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Red Grape Juice and Alzheimer’s Disease
Chapter 86
Red Grape Juice and Alzheimer’s Disease Hojjatollah Alaei, PharmD, PhD, Zahra Siahmard, MSc and Parham Reisi, PhD Isfahan University of Medical Sciences, Isfahan, Iran
LIST OF ABBREVIATIONS AD Alzheimer’s disease CAT catalase GJ grape juice Hcy homocysteine HDL high-density lipoprotein LDL low-density lipoprotein PD Parkinson’s disease RGJ red grape juice SOD superoxide dismutase STZ streptozotocin
INTRODUCTION Alzheimer’s disease (AD) is a senile disease diagnosed with dementia and loss of neurons, especially in the elderly brain [1]. This disease may be caused by oxidative stress, as an imbalance takes place between free radicals and the antioxidant system. Free radicals attack the unsaturated fatty acids of brain tissue cells and cause oxidative lesions [2]. Studies in animal models of AD such as injection of streptozotocin (STZ) into the lateral ventricles of the rat’s brain have shown that the induction of the disease is secondary to the formation of free radicals and oxidative stress [1,2]. Consumption of fruits and vegetables, especially those with high antioxidant activities like grapes, strawberries, spinach, and cranberries, decreases the risk for diseases caused by oxidative stress like AD. They reduce the oxidative metabolism and subsequently reduce free radicals and can be effective in treatment of the disease [3,4]. According to studies on some foodstuffs and beverages, these substances can both prevent the AD and delay its progress. Some of these substances include aged garlic extract; sarcomin; melatonin; ginkgo biloba; green tea; fruit containing resveratrol; foods containing vitamins B, E, and C; Salvia extract; zeatin; and grapes [4–13]. Grapes are one of the most overlooked fruits that are rich in health-protecting antioxidants, including resveratrol and flavonoids. But most people aren’t aware of their health benefits. Antioxidants are found in the pulp of grapes, but mainly they are in the skin, stem, leaves, and seeds. Many factors can affect the amount of antioxidants in grapes, including the kind of grape, its geographic origin, and how it’s processed. Red and purple grapes have higher antioxidants than white or green grapes. However, there are other compounds in grape juice (GJ), which can be functional physiologically (Table 86.1). Studies have shown that wine and GJ have the same health benefits. As seen for red wine, grape extract is a rich source of flavonoids polyphenole such as catkins, quercetins, anthocyanidins, proanthocyanidins, and also nonflavonoids polyphenole like resveratrol, which all are active antioxidants effective in preventing or reversing the destructive effects of old age on the behavior and function of the brain [4].
RAT MODEL OF AD Wistar rats were anesthetized by intraperitoneal (i.p.) injection of chloral hydrate (CH) of 400 mg/kg, and their body temperature was fixed using heating pads. Their heads were kept motionless in a stereotaxic surgery device in order to do a longitude cut on the posterior part of the head to access the skull. Once the stereotaxic coordinates (AP = −0.8, DV = 4.2, and Diet and Nutrition in Dementia and Cognitive Decline. © 2015 2012 Elsevier Inc. All rights reserved.
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TABLE 86.1 Chemical Composition of GJ Chemical Composition
Considerations
Water
Freshly expressed GJ consists of 70–80% water.
Sugars
The most abundant solids present in GJ. Glucose and fructose are the main sugars in the juice.
Organic acids
The principal organic acids found in grapes are tartaric, malic, and to a small extent, citric, amino acids, and many other organic acids.
Phenolic compounds
Next to sugars and acids, they are the most abundant constituents present in grapes.
Nitrogenous compounds
Grapes contain various nitrogenous compounds, including ammonium cations and organic nitrogenous compounds such as amino acids, peptides, and proteins.
Aroma compounds
Grapes contain numerous flavor compounds.
Minerals
Usually 0.2–0.6% of the fresh weight of the fruit. The important mineral compounds include potassium (50–70% of the cations in the juice), sodium, iron, phosphates, sulfate, and chloride.
Pectin substances
Pectin substances are cementing agents present in the cell wall.
L = ±1.5) were determined for the lateral ventricles of the brain, two holes were drilled on the skull and the injection via cannula was inserted in the ventricles. The rat model of Alzheimer’s was created by injecting STZ in lateral ventricles (STZ, 1.5 mg/kg, body weight in saline, 4 µL/injection site) using a microinjection device and Hamilton syringe within 3 min. Two weeks later, the rats were assessed with a passive avoidance learning test to confirm the induction of Alzheimer’s. STZ is a diabetogenic substance that produces behavioral and neurochemical features that resemble those found in human AD. Cognitive deficits and biochemical and structural changes induced by ICV-STZ in the brain mainly were attributed to generating free radicals and inflammatory cytokines, and altering glucose energy metabolism by depleting ATP synthesis. ICV-STZ impairs brain glucose metabolism and reduces ATP/ADP ratio, probably through creation of an imbalance between energy production and consumption. Also, it induces impairments of acetylcholine homeostasis through decreasing acetylcholine transferase activity and affecting choline acetyltransferase activity [2].
GJ AND ANTIOXIDATIVE EFFECTS Grapes are rich antioxidants that are found mainly in the skin, stem, leaves, and seeds of grapes. Some research suggests that whole grapes deliver the same amount of antioxidants that are in GJ but have the added benefit of providing dietary fiber. Red grape juice (RGJ) consumption reduced plasma concentrations of total cholesterol and apolipoprotein B and increased those of HDL-cholesterol. RGJ, like vitamin E, reduced plasma concentrations of oxidized LDL. It is possible that grape polyphenols directly increase the resistance of LDL particles to oxidation in plasma. Other findings reveal that RGJ consumption decreased circulating LDL particles [14]. In the presence of LDL, RGJ increased both the activity and cell surface expression of the LDL receptor and increased the cell total cholesterol content. This is likely to be due to stimulation of LDL-receptor activity, as observed in cultured cells in response to red grape polyphenols [15]; however, other causes, such as an imbalance in nutrient intake produced by the carbohydrate content in RGJ, cannot be ruled out. It has been shown that ingestion of GJ in humans increases serum antioxidant capacity, reduces peroxide formation, decreases platelet aggregation, and improves flow-mediated vasodilatation [16]. Others reported that ingestion of concentrated RGJ as a polyphenol-rich dietary supplement exerts hypolipidemic and antioxidant effects in some patients [16]. The variety of polyphenols present in the RGJ concentrate, including flavonols, anthocyanins, flavan-3-ols, procyanidins, and phenolic acids, and the limited availability of pure compounds make the search for the active compound(s) a complex task. The finding that other potent antioxidants do not mimic the effects of RGJ indicates that antioxidant protection is not responsible for the effects of RGJ on LDL-receptor activity [17,18].
GJ AND LIPID PROFILE In addition to their antioxidant activity, polyphenols, which are the main component of RGJ, also possess many different biological properties that may contribute to their cardioprotective effects, including the ability to inhibit platelet activity and thrombosis [19,20] and the potential to reduce plasma lipids. In vivo studies showed that administration of dealcoholized
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350 +++
Latency(s)
300
+++
250 200 150 100 50
**
0 Sham
Grape juice
Alzheimer
Alzheimer-grape juice
FIGURE 86.1 Comparison of mean latency in Alzheimer and Alzheimer-GJ 24 h after electric shock using shuttle box. The results showed that GJ was effective in treatment of learning and memory dysfunction. (Mean ± SEM) **Comparison of Alzheimer group with sham group (P < 0.01). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001). +++ Comparison of GJ with Alzheimer group (P < 0.001) [30].
red wine [21] and grape seed procyanidins [22] lowered plasma cholesterol in laboratory animals with diet-induced hypercholesterolemia. In a 2005 study, reduction of cholesterol LDL plasma concentration was reported in women consuming a lyophilized grape powder [14]. The mechanisms underlying this hypolipidemic effect may involve the inhibition of hepatic lipid synthesis [23] and lipoprotein secretion [24] or increased cholesterol elimination via bile acids [22]. Consumption of RGJ in healthy subjects reduced the concentration of oxidized LDL and increased the concentration of cholesterol-standardized α-tocopherol. RGJ supplementation also caused a significant decrease in LDL cholesterol and apolipoprotein B-100 concentrations, while increasing the concentrations of HDL cholesterol and apolipoprotein A-I [25]. Red wine polyphenols [15] and green tea catechins [26] increase LDL-receptor expression in a humans and reduce cholesterol absorption. In this respect, saponins, which can interfere with dietary fat assimilation, were recently reported to be present in grapes and wines [16]. Therefore, both the inhibition of intestinal absorption of cholesterol and the accelerated clearance of plasma LDL may account for the observed hypolipidemic action of RGJ. Using RGJ with other dietary supplementation improves the lipoprotein profile, reduces plasma concentrations of oxidized LDL, and may favor a reduction in cardiovascular disease risk. Meta-analysis of four large prospective studies has shown that for about 2% increase from an individual with normal HDL-C level, the incidence of coronary events decreases by 2% in men and 3% in women [27]. Purple GJ consumption improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease [28]. Another study showed that RGJ consumption lowers homocysteine (Hcy) levels [29]. Lower Hcy concentrations may introduce another possible mechanism for the vascular protective effects in populations that consume RGJ.
GJ AND COGNITION Generally, grapes, particularly red ones, have a tremendous effect on memory boosting and even on Alzheimer’s (Figures 86.1–86.4) [4,31]. Investigators indicate that using GJ improved cognitive performance in aging rats [4], greater flavonoid intake being associated with higher baseline cognitive performance and reduced decline over time in older humans [32], as well as studies supporting an inverse association between consumption of fruit/vegetable juice and AD risk in humans [32]. The protective effect of RGJ and GSE against memory deficits and LTP inhibition is due to the antioxidant effect of these compounds on glutamate activities in the brain [33]. Moreover, flavonoid compounds reduced cognitive decline in older adults due to powerful antioxidant and anti-inflammatory properties [34]. Both oxidative stress and inflammation are thought to be important contributors to cognitive impairment, and higher consumption of total flavonoids is associated with a slower progression of cognitive decline in older women [35]. Polyphenoles are naturally occurring phytochemicals found in fruits and vegetables, exhibiting strong neuroprotective properties [36]. These compounds of GJ are known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases like AD [37]. In a study to assess the effects of 21 days of treatment with grapes on AD, after induction of AD, learning was assessed in rats by passive avoidance test. In the rats receiving electrical shock after induction of AD, mean latency for the first entry to the dark room 24 h and 1 week after the shock for the Alzheimer’s group was significantly less than that of the sham group (P < 0.01), which showed the incidence of Alzheimer’s in this group was due to learning dysfunction and memory consolidation following the injection of STZ. However, latency for the first entry to the dark room 24 h and 1 week after the shock for the Alzheimer-GJ group was significantly more than that of the Alzheimer’s group (P < 0.001) (Figures 86.1 and 86.2).
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350 +++
Latency(s)
300
+++
250 200 150 100 50
**
0 Sham
Grape juice
Alzheimer
Alzheimer-grape juice
FIGURE 86.2 Comparison of mean latency in Alzheimer and Alzheimer-GJ 1 week after electric shock using shuttle box. The results showed that GJ was effective in treatment of learning and memory dysfunction. (Mean ± SEM) ** Comparison of Alzheimer group with sham group (P < 0.01). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001). +++ Comparison of GJ with Alzheimer group (P < 0.001) [30]. 350 +++
Latency(s)
300 250 200 150
***
100 50 0
Sham
Alzheimer
Alzheimer-grape juice
FIGURE 86.3 Comparison of mean latency in Alzheimer and Alzheimer-GJ 24 h after treatment using shuttle box. The results showed that GJ was effective in treatment of impaired learning and memory storage. (Mean ± SEM) ***Comparison of Alzheimer group with sham group (P < 0.001). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001) [30]. 400 350 +++
Latency(s)
300 250 200 150
***
100 50 0
Sham
Alzheimer
Alzheimer-grape juice
FIGURE 86.4 Comparison of mean latency in Alzheimer and Alzheimer-GJ 1 week after treatment using shuttle box. The results showed that GJ was effective in treatment of impaired learning and memory storage. (Mean ± SEM) ***Comparison of Alzheimer group with sham group (P < 0.001). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001) [30].
In the rats receiving electrical shock before induction of AD, mean latency for the first entry to the dark room 24 h and 1 week after the treatment for the Alzheimer group was significantly less than that of the sham group (P < 0.001), which showed the incidence of Alzheimer’s in this group was due to the loss of memory location following the injection of STZ. However, latency for the first entry to the dark room in the Alzheimer-GJ group was significantly more than that of the Alzheimer’s group (P < 0.001) (Figures 86.3 and 86.4).
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Before treatment After treatment
Number of rotations/60 min
300
#
250 200 * 150 100 50 0 Sham
PD group
PD-Gl
FIGURE 86.5 Comparing total number of rotations before and after the treatment in sham, PD, and PD-GJ groups (n = 6). GJ significantly decreased total number of rotations after the treatment (*P < 0.05), but there were no significant differences between before and after measures in sham and PD groups. There were significant differences between sham and PD groups before the experiment (∞P < 0.05) and also after the experiment in the number of rotations (#P < 0.05). Data are presented as mean ± SEM. PD, Parkinson’s disease; PD-GJ, PD treated with GJ [38].
APPLICATIONS TO OTHER DEMENTIAS GJ contains high levels of polyphenole compounds such as flavonoids and nonflavonoids [3]. These compounds improve endothelial function, increase antioxidant capacity, reduce native plasma protein oxidation, and decrease platelet aggregation [17]. Various concentrations of Concord GJ can be useful in reversing cognitive and motor deficits in aging [4]. Dani et al. reported that activity of catalase (CAT) and superoxide dismutase (SOD) enzymes were increased after chronic intake of purple GJ [3]. It is worth mentioning that SOD activity decreases in neurodegenerative disorders such as Parkinson’s disease (PD) (Figure 86.5) [3,39]. Therefore, it is possible that GJ is able to raise activity of the enzymatic antioxidant defenses [3]. ShukittHale et al. reported that 50% dose of Concord GJ improves motor function in aging rats on the psychomotor tests such as rod walking, wire suspension, and small plank, probably due to the effects of polyphenolics on the neuronal parameters [4]. It has been demonstrated that the total number of rotations was decreased after intake of red GJ, which is probably due to the increase in activities of antioxidant enzymes and affecting of neuronal parameters. Therefore, richer content of phenolic compounds and higher amounts of resveratrol and anthocyanins should be able to treat PD in rats probably due to different mechanisms. In addition, it has been shown that treatment by red GJ together with treadmill exercise presented protective effects on parkinsonian rats similar to the PD-GJ group. Therefore, GJ plays a major role in reducing the number of rotations in the Parkinson’s model. Grape extract protects patients from low density of lipoprotein cholesterol oxidation and reduction of destructive effects of oxidative stress on rats’ brain neurons [4,31]. Grape seed extract relaxes the mind and supports sleep by increasing synthesis of neurotransmitter serotonin and decreasing the effects of internal and external stresses through its antioxidant property (http://www.finecurepharma.com/sleep-support.htm). GJ is able to protect from lipid and protein oxidative damage, decrease nitric oxide content, and increase enzymatic defenses in brain tissues following pentylenetetrazole-induced seizures. In general, it is possible that GJs can provide further insight into natural neuroprotective compounds and may lead to the development of new therapeutic strategies for epileptic patients [40]. Resveratrol, another compound of GJ, reduces tactile allodynia produced by neuropathic pain and diabetic neuropathy. Resveratrol is synthesized in the skin of grapes and shows effects on PD, Huntington’s disease, and nerve injury. It attenuates the incidence of convulsions in the kainic acid model when it is administered as pre- and posttreatment through protection from damage to the hippocampus [38]. Therefore, GJ has neuroprotective activity that supports the use of this fruit in various traditional medicines for the treatment of tissue disorders.
PRACTICAL ISSUES Grapes possess health-promoting effects attributed to their supply of a wide variety of bioactive phenolics. There have been no clinical trials about RGJ, but whole commercial RGJs used as food supplements are potentially useful against both
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physiological and induced cardiac oxidative stress. The results indicated a good antioxidant stability of the juice sample to lyophilization that may be reasonably regarded as a suitable process for the formulation of food supplements. It is suggested that the juice sample can be employed as a food supplement with prospective cardioprotective benefits; however, further studies are needed to optimize its dosages to avoid harmful prooxidant effects. Regular consumption of purple GJ also in the absence of other red, blue, or purple fruits benefited immunity in healthy, middle-aged human subjects [41]. In humans, grape polyphenole demonstrated effects such as maintenance of endothelial function, increase in antioxidant capacity and protection against LDL oxidation and reducing atherosclerosis, lowering blood pressure, reducing inflammation, and activating novel proteins that prevent cell senescence, e.g., Sirtuin 1. However, using grapes, wine, and GJs adds a low risk of exposure to ochratoxin A, which mycotoxin is considered one of the most harmful contaminants to human health [42]. Red grape polyphenols also are considered to promote cardiovascular health and are involved in multiple biological functions, and short-term intake of this extract altered microbial protein fermentation. Other findings suggest that GJ and all polyphenols tested were able to modulate the coenzyme activities and reduced platelet aggregation. Moderate red wine and GJ consumption modulates the hydrolysis of the adenine nucleotides and decreases platelet aggregation in STZ-induced diabetic rats. Therefore, RGJ could contribute to the prevention of platelet abnormality and, consequently, vascular complications in the diabetic state [43]. Procyanidin B2 is another compound that is widely found in GJ and protects against oxidative injury in colonic cells to prevent oxidative stress–related intestinal injury and gut pathologies [44]. In healthy volunteers, consumption of a moderate amount of red wine reduces plasma anandamide and 2-arachidonoylglycerol concentrations, whereas non-alcoholic liquid GJ does not affect plasma ECs, but organic GJ intake improved glucose homeostasis and microvascular function, which may be due to its high concentration of polyphenols [45]. Aromatase inhibitors prevent the conversion of androgens to estrogen and occur naturally in RGJ and may explain the observation that red wine does not appear to increase breast cancer risk in premenopausal women [46]. Other findings indicate that red fruit juices are potent inducers of endothelium-dependent relaxations in the porcine coronary artery. This effect involves both endothelium-derived NO and EDHF and appears to be dependent on their polyphenolic composition rather than on the polyphenolic content [47].
SUMMARY POINTS ● ● ● ● ●
Grapes are rich in health-protecting antioxidants. GJ delivers the same amount of antioxidants that are in wine. Using RGJs improves learning and memory. GJs have positive effects in AD. GJ exerts hypolipidemic actions.
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Red Grape Juice and Alzheimer’s Disease Hojjatollah Alaei, PharmD, PhD, Zahra Siahmard, MSc and Parham Reisi, PhD Isfahan University of Medical Sciences, Isfahan, Iran
LIST OF ABBREVIATIONS AD Alzheimer’s disease CAT catalase GJ grape juice Hcy homocysteine HDL high-density lipoprotein LDL low-density lipoprotein PD Parkinson’s disease RGJ red grape juice SOD superoxide dismutase STZ streptozotocin
INTRODUCTION Alzheimer’s disease (AD) is a senile disease diagnosed with dementia and loss of neurons, especially in the elderly brain [1]. This disease may be caused by oxidative stress, as an imbalance takes place between free radicals and the antioxidant system. Free radicals attack the unsaturated fatty acids of brain tissue cells and cause oxidative lesions [2]. Studies in animal models of AD such as injection of streptozotocin (STZ) into the lateral ventricles of the rat’s brain have shown that the induction of the disease is secondary to the formation of free radicals and oxidative stress [1,2]. Consumption of fruits and vegetables, especially those with high antioxidant activities like grapes, strawberries, spinach, and cranberries, decreases the risk for diseases caused by oxidative stress like AD. They reduce the oxidative metabolism and subsequently reduce free radicals and can be effective in treatment of the disease [3,4]. According to studies on some foodstuffs and beverages, these substances can both prevent the AD and delay its progress. Some of these substances include aged garlic extract; sarcomin; melatonin; ginkgo biloba; green tea; fruit containing resveratrol; foods containing vitamins B, E, and C; Salvia extract; zeatin; and grapes [4–13]. Grapes are one of the most overlooked fruits that are rich in health-protecting antioxidants, including resveratrol and flavonoids. But most people aren’t aware of their health benefits. Antioxidants are found in the pulp of grapes, but mainly they are in the skin, stem, leaves, and seeds. Many factors can affect the amount of antioxidants in grapes, including the kind of grape, its geographic origin, and how it’s processed. Red and purple grapes have higher antioxidants than white or green grapes. However, there are other compounds in grape juice (GJ), which can be functional physiologically (Table 86.1). Studies have shown that wine and GJ have the same health benefits. As seen for red wine, grape extract is a rich source of flavonoids polyphenole such as catkins, quercetins, anthocyanidins, proanthocyanidins, and also nonflavonoids polyphenole like resveratrol, which all are active antioxidants effective in preventing or reversing the destructive effects of old age on the behavior and function of the brain [4].
RAT MODEL OF AD Wistar rats were anesthetized by intraperitoneal (i.p.) injection of chloral hydrate (CH) of 400 mg/kg, and their body temperature was fixed using heating pads. Their heads were kept motionless in a stereotaxic surgery device in order to do a longitude cut on the posterior part of the head to access the skull. Once the stereotaxic coordinates (AP = −0.8, DV = 4.2, and Diet and Nutrition in Dementia and Cognitive Decline. © 2015 2012 Elsevier Inc. All rights reserved.
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TABLE 86.1 Chemical Composition of GJ Chemical Composition
Considerations
Water
Freshly expressed GJ consists of 70–80% water.
Sugars
The most abundant solids present in GJ. Glucose and fructose are the main sugars in the juice.
Organic acids
The principal organic acids found in grapes are tartaric, malic, and to a small extent, citric, amino acids, and many other organic acids.
Phenolic compounds
Next to sugars and acids, they are the most abundant constituents present in grapes.
Nitrogenous compounds
Grapes contain various nitrogenous compounds, including ammonium cations and organic nitrogenous compounds such as amino acids, peptides, and proteins.
Aroma compounds
Grapes contain numerous flavor compounds.
Minerals
Usually 0.2–0.6% of the fresh weight of the fruit. The important mineral compounds include potassium (50–70% of the cations in the juice), sodium, iron, phosphates, sulfate, and chloride.
Pectin substances
Pectin substances are cementing agents present in the cell wall.
L = ±1.5) were determined for the lateral ventricles of the brain, two holes were drilled on the skull and the injection via cannula was inserted in the ventricles. The rat model of Alzheimer’s was created by injecting STZ in lateral ventricles (STZ, 1.5 mg/kg, body weight in saline, 4 µL/injection site) using a microinjection device and Hamilton syringe within 3 min. Two weeks later, the rats were assessed with a passive avoidance learning test to confirm the induction of Alzheimer’s. STZ is a diabetogenic substance that produces behavioral and neurochemical features that resemble those found in human AD. Cognitive deficits and biochemical and structural changes induced by ICV-STZ in the brain mainly were attributed to generating free radicals and inflammatory cytokines, and altering glucose energy metabolism by depleting ATP synthesis. ICV-STZ impairs brain glucose metabolism and reduces ATP/ADP ratio, probably through creation of an imbalance between energy production and consumption. Also, it induces impairments of acetylcholine homeostasis through decreasing acetylcholine transferase activity and affecting choline acetyltransferase activity [2].
GJ AND ANTIOXIDATIVE EFFECTS Grapes are rich antioxidants that are found mainly in the skin, stem, leaves, and seeds of grapes. Some research suggests that whole grapes deliver the same amount of antioxidants that are in GJ but have the added benefit of providing dietary fiber. Red grape juice (RGJ) consumption reduced plasma concentrations of total cholesterol and apolipoprotein B and increased those of HDL-cholesterol. RGJ, like vitamin E, reduced plasma concentrations of oxidized LDL. It is possible that grape polyphenols directly increase the resistance of LDL particles to oxidation in plasma. Other findings reveal that RGJ consumption decreased circulating LDL particles [14]. In the presence of LDL, RGJ increased both the activity and cell surface expression of the LDL receptor and increased the cell total cholesterol content. This is likely to be due to stimulation of LDL-receptor activity, as observed in cultured cells in response to red grape polyphenols [15]; however, other causes, such as an imbalance in nutrient intake produced by the carbohydrate content in RGJ, cannot be ruled out. It has been shown that ingestion of GJ in humans increases serum antioxidant capacity, reduces peroxide formation, decreases platelet aggregation, and improves flow-mediated vasodilatation [16]. Others reported that ingestion of concentrated RGJ as a polyphenol-rich dietary supplement exerts hypolipidemic and antioxidant effects in some patients [16]. The variety of polyphenols present in the RGJ concentrate, including flavonols, anthocyanins, flavan-3-ols, procyanidins, and phenolic acids, and the limited availability of pure compounds make the search for the active compound(s) a complex task. The finding that other potent antioxidants do not mimic the effects of RGJ indicates that antioxidant protection is not responsible for the effects of RGJ on LDL-receptor activity [17,18].
GJ AND LIPID PROFILE In addition to their antioxidant activity, polyphenols, which are the main component of RGJ, also possess many different biological properties that may contribute to their cardioprotective effects, including the ability to inhibit platelet activity and thrombosis [19,20] and the potential to reduce plasma lipids. In vivo studies showed that administration of dealcoholized
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0 Sham
Grape juice
Alzheimer
Alzheimer-grape juice
FIGURE 86.1 Comparison of mean latency in Alzheimer and Alzheimer-GJ 24 h after electric shock using shuttle box. The results showed that GJ was effective in treatment of learning and memory dysfunction. (Mean ± SEM) **Comparison of Alzheimer group with sham group (P < 0.01). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001). +++ Comparison of GJ with Alzheimer group (P < 0.001) [30].
red wine [21] and grape seed procyanidins [22] lowered plasma cholesterol in laboratory animals with diet-induced hypercholesterolemia. In a 2005 study, reduction of cholesterol LDL plasma concentration was reported in women consuming a lyophilized grape powder [14]. The mechanisms underlying this hypolipidemic effect may involve the inhibition of hepatic lipid synthesis [23] and lipoprotein secretion [24] or increased cholesterol elimination via bile acids [22]. Consumption of RGJ in healthy subjects reduced the concentration of oxidized LDL and increased the concentration of cholesterol-standardized α-tocopherol. RGJ supplementation also caused a significant decrease in LDL cholesterol and apolipoprotein B-100 concentrations, while increasing the concentrations of HDL cholesterol and apolipoprotein A-I [25]. Red wine polyphenols [15] and green tea catechins [26] increase LDL-receptor expression in a humans and reduce cholesterol absorption. In this respect, saponins, which can interfere with dietary fat assimilation, were recently reported to be present in grapes and wines [16]. Therefore, both the inhibition of intestinal absorption of cholesterol and the accelerated clearance of plasma LDL may account for the observed hypolipidemic action of RGJ. Using RGJ with other dietary supplementation improves the lipoprotein profile, reduces plasma concentrations of oxidized LDL, and may favor a reduction in cardiovascular disease risk. Meta-analysis of four large prospective studies has shown that for about 2% increase from an individual with normal HDL-C level, the incidence of coronary events decreases by 2% in men and 3% in women [27]. Purple GJ consumption improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease [28]. Another study showed that RGJ consumption lowers homocysteine (Hcy) levels [29]. Lower Hcy concentrations may introduce another possible mechanism for the vascular protective effects in populations that consume RGJ.
GJ AND COGNITION Generally, grapes, particularly red ones, have a tremendous effect on memory boosting and even on Alzheimer’s (Figures 86.1–86.4) [4,31]. Investigators indicate that using GJ improved cognitive performance in aging rats [4], greater flavonoid intake being associated with higher baseline cognitive performance and reduced decline over time in older humans [32], as well as studies supporting an inverse association between consumption of fruit/vegetable juice and AD risk in humans [32]. The protective effect of RGJ and GSE against memory deficits and LTP inhibition is due to the antioxidant effect of these compounds on glutamate activities in the brain [33]. Moreover, flavonoid compounds reduced cognitive decline in older adults due to powerful antioxidant and anti-inflammatory properties [34]. Both oxidative stress and inflammation are thought to be important contributors to cognitive impairment, and higher consumption of total flavonoids is associated with a slower progression of cognitive decline in older women [35]. Polyphenoles are naturally occurring phytochemicals found in fruits and vegetables, exhibiting strong neuroprotective properties [36]. These compounds of GJ are known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases like AD [37]. In a study to assess the effects of 21 days of treatment with grapes on AD, after induction of AD, learning was assessed in rats by passive avoidance test. In the rats receiving electrical shock after induction of AD, mean latency for the first entry to the dark room 24 h and 1 week after the shock for the Alzheimer’s group was significantly less than that of the sham group (P < 0.01), which showed the incidence of Alzheimer’s in this group was due to learning dysfunction and memory consolidation following the injection of STZ. However, latency for the first entry to the dark room 24 h and 1 week after the shock for the Alzheimer-GJ group was significantly more than that of the Alzheimer’s group (P < 0.001) (Figures 86.1 and 86.2).
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350 +++
Latency(s)
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250 200 150 100 50
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Grape juice
Alzheimer
Alzheimer-grape juice
FIGURE 86.2 Comparison of mean latency in Alzheimer and Alzheimer-GJ 1 week after electric shock using shuttle box. The results showed that GJ was effective in treatment of learning and memory dysfunction. (Mean ± SEM) ** Comparison of Alzheimer group with sham group (P < 0.01). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001). +++ Comparison of GJ with Alzheimer group (P < 0.001) [30]. 350 +++
Latency(s)
300 250 200 150
***
100 50 0
Sham
Alzheimer
Alzheimer-grape juice
FIGURE 86.3 Comparison of mean latency in Alzheimer and Alzheimer-GJ 24 h after treatment using shuttle box. The results showed that GJ was effective in treatment of impaired learning and memory storage. (Mean ± SEM) ***Comparison of Alzheimer group with sham group (P < 0.001). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001) [30]. 400 350 +++
Latency(s)
300 250 200 150
***
100 50 0
Sham
Alzheimer
Alzheimer-grape juice
FIGURE 86.4 Comparison of mean latency in Alzheimer and Alzheimer-GJ 1 week after treatment using shuttle box. The results showed that GJ was effective in treatment of impaired learning and memory storage. (Mean ± SEM) ***Comparison of Alzheimer group with sham group (P < 0.001). +++ Comparison of Alzheimer-GJ with Alzheimer group (P < 0.001) [30].
In the rats receiving electrical shock before induction of AD, mean latency for the first entry to the dark room 24 h and 1 week after the treatment for the Alzheimer group was significantly less than that of the sham group (P < 0.001), which showed the incidence of Alzheimer’s in this group was due to the loss of memory location following the injection of STZ. However, latency for the first entry to the dark room in the Alzheimer-GJ group was significantly more than that of the Alzheimer’s group (P < 0.001) (Figures 86.3 and 86.4).
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Before treatment After treatment
Number of rotations/60 min
300
#
250 200 * 150 100 50 0 Sham
PD group
PD-Gl
FIGURE 86.5 Comparing total number of rotations before and after the treatment in sham, PD, and PD-GJ groups (n = 6). GJ significantly decreased total number of rotations after the treatment (*P < 0.05), but there were no significant differences between before and after measures in sham and PD groups. There were significant differences between sham and PD groups before the experiment (∞P < 0.05) and also after the experiment in the number of rotations (#P < 0.05). Data are presented as mean ± SEM. PD, Parkinson’s disease; PD-GJ, PD treated with GJ [38].
APPLICATIONS TO OTHER DEMENTIAS GJ contains high levels of polyphenole compounds such as flavonoids and nonflavonoids [3]. These compounds improve endothelial function, increase antioxidant capacity, reduce native plasma protein oxidation, and decrease platelet aggregation [17]. Various concentrations of Concord GJ can be useful in reversing cognitive and motor deficits in aging [4]. Dani et al. reported that activity of catalase (CAT) and superoxide dismutase (SOD) enzymes were increased after chronic intake of purple GJ [3]. It is worth mentioning that SOD activity decreases in neurodegenerative disorders such as Parkinson’s disease (PD) (Figure 86.5) [3,39]. Therefore, it is possible that GJ is able to raise activity of the enzymatic antioxidant defenses [3]. ShukittHale et al. reported that 50% dose of Concord GJ improves motor function in aging rats on the psychomotor tests such as rod walking, wire suspension, and small plank, probably due to the effects of polyphenolics on the neuronal parameters [4]. It has been demonstrated that the total number of rotations was decreased after intake of red GJ, which is probably due to the increase in activities of antioxidant enzymes and affecting of neuronal parameters. Therefore, richer content of phenolic compounds and higher amounts of resveratrol and anthocyanins should be able to treat PD in rats probably due to different mechanisms. In addition, it has been shown that treatment by red GJ together with treadmill exercise presented protective effects on parkinsonian rats similar to the PD-GJ group. Therefore, GJ plays a major role in reducing the number of rotations in the Parkinson’s model. Grape extract protects patients from low density of lipoprotein cholesterol oxidation and reduction of destructive effects of oxidative stress on rats’ brain neurons [4,31]. Grape seed extract relaxes the mind and supports sleep by increasing synthesis of neurotransmitter serotonin and decreasing the effects of internal and external stresses through its antioxidant property (http://www.finecurepharma.com/sleep-support.htm). GJ is able to protect from lipid and protein oxidative damage, decrease nitric oxide content, and increase enzymatic defenses in brain tissues following pentylenetetrazole-induced seizures. In general, it is possible that GJs can provide further insight into natural neuroprotective compounds and may lead to the development of new therapeutic strategies for epileptic patients [40]. Resveratrol, another compound of GJ, reduces tactile allodynia produced by neuropathic pain and diabetic neuropathy. Resveratrol is synthesized in the skin of grapes and shows effects on PD, Huntington’s disease, and nerve injury. It attenuates the incidence of convulsions in the kainic acid model when it is administered as pre- and posttreatment through protection from damage to the hippocampus [38]. Therefore, GJ has neuroprotective activity that supports the use of this fruit in various traditional medicines for the treatment of tissue disorders.
PRACTICAL ISSUES Grapes possess health-promoting effects attributed to their supply of a wide variety of bioactive phenolics. There have been no clinical trials about RGJ, but whole commercial RGJs used as food supplements are potentially useful against both
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physiological and induced cardiac oxidative stress. The results indicated a good antioxidant stability of the juice sample to lyophilization that may be reasonably regarded as a suitable process for the formulation of food supplements. It is suggested that the juice sample can be employed as a food supplement with prospective cardioprotective benefits; however, further studies are needed to optimize its dosages to avoid harmful prooxidant effects. Regular consumption of purple GJ also in the absence of other red, blue, or purple fruits benefited immunity in healthy, middle-aged human subjects [41]. In humans, grape polyphenole demonstrated effects such as maintenance of endothelial function, increase in antioxidant capacity and protection against LDL oxidation and reducing atherosclerosis, lowering blood pressure, reducing inflammation, and activating novel proteins that prevent cell senescence, e.g., Sirtuin 1. However, using grapes, wine, and GJs adds a low risk of exposure to ochratoxin A, which mycotoxin is considered one of the most harmful contaminants to human health [42]. Red grape polyphenols also are considered to promote cardiovascular health and are involved in multiple biological functions, and short-term intake of this extract altered microbial protein fermentation. Other findings suggest that GJ and all polyphenols tested were able to modulate the coenzyme activities and reduced platelet aggregation. Moderate red wine and GJ consumption modulates the hydrolysis of the adenine nucleotides and decreases platelet aggregation in STZ-induced diabetic rats. Therefore, RGJ could contribute to the prevention of platelet abnormality and, consequently, vascular complications in the diabetic state [43]. Procyanidin B2 is another compound that is widely found in GJ and protects against oxidative injury in colonic cells to prevent oxidative stress–related intestinal injury and gut pathologies [44]. In healthy volunteers, consumption of a moderate amount of red wine reduces plasma anandamide and 2-arachidonoylglycerol concentrations, whereas non-alcoholic liquid GJ does not affect plasma ECs, but organic GJ intake improved glucose homeostasis and microvascular function, which may be due to its high concentration of polyphenols [45]. Aromatase inhibitors prevent the conversion of androgens to estrogen and occur naturally in RGJ and may explain the observation that red wine does not appear to increase breast cancer risk in premenopausal women [46]. Other findings indicate that red fruit juices are potent inducers of endothelium-dependent relaxations in the porcine coronary artery. This effect involves both endothelium-derived NO and EDHF and appears to be dependent on their polyphenolic composition rather than on the polyphenolic content [47].
SUMMARY POINTS ● ● ● ● ●
Grapes are rich in health-protecting antioxidants. GJ delivers the same amount of antioxidants that are in wine. Using RGJs improves learning and memory. GJs have positive effects in AD. GJ exerts hypolipidemic actions.
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