neuronal cells and found that CGA strongly inhibited apoptotic nuclear condensation induced by hydrogen peroxide (H2O2) in neuronal cells. When primary neuronal cultures were treated with 50 μM H2O2 for 24 hours, either with or without pre-treatment of 12.5–100 μM CGA for an hour, the cultures pre-treated with CGA showed clear protection against H2O2-mediated neuronal cell death.40 The results suggest that CGA treatment could protect against neurological degeneration associated with oxidative stress in the brain.40 Using cultures of retinal ganglion cells, Nakajima et al. 41 reported that CGA increased cellular protection against oxidative stress induced by L-buthionine(S,R)-sulfoximine to deplete glutathione in combination with glutamate to inhibit cystine uptake. In addition, they noted reduced lipid peroxidation in homogenates of mouse forebrain treated with CGA.41 Cho et al. 42 demonstrated similar neuroprotection against H2O2-induced oxidative stress in PC12 cells treated with CGA. Specifically, the treated cells exhibited less production of ROS, reduced nuclear condensation, and DNA fragmentation, as well as inhibited cleavage of poly(ADP-ribose) polymerase and downregulation of Bcl-X(L) and caspase-3.42 The H2O2 activation of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase was also inhibited with CGA treatment.42 While some researchers investigated the antioxidant properties of CGA, others sought to determine whether CGA could play a role in the prevention of certain neurodegenerative conditions. For example, Han et al. 6 sought to determine if CGA had a neuroprotective effect against the overexpression of the amyloid-β (Aβ) protein associated with the pathogenesis of Alzheimer’s disease (AD). When human neuroblastoma clonal SH-SY5Y cells were incubated with 10 μM Aβ along with 20 μM CGA, the cells were significantly more viable compared to SH-SY5Y cells incubated solely in 10 μM Aβ.6 The incubation with CGA also reversed the cell death induced by Aβ.6 These results further suggest that CGA has a
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in the brain.7 Aging is associated with a decrease in efficient energy production and the accumulation of damage from reactive oxygen species (ROS).33,34 ROS-induced damage to mitochondria can result in decreased intracellular levels of adenosine triphosphate (ATP) that can trigger numerous detrimental processes and lead to cellular dysfunction and death.33,34 The brain is especially vulnerable to ROS because of its high oxygen consumption, limited antioxidant capacity, and high concentrations of the catalytic metal, iron.35 In this light, there has been intensive search for pharmacological and dietary interventions that might protect the brain against oxidative stress. Table 2. Approximate content of CGA in various food and beverage sources CGA (mg/g)
Instant coffee Medium roasted commercial coffee Potatoes Blueberries Apples Elderberries Sweet cherries Sour cherries Chokeberries Cherry tomatoes Apricots Plums Commercial black tea Commercial green tea
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30–40 2.97
30
0.3149–2.401 0.2439 0.014–0.284 0.0649 0.019–0.062 0.0523 0.0369 0.013–0.038 0.02126 0.009–0.026 0.0006 0.0006–0.0013
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21 17 18 18 18 18 23 22 20 32 32
Values were determined experimentally using differing methods for fresh products.
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at the cellular level, there have also been a number of pre-clinical studies conducted to assess effects of CGA on the brain and cognition in animal models. Another study conducted by Shen et al. 36 showed that CGA protected rat brain cerebellum from oxidative damage induced by methotrexate (MTX). MTX is used as a cytotoxic chemotherapeutic agent for many neoplastic diseases, but it causes severe neurotoxic effects by inducing oxidative stress in the CNS.48 When rats were given intraperitoneal (i.p.) injections of 100 mg/kg/day of CGA for 24 days followed by an i.p. injection of MTX (20 mg/kg) on day 21, oxidative damage to the rat cerebellum induced by MTX was greatly attenuated.36 As discussed previously, Han et al. 6 were able to show that CGA prevents the overexpression of Aβ in human neuroblastoma cells, but they also found that the administration of CGA improved spatial learning and memory in SAMP8 mice. These mice are a substrain of senescence-accelerated-prone mice (SAMP) that exhibit age-related deterioration in learning and memory and also have plaques that resemble ADlike depositions of Aβ.33,34,49 Beginning at 3 months of age, half the SAMP8 mice were orally administered CGA in drinking water at 6.7 mg/kg/day for a month, while the other half were given normal drinking water for this time period.6 Spatial learning and memory were evaluated using the Morris water maze (MWM) by measuring escape latency time to find the hidden platform over a 30-day trial period.6 The SAMP8 mice administered CGA at 6.7 mg/kg/day exhibited decreased escape latency time when compared to the SAMP8 mice provided normal drinking water; thus, CGA administration was determined to improve spatial learning and memory.6 As an additional model of learning and memory impairment, scopolamine has also been used to induce cognitive impairment in rodents.7,39 Scopolamine is a muscarinic receptor antagonist that elevates oxidative stress in the brain by inhibiting ATPase and significantly increasing AChE and malondialdehyde levels in the hippocampus and cortex.50–52 Because scopolamine produces symptoms of AD, it is often used experimentally to induce these symptoms as a model of cognitive impairment observed in the disease.53,54 In their study, Kwon et al. 7 examined the effects of CGA on scopolamine-induced memory and learning impairments in mice using three different paradigms: (1) the Y-maze; (2) passive avoidance; and (3) the MWM. Mice were given peroral ( p.o.) administrations of 0, 3, 6, or 9 mg/kg CGA in distilled water 1 hour prior to the Y-maze test and the training trials of the MWM and passive avoidance tests, and then 30 minutes later, memory impairment was induced using i.p. administrations of 0.5 mg/kg scopolamine.7 In the Y-maze, the degree of spontaneous alternation
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neuroprotective effect on Aβ-treated SH-SY5Y cells and support the idea that CGA could be used as a preventative agent against Aβ-induced pathology associated with AD.6 Another recent in vitro study by Oboh et al. 43 with a focus on AD investigated the effects of CGA on acetylcholinesterase (AChE) and butylcholinesterase (BChE). The inhibition of AChE and BChE are significant to AD treatment because their inactivity prevents the breakdown of acetylcholine (ACh) and butylcholine (BCh), increasing the concentrations of these neurotransmitters in the synaptic cleft, and thus increasing communication between neurons that utilize these neurotransmitters.43 Inhibition of AChE represents the primary treatment modality against the cognitive impairment observed in AD.44,45 The results demonstrated that CGA inhibited AChE and BChE in rat brain homogenates in vitro in a dose-dependent manner and thus suggested a new treatment modality for AD.43 In addition to possible effects on AD, other researchers have even demonstrated that CGA is a strong candidate as a preventative agent for Parkinson’s disease (PD).37 PD is a neurodegenerative disease associated with the formation of alpha-synuclein (α-syn) containing Lewy bodies in the substantia nigra and the degeneration of neurons in this brain region that produce the neurotransmitter, dopamine.46,47 It is postulated that the overexpression of α-syn induces the loss of dopaminergic neurons.37 The oligomerization of α-syn is thought to be a necessary step for pathogenic toxicity.37 A recent study by Teraoka et al. 37 showed that α-syn can only oligomerize by interacting with dopamine in its oxidized form. CGA was shown to inhibit the oxidation of dopamine, the interaction of oxidized dopamine with α-syn, and α-syn oligomerization.37 Overall, the results indicate that CGA is a promising candidate for the preventative treatment of PD.37 CGA has also been shown to reduce neuroinflammation resulting from overactive primary microglia in the brain.36 These mononuclear phagocytes release cytokines during inflammation, and it is the overproduction of cytotoxic factors, including nitric oxide (NO) and tumor necrosis factor alpha (TNFα), that can result in neurotoxic effects.36 Shen et al. 36 showed that CGA suppresses TNF-α release and NO production in primary microglia that were activated by lipopolysaccharide (LPS) treatment. This evidence suggests that CGA increases the survival of dopaminergic neurons by inhibiting LPS-induced microglial activation and therefore has potential neuroprotective effects against neurodegenerative disease caused by overactive microglia.36
Cognitive and neuroprotective effects of CGA
Pre-clinical studies While a substantial amount of research has been dedicated to ascertaining the effects of CGA on the brain
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In addition to ameliorating learning and memory deficits, CGA has also been documented to reduce anxiety and improve motor function in rodent models.15,58 A study by Hovatta et al. 59 revealed that anxiety-related behavior in mice is mediated by the expression of two cerebral genes, glyoxalase 1 and glutathione reductase 1, that protect cells from oxidative damage. These researchers found that inhibition of glutathione reductase 1 decreased anxietyrelated behavior, while overexpression of both genes led to increased anxiety-related behavior.59 Using this information, Bouayed et al. 15 examined the relationship between CGA supplementation and anxiety in mice. To examine anxiety-like behavior, the light/dark choice test, elevated plus maze, and free exploratory test were used.15 All drugs were administered i.p. 30 minutes before each test and at a volume of 10 ml/kg.15 For the light/dark choice test, mice were given physiological saline at 0.9% NaCl as the control group, CGA at 2, 10, 20, or 40 mg/kg in saline, or diazepam, a well-known anxiolytic, at 1 mg/kg in saline.15 Mice were given the same concentrations of physiological saline and diazepam for the free exploratory test, but were only given CGA at 20 mg/kg.15 For the elevated plus maze, the same concentrations of physiological saline, CGA, and diazepam were given as in the free exploratory test, but were divided into two additional treatment groups: a combination of CGA at 20 mg/kg and flumazenil at 5 mg/kg, as well as a combination of diazepam at 1 mg/kg and flumazenil at 5 mg/kg.15 Because flumazenil is a common benzodiazepine receptor antagonist, these investigators wanted to determine if the CGA reduced anxiety in the same manner as diazepam by activating benzodiazepine receptors.15 The results of the study indicate that CGA at 20 mg/kg decreased anxiety-related behavior similarly to diazepam at 1 mg/kg. Because the effects of CGA and diazepam were both blocked by flumazenil, the anti-anxiety effect of CGA was determined to be a result of its activity as a benzodiazepine receptor agonist.15 The effects of CGA on sensory-motor function after induced ischemia have also been investigated.58 Rats received middle cerebral artery occlusion to induce ischemia and were then given i.p. injections of 3, 10, and 30 mg/kg CGA at 0 and 2 hours following induction.58 Sensory-motor function was determined using the balance-beam test. Sensorymotor functional deficits in rats following ischemia were significantly reduced with treatments of 3, 10, and 30 mg/kg CGA in a dose-dependent manner.58 Overall, results suggest that CGA has a neuroprotective effect against ischemia-induced neuronal damage and its resulting sensory-motor functional deficit.58
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behavior is an indicator of short-term memory.7 CGA administered at 6 or 9 mg/kg resulted in significant increases in spontaneous alternation behavior and alleviated the decrease in performance caused by scopolamine.7 Oral treatment with 9 mg/kg CGA in the passive avoidance test and 6 or 9 mg/kg CGA in the MWM test also significantly attenuated the scopolamine-induced memory impairments.7 Jang et al. 39 studied the effect of instant decaffeinated coffee (IDC) containing CGA on scopolamine-induced memory impairment in rats. CGA was not studied directly, but rather, IDC containing high levels of CGA and other phytochemicals was used.39 For the MWM, IDC of 1 ml at 120 or 240 mg/kg in distilled water was administered p.o. using an oral gavage once a day for 6 days and then an hour before the first trial for five consecutive days in the water maze.39 IDC was then administered at the same concentrations 1 hour before the acquisition trial and retention trial in the passive avoidance test for the following 2 days.39 About 30 minutes before each task in the MWM and the passive avoidance test, memory impairment was induced by injecting scopolamine i.p. at 0.75 mg/kg in saline.39 The control group was given distilled water p.o. and saline i.p. following the same time schedule.39 The results demonstrate that IDC at these concentrations prevented scopolamine-induced memory impairment in rats.39 Although CGA was not examined directly, this study provides further support of the potential cognitive effects of CGA acting through cholinergic mechanisms. Learning and memory impairment similar to that caused by scopolamine has also been induced in mice by injecting the excitotoxin, kainic acid (KA), directly into the hippocampus.55 In one study, 0.5 μl of KA was injected directly into the hippocampus of mice to induce cognitive impairment associated with neuronal degeneration to that brain region.55 After 2 days of recovery, mice were divided into two groups and were given two daily intragastric administrations of 1 ml CGA or 1 ml physiological saline for 35 days.55 The purpose of this study was to determine if CGA had a protective effect on nitric oxide synthase (nNOS) positive neurons, because nNOS is necessary for NO production and processes of normal learning and memory.56,57 Spatial learning and memory was tested using the Y-maze, and results indicated that mice administered CGA showed milder memory impairment and quicker recovery compared to control KA-treated mice.55 When brains were harvested at days 7 and 35, analysis also showed that CGA-treated mice had more nNOS positive neurons in the hippocampus indicating less KA-induced neurodegeneration.55 Both results support the conclusion that CGA exerts neuroprotective effects against excitotoxicity.
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While numerous studies have been dedicated to determining the effects of CGA on the brain and cognition in rodent models, few studies have been conducted in humans. On one hand, the effects of coffee on human cognitive processes has been extensively studied, but the main focus of these studies was on caffeine and not the other phenolic compounds like CGA found in this popular beverage.5 Smith60 reported that the most common effects of caffeine on human behavior include improved reaction time, increased alertness, decreased fatigue, increased vigilance, and improved performance on tasks requiring a sustained response. Caffeine has also been documented to affect habitual and non-habitual users differently.61 In habitual users, caffeine tended to improve mood more significantly than in non-habitual users, but performance was improved more in non-habitual users (Ha62skell). Caffeine also affects those of varying age differently, with older individuals displaying greater effects of caffeine on performance than younger individuals.61 Overall, it is broadly accepted that caffeine exerts positive effects on cognitive and behavioral processes, but few reports investigate whether CGA, the most abundant family of compounds in coffee, has any effect on these processes.5 A recent study conducted in a healthy elderly population sought to determine whether acute CGA administration could improve mood and cognition by comparing decaffeinated coffee with regular CGA content to decaf coffee with elevated CGA content.5 The volunteers selected consumed no more than eight cups of coffee a week and were placed one of four different treatment groups: 6 g of soluble regular decaf coffee with 224 mg total CGA and only 5 mg caffeine, 6 g of soluble decaf coffee with a high CGA content of 521 mg and 11 mg caffeine, 6 g of soluble caffeinated coffee with 224 mg CGA and 167 mg caffeine, or 6 g of a placebo made of maltodextrin mixed with coffee flavor.5 A neuropsychological assessment of each participant was completed using a series of mood, cognitive, and event-related potential tasks performed in a fixed order.5 For 24 hours prior to initial testing, participants refrained from food and drink containing alcohol, CGA, caffeine, or high polyphenol content.5 After baseline values for neuropsychological testing and EEG readings were determined, participants consumed three cups of the soluble coffee according to the treatment groups they were assigned.5 When peak CGA blood concentrations were reached at ∼40 minutes after coffee consumption, neuropsychological testing and EEG recording were again conducted.5 The results of the study revealed that decaf coffee with high amounts of CGA had some positive effects on
mood-related processes including a decrease in mental fatigue and headaches along with an increase in alertness relative to decaf coffee with regular amounts of CGA.5 Apart from this pilot study, sparse research has been dedicated to ascertaining the direct effects of CGA on cognition in humans. However, a limited number of clinical studies focus on CGA and its effect on other human health issues. Hoelzl et al. 29 demonstrated that coffee with high levels of CGA shields humans against the oxidative damage of proteins, lipids, and DNA associated with a number of diseases. Researchers measured oxidative damage to macromolecules by assessing certain primary outcomes including lipid peroxidation, oxidatively damaged DNA, and modifications of proteins.29 Healthy adults of both sexes were chosen for study and divided into two groups (18 coffee/water and 18 water/coffee).29 Prior to the study, participants limited excessive physical exercise and reduced consumption of coffee, fruit juices, and other dietary factors that could affect the measure of oxidative damage.29 Coffee used for the study contained a high CGA content of ∼300 mg per 200 ml cup.29 The coffee/water group consumed 800 ml/day of coffee following a week of dietary restriction.29 After a 5-week washout period and an additional week of dietary restriction, participants then consumed 800 ml/day of water instead of coffee.29 The water/coffee group followed the exact same protocol but in a reversed order.29 The results of the statistical analyses indicated that the biomarkers of macromolecular oxidative damage chosen as the primary outcomes for this study were lower when coffee was consumed compared to when water was consumed, suggesting that the consumption of coffee with high levels of CGA can protect healthy adults from the oxidative damage to certain macromolecules.29 Another study suggested that CGA has an antagonistic effect on glucose transport and intestinal absorption rates.30 On three separate occasions, the same nine healthy volunteers were asked to fast overnight, refrain from strenuous activity and caffeine or alcohol consumption, and consume a high carbohydrate diet (>200 g) the day before each study day.30 Upon arrival at the clinic, a baseline blood sample was taken.30 Researchers used both caffeinated and decaffeinated coffee with high contents of CGA.30 The subjects then consumed 400 ml of either glucose dissolved in water (control), caffeinated coffee, or decaffeinated coffee, and blood samples were taken frequently over the following 3 hours.30 Overall, both caffeinated and decaffeinated coffee significantly decreased postprandial glucose-dependent insulinotropic polypeptide (GIP) secretion compared to the control.30 The magnitude of GIP response has a direct effect on the rate of absorption
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is accelerating to determine its possible physiological effects and health benefits. As humans age, there is increased vulnerability to oxidative stress that can lead to cellular dysfunction and death.33,34 The brain is particularly vulnerable to oxidative damage due to its limited antioxidant capacity, and it is the oxidative damage resulting from an inability to deal with ROS that can lead to neurodegenerative conditions including AD and PD.35 The antioxidant properties of CGA are of particular interest to researchers because CGA has been shown to cross the BBB in its pure form or as a metabolite.2,38,60 The evidence collected in various studies suggests that CGA could attenuate cognitive decline and reduce the risk of neurodegeneration. Further studies should assess the bioavailability of CGA at target sites over extended periods of exposure to ascertain whether neuroprotective effects are long term or solely acute.40 The majority of studies have established only acute effects. In addition, it should be noted that studies on the pharmacokinetics of CGA are sparse. The in vivo effects of CGA that we have cited could in fact be due to metabolites of CGA, some identified and others yet unidentified. To this point, a rat study conducted by Gonthier et al. 63 concluded that the bioavailability of CGA might depend on its metabolism by gut microflora. However, a follow-up in vitro study by Gonthier et al. 63 using human fecal microbiota concluded that esterification does not influence the metabolism of caffeic, chlorogenic, and caftaric acids by gut microbiota. Further research is also needed to determine possible toxicity of CGA at high doses or with extended exposure. In this review, we reported on two specific in vitro studies providing evidence of CGA’s antioxidant activity in neuronal cells and in the brain.36,40 More specifically, researchers also looked at CGA as a preventative agent against neurodegenerative diseases and found that CGA prevented the formation of senile plaques associated with AD,6 inhibited AChE and BChE, prolonging the effects of ACh and BCh,43 prevented the oligomerization of α-syn associated with PD,37 and reduced inflammation brought on by primary microglia in the brain.36 There have also been a number of pre-clinical studies conducted to determine the effect of CGA on cognition in rodent models. The results of these studies indicate that CGA has the potential to improve spatial learning and memory,6 attenuate scopolamine-induced memory impairment,7,39 lessen memory impairment,6,7 reduce anxiety and improve motor function,15,58 and protect against ischemia-induced neuronal damage.58 While there have been a limited number of clinical studies with a focus on CGA specifically, the outcomes of these few are promising regarding potential for
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of glucose in the small intestines.30 These data suggest that coffee high in CGA content could decrease the rate of intestinal absorption of glucose and could positively affect glucose tolerance in humans, which could have beneficial effects on brain aging.30 Other studies link CGA consumption to weight loss in overweight individuals.3,4,62 Vinson et al. 4 conducted a 22-week study of 16 overweight individuals to investigate the efficacy of a green coffee extract with high concentrations of CGA to reduce weight and overall body mass. Participants were given lowdose green coffee extract at 700 mg, high-dose green coffee extract at 1050 mg, or placebo daily for 6-week time periods followed by 2-week washout periods.4 Test subjects were divided randomly into groups: low-dose/placebo/high-dose arrangement (n = 4), high-dose/low-dose/placebo arrangement (n = 6), or placebo/high-dose/low-dose (n = 6).4 Baseline values for body weight, body fat percentage, and body mass index (BMI) were measured prior to the study and at 6, 8, 14, 16, and 22 weeks following.4 A significant decrease in body weight, BMI, and percent body fat was observed during the periods the subjects were taking green coffee extract.4 The results suggest that green coffee extract high in CGA taken over extended periods of time could reduce weight in overweight individuals.4 Similar results were achieved by Dellalibera et al. 3 when studying the effects of Svetol®, another green coffee extract high in CGA, on weight loss. Fifty overweight individuals were selected for study and randomized into two groups: a control group (n = 20) receiving a placebo and a treatment group (n = 30) receiving Svetol®.3 For a total of 60 days, each subject took two capsules of placebo or Svetol® with a meal.3 Changes in muscle mass/fat mass ratio, BMI, and weight between baseline and the end of 60 days were recorded.3 Fat mass, BMI, and weight significantly decreased over the total test period, and the results again suggested that green coffee extracts high in CGA could reduce weight in overweight individuals.3 In conclusion, the effects of CGA on human cognition have not been studied extensively. Many human studies have demonstrated that coffee improves cognitive performance, but its components have not been isolated and studied individually.39 Coffee is a complex chemical mixture composed of ∼7–9% polyphenols and 1% caffeine, so it is necessary to isolate the components for study to determine whether it is the combination of these chemicals or one individually that helps prevent memory impairment.39
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Summary CGA is an antioxidant widely distributed in the human diet. Research on this interesting compound
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Disclaimer statements Contributors E.H. conducted the literature review and she and D.K.I. summarized the findings and co-wrote the review.
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References
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role for the microsomal glucose-6-phosphate translocase in brain tumor progression. Cancer Res Int 2006;6:7. Tanaka T, Kojima T, Kawamori T, Wang A, Suzui M, Okamoto K, et al. Inhibition of 4-nitroquinoline-1-oxide-induced rat tongue carcinogenesis by the naturally occurring plant phenolics caffeic, ellagic, chlorogenic and ferulic acids. Carcinogenesis 1993;14:1321–5. Xu R, Kang Q, Ren J, Li Z, Xu X. Antitumor molecular mechanism of chlorogenic acid on inducting genes GSK-3β and APC and inhibiting gene β-catenin. J Anal Methods Chem 2013;2013: 1–7. Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, et al. Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 1999;59:2347–52. Ho L, Verghese M, Wang J, Zhao W, Chen F, Knable LA, et al. Dietary supplementation with decaffeinated green coffee improves diet-induced insulin resistance and brain energy metabolism in mice. Nutr Neurosci 2012;15:37–45. Bouayed J, Rammal H, Dicko A, Younos C, Soulimani R. Chlorogenic acid, a polyphenol from Prunus domestica (Mirabelle), with coupled anxiolytic and antioxidant effects. J Neurol Sci 2007;262:77–84. Bagdas D, Cinklic N, Ozboluk HY, Ozyigit MO, Gurun MS. Antihyperalgesic activity of chlorogenic acid and in experimental neuropathic pain. J Nat Med 2013;67:698–704. Bai X, Zhang H, Ren S. Antioxidant activity and HPLC analysis of polyphenol-enriched extracts from industrial apple pomace. J Sci Food Agric 2013;93(10):2502–6. Jakobek L, Šeruga M, Voc´a S, Šindrak Z, Dobricˇ evic´ N. Flavonol and phenolic acid composition of sweet cherries (cv. Lapins) produced on six different vegetative rootstocks. Sci Hortic 2009;123:23–8. Kim DO, Heo HJ, Kim YJ, Yang HS, Lee CY. Sweet and sour cherry phenolics and their protective effects on neuronal cells. J Agric Food Chem 2005;53:9921–7. Kim DO, Jeong SW, Lee CY. Antioxidant capacity of phenolic phytochemicals from various cultivars of plums. Food Chem 2003;81:321–6. Jakobek L, Seruga M. Influence of anthocyanins, flavonols and phenolic acids on the antiradical activity of berries and small fruits. Int J Food Prop 2012;15:122–33. Erdogan S, Erdemoglu S. Evaluation of polyphenol contents in differently processed apricots using accelerated solvent extraction followed by high-performance liquid chromatography–diode array detector. Int J Food Sci Nutr 2011;62(7):729–39. Davies JN, Graeme EH. The constituents of tomato fruit the influence of environment, nutrition, and genotype. Crit Rev Food Sci Nutr 1981;15:205–80. Slimestad R, Verheul MJ. Content of chalconaringenin and chlorogenic acid in cherry tomatoes is strongly reduced during postharvest ripening. J Agric Food Chem 2005;53(18): 7251–6. Im HW, Suh BS, Lee SU, Kozukue N, Ohnisi-Kameyama M, Levin CE, et al. Analysis of phenolic compounds by high-performance liquid chromatography and liquid chromatography/ mass spectrometry in potato plant flowers, leaves, stems, and tubers and in home-processed potatoes. J Agric Food Chem 2008;56(9):3341–9. Lachman J, Hamouz K, Musilová J, Hejtmánková K, Kotíková Z, Pazderu˚ K, et al. Effect of peeling and three cooking methods on the content of selected phytochemicals in potato tubers with various colour of flesh. Food Chem 2013;318(2–3):1189–97. Veljkovic JN, Pavlovic AN, Mitic SS, Tosic SB, Stojanovic GS, Kalicanin BM, et al. Evaluation of individual phenolic compounds and antioxidant properties of black, green, herbal and fruit tea infusions consumed in Serbia: spectrophotometrical and electrochemical approaches. J Food Nutr Res 2013;52: 12–24. Wang Y, Ho CT. Polyphenolic chemistry of tea and coffee: a century of progress. J Agric Food Chem 2009;57(18):8109–14. Hoelzl C, Knasmüller S, Wagner KH, Elbling L, Huber W, Kager N, et al. Instant coffee with high chlorogenic acid levels protects humans against oxidative damage of macromolecules. Mol Nutr Food Res 2010;54:1722–33. Johnston KL, Clifford MN, Morgan LM. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine. Am J Clin Nutr 2003;78:728–33.
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neuroprotection. The results of the studies where CGA was administered to humans demonstrate the potential of CGA to protect against oxidative damage of various macromolecules,29 positively affect glucose tolerance,30 and even decrease blood pressure.8 A recent study even revealed that decaf coffee with high amounts of CGA had positive effects on moodrelated processes relative to decaf coffee with normal amounts of CGA.5 Because CGA is likely a major polyphenol in the human diet and research has shown that CGA is a promising candidate as a preventative agent against neurodegenerative diseases, further studies will most certainly be conducted with a focus on the effects of CGA on the nervous system and cognition.
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1 Clifford MN. Chlorogenic acids and other cinnamates – nature, occurrence and dietary burden. J Sci Food Agric 1999;79: 362–72. 2 Ito H, Sun XL, Watanabe M, Okamoto M, Hatano T. Chlorogenic acid and its metabolite m-coumaric acid evoke neurite outgrowth in hippocampal neuronal cells. Biosci Biotechnol Biochem 2008;72:885–8. 3 Dellalibera O, Lemaire B, Lafay S. Svetol®, green coffee extract, induces weight loss and increases the lean to fat mass ratio in volunteers with overweight problem. Phytothérapie 2006;4:1–4. 4 Vinson JA, Burnham Br, Nagendran MV. Randomized, doubleblind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects. Diabetes Metab Syndr Obes 2012;5:21–7. 5 Cropley V, Croft R, Silber B, Neale C, Scholey A, Stough C, et al. Does coffee enriched with chlorogenic acids improve mood and cognition after acute administration in healthy elderly? A pilot study. Psychopharm 2012;219:737–49. 6 Han J, Miyamae Y, Shigemori H, Isoda H. Neuroprotective effect of 3,5-di-o-caffeoylquinic acid on SH-SY5Y cells and senescense-accelerated-prone mice 8 through the up-regulation of phosphoglycertate kinase 1. Neuroscience 2010;169:1039–45. 7 Kwon SH, Lee HK, Kim JA, Hone SI, Kim HC, Jo TH, et al. Neuroprotective effects of chlorogenic acid on scopolamineinduced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. Eur J Pharmacol 2010;649:210–7. 8 Mubarak A, Bondonno CP, Liu AH, Considine MJ, Rich L, Mas E, et al. Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial. J Agric Food Chem 2012;60:9130–6. 9 Namba T, Matsuse T. A historical study of coffee in Japanese and Asian countries: focusing the medicinal uses in Asian traditional medicines. J Jpn Hist Pharm 2002;37:65–75. 10 Belkaid A, Currie JC, Desgagnés J, Annabi B. The chemopreventive properties of chlorogenic acid reveal a potential new
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48 Vardi N, Parlakpinar H, Ates B. Beneficial effects of chlorogenic acid on methotrexate-induced cerebellar Purkinje cell damage in rats. J Chem Neuroanat 2012;43:43–7. 49 Yagi H, Katoh S, Akiguchi I, Takeda T. Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory. Brain Res 1988;474:86–93. 50 Ben-Barak J, Dudai Y. Scopolamine induces an increase in muscarinic receptor level in rat hippocampus. Brain Res 1980; 193:309–13. 51 Fan Y, Hu J, Li J, Yang Z, Xin X, Wang J, et al. Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms. Neurosci Lett 2005;374:222–6. 52 Sakurai T, Kato T, Mori K, Takano E, Watabe S, Nabeshima T. Nefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis study. Neurosci Lett 1998;246:69–72. 53 Beatty WW, Butters N, Janowsky DS. Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia. Behav Neural Biol 1986;45:196–211. 54 Kopelman MD, Corn TH. Cholinergic ‘blockade’ as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome. Brain 1988;111:1079–110. 55 Tu Q, Tang X, Hu Z. Chlorogenic acid protection of neuronal nitric oxide synthase-positive neurons in the hippocampus of mice with impaired learning and memory. Neural Regen Res 2008;3(11):1218–21. 56 Böhme GA, Bon C, Lemaire M, Reibaud M, Piot O, Stutzmann JM, et al. Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats. Proc Natl Acad Sci USA 1993;90:9191–4. 57 Tu QY, Tang XQ, Liu ZQ. Effect of NOS positive neurons in rats with learning-remembering barrier. Bull Hunan Med Univ 2001; 26:331–4. 58 Lee K, Lee JS, Jang HJ, Kim SM, Chang MS, Park SH, et al. Chlorogenic acid ameliorates brain damage and edema by inhibiting matrixmetalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur J Pharm 2012;689:89–95. 59 Hovatta L, Tennant RS, Helton R, Marr RA, Singer O, Redwine JM, et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 2005;438:662–6. 60 Smith A. Effects of caffeine on human behavior. Food Chem Toxicol 2002;40:1243–55. 61 Haskell CF, Kennedy DO, Wesnes KA, Scholey AB. Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine. Psychopharmacology 2005;179:813–25. 62 Thom E. The effect of chlorogenic acid enriched coffee on glucose absorption in healthy volunteers and its effect on body mass when used long-term in overweight and obese people. J Int Med Res 2007;35:900–8. 63 Gonthier MP, Verny MA, Besson C, Rémésy C, Scalbert A. Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. J Nutr 2003;133:1853–9. 64 Per´ez-Jimen´ez J, Fezeu L, Touvier M, Arnault N, Manach C, Hercberg S, et al. Dietary intake of 337 polyphenols in French adults. Am J Clin Nutr 2011;93:1220–8. 65 Gonthier MP, Remesy C, Scalbert A, Cheynier V, Souquet JM, Poutanen K, et al. Microbial metabolism of caffeic acid and its esters chlorogenic and caftaric acids by human faecal microbiota in vitro. Biomed Pharmacother 2006;60:536–40.
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31 Schrader K, Kiehne A, Engelhardt UH, Maier HG. Determination of chlorogenic acids with lactones in roasted coffee. J Sci Food Agric 1999;71(3):392–8. 32 Samanidou V, Tsagiannidis A, Sarakatsianos I. Simultaneous determination of polyphenols and major purine alkaloids in Greek Sideritis species, herbal extracts, green tea, black tea, and coffee by high-performance liquid chromatography-diode array detection. J Sep Sci 2012;35(4):608–15. 33 Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995;38:357–66. 34 Huang FN, Zhang BL, Li WB, Cui X, Han ZT, Fang ZY. Effects of free radicals and amyloid beta protein on the currents of expressed rat receptors in Xenopus oocytes. Chin J Appl Physiol 2001;17:109–12. 35 Marksberry WR, Lovell MA. Damage to lipids, proteins, DNA and RNA in mild cognitive impairment. Arch Neurol 2007;64: 954–6. 36 Shen W, Qi R, Zhang J, Wang Z, Wang H, Hu C, et al. Chlorogenic acid inhibits LPS-induced microglial activation and improves survival of dopaminergic neurons. Brain Res Bull 2012;88:487–94. 37 Teraoka M, Nakaso K, Kusumoto C, Katano S, Tajima N, Yamashita A, et al. Cytoprotective effect of chlorogenic acid against α-synuclein-related toxicity in catecholaminergic PC12 cells. J Clin Biochem Nutr 2012;51:122–7. 38 Chu YF, Brown PH, Lyle BJ, Chen Y, Black RM, Williams CE, et al. Roasted coffees high in lipophilic antioxidants and chlorogenic acid lactones are more neuroprotective than green coffees. J Agric Food Chem 2009;57:9801–8. 39 Jang YJ, Kim J, Shim J, Kim CY, Jang JH, Lee KW, et al. Decaffeinated coffee prevents scopolamine-induced memory impairment in rats. Behav Brain Res 2013;245:113–9. 40 Kim J, Lee S, Shim J, Kim HW, Kim J, Jang YJ, et al. Caffeinated coffee, decaffeinated coffee, and the phenolic phytochemical chlorogenic acid up-regulate NQO1 expression and prevent H2O2-induced apoptosis in primary cortical neurons. Neurochem Int 2012;60:466–74. 41 Nakajima Y, Shimazawa M, Mishima S, Hara H. Water extract of propolis and its main constituents, caffeoylquinic acid derivatives, exert neuroprotective effects via antioxidant actions. Life Sci 2007;80:370–7. 42 Cho ES, Jang YJ, Hwang MK, Kang NJ, Lee KW, Lee HJ. Attenuation of oxidative neuronal cell death by coffee phenolic phytochemicals. Mutat Res 2009;661:18–24. 43 Oboh G, Agunloye OM, Akinyemi AJ, Ademiluyi AO, Adefegha SA. Comparative study on the inhibitory effect of caffeic and chlorogenic acids on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced oxidative stress in rats’ brain-in vitro. Neurochem Res 2013;38:413–9. 44 Arnold SE, Kumar A. Reversible dementias. Med Clin North Am 1993;77:215–30. 45 Orhan I, Sener B, Choudhary MI, Khalid A. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some Turkish medicinal plants. J Ethnopharmacol 2004;91:57–60. 46 Mizuno Y, Hattori N, Kubo S, Sato S, Nishioka K, Hatano T, et al. Progress in the pathogenesis and genetics of Parkinson’s disease. Philos Trans R Soc Lond B Biol Sci 2008; 363:2215–27. 47 Spillantini MG, Crowther RA, Jakes R, Masegawa M, Goedert M. α-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 1998;95:6469–73.
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Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, USA
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Objectives: The aim of this review was to provide an overview of studies conducted to determine the effects of chlorogenic acid (CGA) on cognition and neurological health. Methods: A literature search was conducted using PubMed and various search terms including chlorogenic acid, CGA, CA, memory, neuroscience, cognition, nutrition, antioxidant, pharmacokinetics, neuroprotection, and neurodegeneration. Results: Many studies have linked CGA consumption to a wide range of health benefits, including neuroprotection, cardioprotection, weight loss, chemopreventive properties, anti-inflammatory activity, decreased blood pressure, decreased diet-induced insulin resistance, decreased blood pressure, anxiolytic effects, and antihyperalgesic effects. Pre-clinical and clinical studies both provide evidence that CGA supplementation could protect against neurological degeneration and the resulting diseases associated with oxidative stress in the brain; however, no formal, well-controlled studies have been performed to date. Discussion: Recent research suggests that dietary consumption of CGA could produce a wide range of health benefits and physiological effects. There is also mounting evidence that the consumption of polyphenols, including CGA, in the diet could reduce the risk of developing neurodegenerative conditions. Further studies should be conducted with a focus on the effects of CGA on cognition and the nervous system and employing well-designed clinical studies. Keywords: Chlorogenic acid, Antioxidant, Cognition, Memory, Neuroprotection, Neurodegeneration, Alzheimer’s disease, Parkinson’s disease
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As a polyphenol with wide distribution in the human diet, chlorogenic acid (CGA) is gaining increased research attention regarding a wide range of health benefits, a list of which is presented in Table 1. CGAs comprise a family of esters formed between specific trans-cinnamic acids and quinic acid.1 Typically the only CGA commercially available is 5O-caffeoylquinic acid, the molecular structure of which is shown in Fig. 1.1 Ito et al. 2 noted that this form of CGA can pass the blood–brain barrier (BBB) as a metabolite or in its pure form to act directly on the central nervous system (CNS). CGA is also a compound found in a wide variety of food and beverages commonly consumed by humans including fruits, vegetables, olive oil, spices, wine, and coffee.1 Fruit sources include apples,1,17 cherries,18,19 plums,20 berries,21 apricots,22 and Correspondence to: Donald K. Ingram, Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, LSU System, 6400 Perkins Road, Baton Rouge, LA 70808, USA. Email: [email protected]
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1476830514Y.0000000146
tomatoes,23,24 while a common vegetable source is potatoes.1,25,26 CGA is also found in beverages including tea,1,27,28 coffee,28,29 and wine.1 Caffeinated and decaffeinated coffees both contain high amounts of CGA,14 and caffeinated coffee contains more CGA (7–9%) than caffeine (1%).29 A single cup of coffee contains between 70 and 350 mg of CGA, so coffee drinkers could obtain up to 1 g of CGA a day.1 In coffee-consuming populations, CGA is likely one of the major polyphenols in the diet.20 Table 2 provides examples of various food and beverage sources with high contents of CGA. Because CGA is present in a variety of food and beverages consumed daily, research is accelerating to ascertain its nutritional benefits and physiological effects. Antioxidant properties of CGA have been demonstrated in numerous studies including abilities to induce cardioprotective effects,8 anti-tumor activity,12 and even neuroprotective effects.5–7 The neuroprotective effects of CGA have been postulated to stem primarily from its activity as an antioxidant
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Table 1. Purported health benefits of CGA Health benefit
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Weight loss Neuroprotection Cardioprotection Chemopreventive properties Anti-inflammatory activity Decreased diet-induced insulin resistance Decreased blood pressure Anxiolytic effects Antihyperalgesic effects
3,4 5–7 8,9 10–12 13 14 8 15 16
Numerous epidemiological studies have shown strong correlations between the consumption of polyphenols in the diet and reduced risk of developing neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases.36,37 There is mounting evidence that coffee consumption, high in CGA, appears to be neuroprotective and can attenuate cognitive decline.5,14,29,38,39 In this review, we will consider a wide range of basic and clinical studies pertaining to the potential for the CGA to benefit cognition and reduce risk of neurodegeneration.
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Figure 1. Chemical structure of CGA (5-O-caffeoylquinic acid).15
A recent study by Kim et al. 40 investigated the protective effect of CGA on oxidative damage to neuronal cells and found that CGA strongly inhibited apoptotic nuclear condensation induced by hydrogen peroxide (H2O2) in neuronal cells. When primary neuronal cultures were treated with 50 μM H2O2 for 24 hours, either with or without pre-treatment of 12.5–100 μM CGA for an hour, the cultures pre-treated with CGA showed clear protection against H2O2-mediated neuronal cell death.40 The results suggest that CGA treatment could protect against neurological degeneration associated with oxidative stress in the brain.40 Using cultures of retinal ganglion cells, Nakajima et al. 41 reported that CGA increased cellular protection against oxidative stress induced by L-buthionine(S,R)-sulfoximine to deplete glutathione in combination with glutamate to inhibit cystine uptake. In addition, they noted reduced lipid peroxidation in homogenates of mouse forebrain treated with CGA.41 Cho et al. 42 demonstrated similar neuroprotection against H2O2-induced oxidative stress in PC12 cells treated with CGA. Specifically, the treated cells exhibited less production of ROS, reduced nuclear condensation, and DNA fragmentation, as well as inhibited cleavage of poly(ADP-ribose) polymerase and downregulation of Bcl-X(L) and caspase-3.42 The H2O2 activation of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase was also inhibited with CGA treatment.42 While some researchers investigated the antioxidant properties of CGA, others sought to determine whether CGA could play a role in the prevention of certain neurodegenerative conditions. For example, Han et al. 6 sought to determine if CGA had a neuroprotective effect against the overexpression of the amyloid-β (Aβ) protein associated with the pathogenesis of Alzheimer’s disease (AD). When human neuroblastoma clonal SH-SY5Y cells were incubated with 10 μM Aβ along with 20 μM CGA, the cells were significantly more viable compared to SH-SY5Y cells incubated solely in 10 μM Aβ.6 The incubation with CGA also reversed the cell death induced by Aβ.6 These results further suggest that CGA has a
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in the brain.7 Aging is associated with a decrease in efficient energy production and the accumulation of damage from reactive oxygen species (ROS).33,34 ROS-induced damage to mitochondria can result in decreased intracellular levels of adenosine triphosphate (ATP) that can trigger numerous detrimental processes and lead to cellular dysfunction and death.33,34 The brain is especially vulnerable to ROS because of its high oxygen consumption, limited antioxidant capacity, and high concentrations of the catalytic metal, iron.35 In this light, there has been intensive search for pharmacological and dietary interventions that might protect the brain against oxidative stress. Table 2. Approximate content of CGA in various food and beverage sources CGA (mg/g)
Instant coffee Medium roasted commercial coffee Potatoes Blueberries Apples Elderberries Sweet cherries Sour cherries Chokeberries Cherry tomatoes Apricots Plums Commercial black tea Commercial green tea
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30–40 2.97
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0.3149–2.401 0.2439 0.014–0.284 0.0649 0.019–0.062 0.0523 0.0369 0.013–0.038 0.02126 0.009–0.026 0.0006 0.0006–0.0013
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21 17 18 18 18 18 23 22 20 32 32
Values were determined experimentally using differing methods for fresh products.
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at the cellular level, there have also been a number of pre-clinical studies conducted to assess effects of CGA on the brain and cognition in animal models. Another study conducted by Shen et al. 36 showed that CGA protected rat brain cerebellum from oxidative damage induced by methotrexate (MTX). MTX is used as a cytotoxic chemotherapeutic agent for many neoplastic diseases, but it causes severe neurotoxic effects by inducing oxidative stress in the CNS.48 When rats were given intraperitoneal (i.p.) injections of 100 mg/kg/day of CGA for 24 days followed by an i.p. injection of MTX (20 mg/kg) on day 21, oxidative damage to the rat cerebellum induced by MTX was greatly attenuated.36 As discussed previously, Han et al. 6 were able to show that CGA prevents the overexpression of Aβ in human neuroblastoma cells, but they also found that the administration of CGA improved spatial learning and memory in SAMP8 mice. These mice are a substrain of senescence-accelerated-prone mice (SAMP) that exhibit age-related deterioration in learning and memory and also have plaques that resemble ADlike depositions of Aβ.33,34,49 Beginning at 3 months of age, half the SAMP8 mice were orally administered CGA in drinking water at 6.7 mg/kg/day for a month, while the other half were given normal drinking water for this time period.6 Spatial learning and memory were evaluated using the Morris water maze (MWM) by measuring escape latency time to find the hidden platform over a 30-day trial period.6 The SAMP8 mice administered CGA at 6.7 mg/kg/day exhibited decreased escape latency time when compared to the SAMP8 mice provided normal drinking water; thus, CGA administration was determined to improve spatial learning and memory.6 As an additional model of learning and memory impairment, scopolamine has also been used to induce cognitive impairment in rodents.7,39 Scopolamine is a muscarinic receptor antagonist that elevates oxidative stress in the brain by inhibiting ATPase and significantly increasing AChE and malondialdehyde levels in the hippocampus and cortex.50–52 Because scopolamine produces symptoms of AD, it is often used experimentally to induce these symptoms as a model of cognitive impairment observed in the disease.53,54 In their study, Kwon et al. 7 examined the effects of CGA on scopolamine-induced memory and learning impairments in mice using three different paradigms: (1) the Y-maze; (2) passive avoidance; and (3) the MWM. Mice were given peroral ( p.o.) administrations of 0, 3, 6, or 9 mg/kg CGA in distilled water 1 hour prior to the Y-maze test and the training trials of the MWM and passive avoidance tests, and then 30 minutes later, memory impairment was induced using i.p. administrations of 0.5 mg/kg scopolamine.7 In the Y-maze, the degree of spontaneous alternation
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neuroprotective effect on Aβ-treated SH-SY5Y cells and support the idea that CGA could be used as a preventative agent against Aβ-induced pathology associated with AD.6 Another recent in vitro study by Oboh et al. 43 with a focus on AD investigated the effects of CGA on acetylcholinesterase (AChE) and butylcholinesterase (BChE). The inhibition of AChE and BChE are significant to AD treatment because their inactivity prevents the breakdown of acetylcholine (ACh) and butylcholine (BCh), increasing the concentrations of these neurotransmitters in the synaptic cleft, and thus increasing communication between neurons that utilize these neurotransmitters.43 Inhibition of AChE represents the primary treatment modality against the cognitive impairment observed in AD.44,45 The results demonstrated that CGA inhibited AChE and BChE in rat brain homogenates in vitro in a dose-dependent manner and thus suggested a new treatment modality for AD.43 In addition to possible effects on AD, other researchers have even demonstrated that CGA is a strong candidate as a preventative agent for Parkinson’s disease (PD).37 PD is a neurodegenerative disease associated with the formation of alpha-synuclein (α-syn) containing Lewy bodies in the substantia nigra and the degeneration of neurons in this brain region that produce the neurotransmitter, dopamine.46,47 It is postulated that the overexpression of α-syn induces the loss of dopaminergic neurons.37 The oligomerization of α-syn is thought to be a necessary step for pathogenic toxicity.37 A recent study by Teraoka et al. 37 showed that α-syn can only oligomerize by interacting with dopamine in its oxidized form. CGA was shown to inhibit the oxidation of dopamine, the interaction of oxidized dopamine with α-syn, and α-syn oligomerization.37 Overall, the results indicate that CGA is a promising candidate for the preventative treatment of PD.37 CGA has also been shown to reduce neuroinflammation resulting from overactive primary microglia in the brain.36 These mononuclear phagocytes release cytokines during inflammation, and it is the overproduction of cytotoxic factors, including nitric oxide (NO) and tumor necrosis factor alpha (TNFα), that can result in neurotoxic effects.36 Shen et al. 36 showed that CGA suppresses TNF-α release and NO production in primary microglia that were activated by lipopolysaccharide (LPS) treatment. This evidence suggests that CGA increases the survival of dopaminergic neurons by inhibiting LPS-induced microglial activation and therefore has potential neuroprotective effects against neurodegenerative disease caused by overactive microglia.36
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Pre-clinical studies While a substantial amount of research has been dedicated to ascertaining the effects of CGA on the brain
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In addition to ameliorating learning and memory deficits, CGA has also been documented to reduce anxiety and improve motor function in rodent models.15,58 A study by Hovatta et al. 59 revealed that anxiety-related behavior in mice is mediated by the expression of two cerebral genes, glyoxalase 1 and glutathione reductase 1, that protect cells from oxidative damage. These researchers found that inhibition of glutathione reductase 1 decreased anxietyrelated behavior, while overexpression of both genes led to increased anxiety-related behavior.59 Using this information, Bouayed et al. 15 examined the relationship between CGA supplementation and anxiety in mice. To examine anxiety-like behavior, the light/dark choice test, elevated plus maze, and free exploratory test were used.15 All drugs were administered i.p. 30 minutes before each test and at a volume of 10 ml/kg.15 For the light/dark choice test, mice were given physiological saline at 0.9% NaCl as the control group, CGA at 2, 10, 20, or 40 mg/kg in saline, or diazepam, a well-known anxiolytic, at 1 mg/kg in saline.15 Mice were given the same concentrations of physiological saline and diazepam for the free exploratory test, but were only given CGA at 20 mg/kg.15 For the elevated plus maze, the same concentrations of physiological saline, CGA, and diazepam were given as in the free exploratory test, but were divided into two additional treatment groups: a combination of CGA at 20 mg/kg and flumazenil at 5 mg/kg, as well as a combination of diazepam at 1 mg/kg and flumazenil at 5 mg/kg.15 Because flumazenil is a common benzodiazepine receptor antagonist, these investigators wanted to determine if the CGA reduced anxiety in the same manner as diazepam by activating benzodiazepine receptors.15 The results of the study indicate that CGA at 20 mg/kg decreased anxiety-related behavior similarly to diazepam at 1 mg/kg. Because the effects of CGA and diazepam were both blocked by flumazenil, the anti-anxiety effect of CGA was determined to be a result of its activity as a benzodiazepine receptor agonist.15 The effects of CGA on sensory-motor function after induced ischemia have also been investigated.58 Rats received middle cerebral artery occlusion to induce ischemia and were then given i.p. injections of 3, 10, and 30 mg/kg CGA at 0 and 2 hours following induction.58 Sensory-motor function was determined using the balance-beam test. Sensorymotor functional deficits in rats following ischemia were significantly reduced with treatments of 3, 10, and 30 mg/kg CGA in a dose-dependent manner.58 Overall, results suggest that CGA has a neuroprotective effect against ischemia-induced neuronal damage and its resulting sensory-motor functional deficit.58
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behavior is an indicator of short-term memory.7 CGA administered at 6 or 9 mg/kg resulted in significant increases in spontaneous alternation behavior and alleviated the decrease in performance caused by scopolamine.7 Oral treatment with 9 mg/kg CGA in the passive avoidance test and 6 or 9 mg/kg CGA in the MWM test also significantly attenuated the scopolamine-induced memory impairments.7 Jang et al. 39 studied the effect of instant decaffeinated coffee (IDC) containing CGA on scopolamine-induced memory impairment in rats. CGA was not studied directly, but rather, IDC containing high levels of CGA and other phytochemicals was used.39 For the MWM, IDC of 1 ml at 120 or 240 mg/kg in distilled water was administered p.o. using an oral gavage once a day for 6 days and then an hour before the first trial for five consecutive days in the water maze.39 IDC was then administered at the same concentrations 1 hour before the acquisition trial and retention trial in the passive avoidance test for the following 2 days.39 About 30 minutes before each task in the MWM and the passive avoidance test, memory impairment was induced by injecting scopolamine i.p. at 0.75 mg/kg in saline.39 The control group was given distilled water p.o. and saline i.p. following the same time schedule.39 The results demonstrate that IDC at these concentrations prevented scopolamine-induced memory impairment in rats.39 Although CGA was not examined directly, this study provides further support of the potential cognitive effects of CGA acting through cholinergic mechanisms. Learning and memory impairment similar to that caused by scopolamine has also been induced in mice by injecting the excitotoxin, kainic acid (KA), directly into the hippocampus.55 In one study, 0.5 μl of KA was injected directly into the hippocampus of mice to induce cognitive impairment associated with neuronal degeneration to that brain region.55 After 2 days of recovery, mice were divided into two groups and were given two daily intragastric administrations of 1 ml CGA or 1 ml physiological saline for 35 days.55 The purpose of this study was to determine if CGA had a protective effect on nitric oxide synthase (nNOS) positive neurons, because nNOS is necessary for NO production and processes of normal learning and memory.56,57 Spatial learning and memory was tested using the Y-maze, and results indicated that mice administered CGA showed milder memory impairment and quicker recovery compared to control KA-treated mice.55 When brains were harvested at days 7 and 35, analysis also showed that CGA-treated mice had more nNOS positive neurons in the hippocampus indicating less KA-induced neurodegeneration.55 Both results support the conclusion that CGA exerts neuroprotective effects against excitotoxicity.
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While numerous studies have been dedicated to determining the effects of CGA on the brain and cognition in rodent models, few studies have been conducted in humans. On one hand, the effects of coffee on human cognitive processes has been extensively studied, but the main focus of these studies was on caffeine and not the other phenolic compounds like CGA found in this popular beverage.5 Smith60 reported that the most common effects of caffeine on human behavior include improved reaction time, increased alertness, decreased fatigue, increased vigilance, and improved performance on tasks requiring a sustained response. Caffeine has also been documented to affect habitual and non-habitual users differently.61 In habitual users, caffeine tended to improve mood more significantly than in non-habitual users, but performance was improved more in non-habitual users (Ha62skell). Caffeine also affects those of varying age differently, with older individuals displaying greater effects of caffeine on performance than younger individuals.61 Overall, it is broadly accepted that caffeine exerts positive effects on cognitive and behavioral processes, but few reports investigate whether CGA, the most abundant family of compounds in coffee, has any effect on these processes.5 A recent study conducted in a healthy elderly population sought to determine whether acute CGA administration could improve mood and cognition by comparing decaffeinated coffee with regular CGA content to decaf coffee with elevated CGA content.5 The volunteers selected consumed no more than eight cups of coffee a week and were placed one of four different treatment groups: 6 g of soluble regular decaf coffee with 224 mg total CGA and only 5 mg caffeine, 6 g of soluble decaf coffee with a high CGA content of 521 mg and 11 mg caffeine, 6 g of soluble caffeinated coffee with 224 mg CGA and 167 mg caffeine, or 6 g of a placebo made of maltodextrin mixed with coffee flavor.5 A neuropsychological assessment of each participant was completed using a series of mood, cognitive, and event-related potential tasks performed in a fixed order.5 For 24 hours prior to initial testing, participants refrained from food and drink containing alcohol, CGA, caffeine, or high polyphenol content.5 After baseline values for neuropsychological testing and EEG readings were determined, participants consumed three cups of the soluble coffee according to the treatment groups they were assigned.5 When peak CGA blood concentrations were reached at ∼40 minutes after coffee consumption, neuropsychological testing and EEG recording were again conducted.5 The results of the study revealed that decaf coffee with high amounts of CGA had some positive effects on
mood-related processes including a decrease in mental fatigue and headaches along with an increase in alertness relative to decaf coffee with regular amounts of CGA.5 Apart from this pilot study, sparse research has been dedicated to ascertaining the direct effects of CGA on cognition in humans. However, a limited number of clinical studies focus on CGA and its effect on other human health issues. Hoelzl et al. 29 demonstrated that coffee with high levels of CGA shields humans against the oxidative damage of proteins, lipids, and DNA associated with a number of diseases. Researchers measured oxidative damage to macromolecules by assessing certain primary outcomes including lipid peroxidation, oxidatively damaged DNA, and modifications of proteins.29 Healthy adults of both sexes were chosen for study and divided into two groups (18 coffee/water and 18 water/coffee).29 Prior to the study, participants limited excessive physical exercise and reduced consumption of coffee, fruit juices, and other dietary factors that could affect the measure of oxidative damage.29 Coffee used for the study contained a high CGA content of ∼300 mg per 200 ml cup.29 The coffee/water group consumed 800 ml/day of coffee following a week of dietary restriction.29 After a 5-week washout period and an additional week of dietary restriction, participants then consumed 800 ml/day of water instead of coffee.29 The water/coffee group followed the exact same protocol but in a reversed order.29 The results of the statistical analyses indicated that the biomarkers of macromolecular oxidative damage chosen as the primary outcomes for this study were lower when coffee was consumed compared to when water was consumed, suggesting that the consumption of coffee with high levels of CGA can protect healthy adults from the oxidative damage to certain macromolecules.29 Another study suggested that CGA has an antagonistic effect on glucose transport and intestinal absorption rates.30 On three separate occasions, the same nine healthy volunteers were asked to fast overnight, refrain from strenuous activity and caffeine or alcohol consumption, and consume a high carbohydrate diet (>200 g) the day before each study day.30 Upon arrival at the clinic, a baseline blood sample was taken.30 Researchers used both caffeinated and decaffeinated coffee with high contents of CGA.30 The subjects then consumed 400 ml of either glucose dissolved in water (control), caffeinated coffee, or decaffeinated coffee, and blood samples were taken frequently over the following 3 hours.30 Overall, both caffeinated and decaffeinated coffee significantly decreased postprandial glucose-dependent insulinotropic polypeptide (GIP) secretion compared to the control.30 The magnitude of GIP response has a direct effect on the rate of absorption
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is accelerating to determine its possible physiological effects and health benefits. As humans age, there is increased vulnerability to oxidative stress that can lead to cellular dysfunction and death.33,34 The brain is particularly vulnerable to oxidative damage due to its limited antioxidant capacity, and it is the oxidative damage resulting from an inability to deal with ROS that can lead to neurodegenerative conditions including AD and PD.35 The antioxidant properties of CGA are of particular interest to researchers because CGA has been shown to cross the BBB in its pure form or as a metabolite.2,38,60 The evidence collected in various studies suggests that CGA could attenuate cognitive decline and reduce the risk of neurodegeneration. Further studies should assess the bioavailability of CGA at target sites over extended periods of exposure to ascertain whether neuroprotective effects are long term or solely acute.40 The majority of studies have established only acute effects. In addition, it should be noted that studies on the pharmacokinetics of CGA are sparse. The in vivo effects of CGA that we have cited could in fact be due to metabolites of CGA, some identified and others yet unidentified. To this point, a rat study conducted by Gonthier et al. 63 concluded that the bioavailability of CGA might depend on its metabolism by gut microflora. However, a follow-up in vitro study by Gonthier et al. 63 using human fecal microbiota concluded that esterification does not influence the metabolism of caffeic, chlorogenic, and caftaric acids by gut microbiota. Further research is also needed to determine possible toxicity of CGA at high doses or with extended exposure. In this review, we reported on two specific in vitro studies providing evidence of CGA’s antioxidant activity in neuronal cells and in the brain.36,40 More specifically, researchers also looked at CGA as a preventative agent against neurodegenerative diseases and found that CGA prevented the formation of senile plaques associated with AD,6 inhibited AChE and BChE, prolonging the effects of ACh and BCh,43 prevented the oligomerization of α-syn associated with PD,37 and reduced inflammation brought on by primary microglia in the brain.36 There have also been a number of pre-clinical studies conducted to determine the effect of CGA on cognition in rodent models. The results of these studies indicate that CGA has the potential to improve spatial learning and memory,6 attenuate scopolamine-induced memory impairment,7,39 lessen memory impairment,6,7 reduce anxiety and improve motor function,15,58 and protect against ischemia-induced neuronal damage.58 While there have been a limited number of clinical studies with a focus on CGA specifically, the outcomes of these few are promising regarding potential for
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of glucose in the small intestines.30 These data suggest that coffee high in CGA content could decrease the rate of intestinal absorption of glucose and could positively affect glucose tolerance in humans, which could have beneficial effects on brain aging.30 Other studies link CGA consumption to weight loss in overweight individuals.3,4,62 Vinson et al. 4 conducted a 22-week study of 16 overweight individuals to investigate the efficacy of a green coffee extract with high concentrations of CGA to reduce weight and overall body mass. Participants were given lowdose green coffee extract at 700 mg, high-dose green coffee extract at 1050 mg, or placebo daily for 6-week time periods followed by 2-week washout periods.4 Test subjects were divided randomly into groups: low-dose/placebo/high-dose arrangement (n = 4), high-dose/low-dose/placebo arrangement (n = 6), or placebo/high-dose/low-dose (n = 6).4 Baseline values for body weight, body fat percentage, and body mass index (BMI) were measured prior to the study and at 6, 8, 14, 16, and 22 weeks following.4 A significant decrease in body weight, BMI, and percent body fat was observed during the periods the subjects were taking green coffee extract.4 The results suggest that green coffee extract high in CGA taken over extended periods of time could reduce weight in overweight individuals.4 Similar results were achieved by Dellalibera et al. 3 when studying the effects of Svetol®, another green coffee extract high in CGA, on weight loss. Fifty overweight individuals were selected for study and randomized into two groups: a control group (n = 20) receiving a placebo and a treatment group (n = 30) receiving Svetol®.3 For a total of 60 days, each subject took two capsules of placebo or Svetol® with a meal.3 Changes in muscle mass/fat mass ratio, BMI, and weight between baseline and the end of 60 days were recorded.3 Fat mass, BMI, and weight significantly decreased over the total test period, and the results again suggested that green coffee extracts high in CGA could reduce weight in overweight individuals.3 In conclusion, the effects of CGA on human cognition have not been studied extensively. Many human studies have demonstrated that coffee improves cognitive performance, but its components have not been isolated and studied individually.39 Coffee is a complex chemical mixture composed of ∼7–9% polyphenols and 1% caffeine, so it is necessary to isolate the components for study to determine whether it is the combination of these chemicals or one individually that helps prevent memory impairment.39
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Summary CGA is an antioxidant widely distributed in the human diet. Research on this interesting compound
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Disclaimer statements Contributors E.H. conducted the literature review and she and D.K.I. summarized the findings and co-wrote the review.
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References
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role for the microsomal glucose-6-phosphate translocase in brain tumor progression. Cancer Res Int 2006;6:7. Tanaka T, Kojima T, Kawamori T, Wang A, Suzui M, Okamoto K, et al. Inhibition of 4-nitroquinoline-1-oxide-induced rat tongue carcinogenesis by the naturally occurring plant phenolics caffeic, ellagic, chlorogenic and ferulic acids. Carcinogenesis 1993;14:1321–5. Xu R, Kang Q, Ren J, Li Z, Xu X. Antitumor molecular mechanism of chlorogenic acid on inducting genes GSK-3β and APC and inhibiting gene β-catenin. J Anal Methods Chem 2013;2013: 1–7. Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, et al. Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 1999;59:2347–52. Ho L, Verghese M, Wang J, Zhao W, Chen F, Knable LA, et al. Dietary supplementation with decaffeinated green coffee improves diet-induced insulin resistance and brain energy metabolism in mice. Nutr Neurosci 2012;15:37–45. Bouayed J, Rammal H, Dicko A, Younos C, Soulimani R. Chlorogenic acid, a polyphenol from Prunus domestica (Mirabelle), with coupled anxiolytic and antioxidant effects. J Neurol Sci 2007;262:77–84. Bagdas D, Cinklic N, Ozboluk HY, Ozyigit MO, Gurun MS. Antihyperalgesic activity of chlorogenic acid and in experimental neuropathic pain. J Nat Med 2013;67:698–704. Bai X, Zhang H, Ren S. Antioxidant activity and HPLC analysis of polyphenol-enriched extracts from industrial apple pomace. J Sci Food Agric 2013;93(10):2502–6. Jakobek L, Šeruga M, Voc´a S, Šindrak Z, Dobricˇ evic´ N. Flavonol and phenolic acid composition of sweet cherries (cv. Lapins) produced on six different vegetative rootstocks. Sci Hortic 2009;123:23–8. Kim DO, Heo HJ, Kim YJ, Yang HS, Lee CY. Sweet and sour cherry phenolics and their protective effects on neuronal cells. J Agric Food Chem 2005;53:9921–7. Kim DO, Jeong SW, Lee CY. Antioxidant capacity of phenolic phytochemicals from various cultivars of plums. Food Chem 2003;81:321–6. Jakobek L, Seruga M. Influence of anthocyanins, flavonols and phenolic acids on the antiradical activity of berries and small fruits. Int J Food Prop 2012;15:122–33. Erdogan S, Erdemoglu S. Evaluation of polyphenol contents in differently processed apricots using accelerated solvent extraction followed by high-performance liquid chromatography–diode array detector. Int J Food Sci Nutr 2011;62(7):729–39. Davies JN, Graeme EH. The constituents of tomato fruit the influence of environment, nutrition, and genotype. Crit Rev Food Sci Nutr 1981;15:205–80. Slimestad R, Verheul MJ. Content of chalconaringenin and chlorogenic acid in cherry tomatoes is strongly reduced during postharvest ripening. J Agric Food Chem 2005;53(18): 7251–6. Im HW, Suh BS, Lee SU, Kozukue N, Ohnisi-Kameyama M, Levin CE, et al. Analysis of phenolic compounds by high-performance liquid chromatography and liquid chromatography/ mass spectrometry in potato plant flowers, leaves, stems, and tubers and in home-processed potatoes. J Agric Food Chem 2008;56(9):3341–9. Lachman J, Hamouz K, Musilová J, Hejtmánková K, Kotíková Z, Pazderu˚ K, et al. Effect of peeling and three cooking methods on the content of selected phytochemicals in potato tubers with various colour of flesh. Food Chem 2013;318(2–3):1189–97. Veljkovic JN, Pavlovic AN, Mitic SS, Tosic SB, Stojanovic GS, Kalicanin BM, et al. Evaluation of individual phenolic compounds and antioxidant properties of black, green, herbal and fruit tea infusions consumed in Serbia: spectrophotometrical and electrochemical approaches. J Food Nutr Res 2013;52: 12–24. Wang Y, Ho CT. Polyphenolic chemistry of tea and coffee: a century of progress. J Agric Food Chem 2009;57(18):8109–14. Hoelzl C, Knasmüller S, Wagner KH, Elbling L, Huber W, Kager N, et al. Instant coffee with high chlorogenic acid levels protects humans against oxidative damage of macromolecules. Mol Nutr Food Res 2010;54:1722–33. Johnston KL, Clifford MN, Morgan LM. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine. Am J Clin Nutr 2003;78:728–33.
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neuroprotection. The results of the studies where CGA was administered to humans demonstrate the potential of CGA to protect against oxidative damage of various macromolecules,29 positively affect glucose tolerance,30 and even decrease blood pressure.8 A recent study even revealed that decaf coffee with high amounts of CGA had positive effects on moodrelated processes relative to decaf coffee with normal amounts of CGA.5 Because CGA is likely a major polyphenol in the human diet and research has shown that CGA is a promising candidate as a preventative agent against neurodegenerative diseases, further studies will most certainly be conducted with a focus on the effects of CGA on the nervous system and cognition.
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1 Clifford MN. Chlorogenic acids and other cinnamates – nature, occurrence and dietary burden. J Sci Food Agric 1999;79: 362–72. 2 Ito H, Sun XL, Watanabe M, Okamoto M, Hatano T. Chlorogenic acid and its metabolite m-coumaric acid evoke neurite outgrowth in hippocampal neuronal cells. Biosci Biotechnol Biochem 2008;72:885–8. 3 Dellalibera O, Lemaire B, Lafay S. Svetol®, green coffee extract, induces weight loss and increases the lean to fat mass ratio in volunteers with overweight problem. Phytothérapie 2006;4:1–4. 4 Vinson JA, Burnham Br, Nagendran MV. Randomized, doubleblind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects. Diabetes Metab Syndr Obes 2012;5:21–7. 5 Cropley V, Croft R, Silber B, Neale C, Scholey A, Stough C, et al. Does coffee enriched with chlorogenic acids improve mood and cognition after acute administration in healthy elderly? A pilot study. Psychopharm 2012;219:737–49. 6 Han J, Miyamae Y, Shigemori H, Isoda H. Neuroprotective effect of 3,5-di-o-caffeoylquinic acid on SH-SY5Y cells and senescense-accelerated-prone mice 8 through the up-regulation of phosphoglycertate kinase 1. Neuroscience 2010;169:1039–45. 7 Kwon SH, Lee HK, Kim JA, Hone SI, Kim HC, Jo TH, et al. Neuroprotective effects of chlorogenic acid on scopolamineinduced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. Eur J Pharmacol 2010;649:210–7. 8 Mubarak A, Bondonno CP, Liu AH, Considine MJ, Rich L, Mas E, et al. Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial. J Agric Food Chem 2012;60:9130–6. 9 Namba T, Matsuse T. A historical study of coffee in Japanese and Asian countries: focusing the medicinal uses in Asian traditional medicines. J Jpn Hist Pharm 2002;37:65–75. 10 Belkaid A, Currie JC, Desgagnés J, Annabi B. The chemopreventive properties of chlorogenic acid reveal a potential new
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48 Vardi N, Parlakpinar H, Ates B. Beneficial effects of chlorogenic acid on methotrexate-induced cerebellar Purkinje cell damage in rats. J Chem Neuroanat 2012;43:43–7. 49 Yagi H, Katoh S, Akiguchi I, Takeda T. Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory. Brain Res 1988;474:86–93. 50 Ben-Barak J, Dudai Y. Scopolamine induces an increase in muscarinic receptor level in rat hippocampus. Brain Res 1980; 193:309–13. 51 Fan Y, Hu J, Li J, Yang Z, Xin X, Wang J, et al. Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms. Neurosci Lett 2005;374:222–6. 52 Sakurai T, Kato T, Mori K, Takano E, Watabe S, Nabeshima T. Nefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis study. Neurosci Lett 1998;246:69–72. 53 Beatty WW, Butters N, Janowsky DS. Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia. Behav Neural Biol 1986;45:196–211. 54 Kopelman MD, Corn TH. Cholinergic ‘blockade’ as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome. Brain 1988;111:1079–110. 55 Tu Q, Tang X, Hu Z. Chlorogenic acid protection of neuronal nitric oxide synthase-positive neurons in the hippocampus of mice with impaired learning and memory. Neural Regen Res 2008;3(11):1218–21. 56 Böhme GA, Bon C, Lemaire M, Reibaud M, Piot O, Stutzmann JM, et al. Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats. Proc Natl Acad Sci USA 1993;90:9191–4. 57 Tu QY, Tang XQ, Liu ZQ. Effect of NOS positive neurons in rats with learning-remembering barrier. Bull Hunan Med Univ 2001; 26:331–4. 58 Lee K, Lee JS, Jang HJ, Kim SM, Chang MS, Park SH, et al. Chlorogenic acid ameliorates brain damage and edema by inhibiting matrixmetalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur J Pharm 2012;689:89–95. 59 Hovatta L, Tennant RS, Helton R, Marr RA, Singer O, Redwine JM, et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 2005;438:662–6. 60 Smith A. Effects of caffeine on human behavior. Food Chem Toxicol 2002;40:1243–55. 61 Haskell CF, Kennedy DO, Wesnes KA, Scholey AB. Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine. Psychopharmacology 2005;179:813–25. 62 Thom E. The effect of chlorogenic acid enriched coffee on glucose absorption in healthy volunteers and its effect on body mass when used long-term in overweight and obese people. J Int Med Res 2007;35:900–8. 63 Gonthier MP, Verny MA, Besson C, Rémésy C, Scalbert A. Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. J Nutr 2003;133:1853–9. 64 Per´ez-Jimen´ez J, Fezeu L, Touvier M, Arnault N, Manach C, Hercberg S, et al. Dietary intake of 337 polyphenols in French adults. Am J Clin Nutr 2011;93:1220–8. 65 Gonthier MP, Remesy C, Scalbert A, Cheynier V, Souquet JM, Poutanen K, et al. Microbial metabolism of caffeic acid and its esters chlorogenic and caftaric acids by human faecal microbiota in vitro. Biomed Pharmacother 2006;60:536–40.
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31 Schrader K, Kiehne A, Engelhardt UH, Maier HG. Determination of chlorogenic acids with lactones in roasted coffee. J Sci Food Agric 1999;71(3):392–8. 32 Samanidou V, Tsagiannidis A, Sarakatsianos I. Simultaneous determination of polyphenols and major purine alkaloids in Greek Sideritis species, herbal extracts, green tea, black tea, and coffee by high-performance liquid chromatography-diode array detection. J Sep Sci 2012;35(4):608–15. 33 Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995;38:357–66. 34 Huang FN, Zhang BL, Li WB, Cui X, Han ZT, Fang ZY. Effects of free radicals and amyloid beta protein on the currents of expressed rat receptors in Xenopus oocytes. Chin J Appl Physiol 2001;17:109–12. 35 Marksberry WR, Lovell MA. Damage to lipids, proteins, DNA and RNA in mild cognitive impairment. Arch Neurol 2007;64: 954–6. 36 Shen W, Qi R, Zhang J, Wang Z, Wang H, Hu C, et al. Chlorogenic acid inhibits LPS-induced microglial activation and improves survival of dopaminergic neurons. Brain Res Bull 2012;88:487–94. 37 Teraoka M, Nakaso K, Kusumoto C, Katano S, Tajima N, Yamashita A, et al. Cytoprotective effect of chlorogenic acid against α-synuclein-related toxicity in catecholaminergic PC12 cells. J Clin Biochem Nutr 2012;51:122–7. 38 Chu YF, Brown PH, Lyle BJ, Chen Y, Black RM, Williams CE, et al. Roasted coffees high in lipophilic antioxidants and chlorogenic acid lactones are more neuroprotective than green coffees. J Agric Food Chem 2009;57:9801–8. 39 Jang YJ, Kim J, Shim J, Kim CY, Jang JH, Lee KW, et al. Decaffeinated coffee prevents scopolamine-induced memory impairment in rats. Behav Brain Res 2013;245:113–9. 40 Kim J, Lee S, Shim J, Kim HW, Kim J, Jang YJ, et al. Caffeinated coffee, decaffeinated coffee, and the phenolic phytochemical chlorogenic acid up-regulate NQO1 expression and prevent H2O2-induced apoptosis in primary cortical neurons. Neurochem Int 2012;60:466–74. 41 Nakajima Y, Shimazawa M, Mishima S, Hara H. Water extract of propolis and its main constituents, caffeoylquinic acid derivatives, exert neuroprotective effects via antioxidant actions. Life Sci 2007;80:370–7. 42 Cho ES, Jang YJ, Hwang MK, Kang NJ, Lee KW, Lee HJ. Attenuation of oxidative neuronal cell death by coffee phenolic phytochemicals. Mutat Res 2009;661:18–24. 43 Oboh G, Agunloye OM, Akinyemi AJ, Ademiluyi AO, Adefegha SA. Comparative study on the inhibitory effect of caffeic and chlorogenic acids on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced oxidative stress in rats’ brain-in vitro. Neurochem Res 2013;38:413–9. 44 Arnold SE, Kumar A. Reversible dementias. Med Clin North Am 1993;77:215–30. 45 Orhan I, Sener B, Choudhary MI, Khalid A. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some Turkish medicinal plants. J Ethnopharmacol 2004;91:57–60. 46 Mizuno Y, Hattori N, Kubo S, Sato S, Nishioka K, Hatano T, et al. Progress in the pathogenesis and genetics of Parkinson’s disease. Philos Trans R Soc Lond B Biol Sci 2008; 363:2215–27. 47 Spillantini MG, Crowther RA, Jakes R, Masegawa M, Goedert M. α-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 1998;95:6469–73.
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