InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Agricultural and Biological Sciences » "Grape and Wine Biotechnology", book edited by Antonio Morata and Iris Loira, ISBN 978-953-51-2693-5, Print ISBN 978-953-51-2692-8, Published: October 19, 2016 under CC BY 3.0 license. © The Author(s).

Chapter 6

Benefits of Vine Leaf on Different Biological Systems

By Denise S. Lacerda, Pedro C. Costa, Cláudia Funchal, Caroline Dani and Rosane Gomez
DOI: 10.5772/64930

Article top


Popular use of vine leaf for health purpose.
Figure 1. Popular use of vine leaf for health purpose.
Effect of different doses (50, 100, and 200 mg/kg) of an organic aqueous vine leaf extract in the (A) carbonyl levels, (B) total sulfhydryl levels, and (C) SOD activity in the kidney of nondiabetic (C) and diabetic (D) rats. Values were represented as mean ± standard error; n = 10/group; ANOVA two‐way + Bonferroni. (#) Different from C0 group, P < 0.05; (*) different from D0 group, P < 0.001.
Figure 2. Effect of different doses (50, 100, and 200 mg/kg) of an organic aqueous vine leaf extract in the (A) carbonyl levels, (B) total sulfhydryl levels, and (C) SOD activity in the kidney of nondiabetic (C) and diabetic (D) rats. Values were represented as mean ± standard error; n = 10/group; ANOVA two‐way + Bonferroni. (#) Different from C0 group, P < 0.05; (*) different from D0 group, P < 0.001.

Benefits of Vine Leaf on Different Biological Systems

Denise S. Lacerda1, Pedro C. Costa2, Cláudia Funchal2, Caroline Dani2 and Rosane Gomez1
Show details


For centuries, the therapeutic benefits of grapes and other byproducts have been empirically used for medical purposes such as bleeding, pain, inflammation, nausea, diarrhea, gastroenteritis, or skin diseases. Moderated intake of the red wine improves parameters as blood lipids, endothelial dysfunction, platelet aggregation, and other risk factors for cardiovascular disease. However, few studies have been explored the potential benefits from vine byproducts. Vine leaves, a waste product from the vine, are also rich source of polyphenols and other therapeutic compounds. In this chapter, we explored the therapeutic properties from vine leaf in different biological systems.

Keywords: polyphenols, organic viticulture, grapevine, natural products, live, heart, kidney, brain

1. Introduction

The production of grapes is considered an economically important activity in many countries, mainly related to the wine production [1]. Beyond their lucrative potential, grapes and their byproducts show nutritional and functional properties [24]. Since centuries ago, grapes have been used for medical purposes, preventing or treating diseases as nausea, diarrhea, gastroenteritis, or skin disorders [5]. More recently, the therapeutic effect of red wine has been reported, and moderate intake has been related to improved blood lipid parameters, endothelial dysfunction, platelet aggregation, and other risk factors for cardiovascular disease [6, 7]. Apart from the grape or wine, studies have been shown that grape byproducts such as juice, or extracts from the skin, seed, or leaf also present therapeutic proprieties [812]. Grape leaves, for example, have been popularly used to stop bleeding, relieve pain, inflammation, and diarrhea (Figure 1) [13, 14].


Figure 1.

Popular use of vine leaf for health purpose.

Therapeutic proprieties by grapes, wine, or byproducts are mainly related to the polyphenolic compounds [7, 15]. Leaves, which are a waste product from the grapevine, usually discarded by grape farmers, are also rich source of polyphenols and other therapeutic compounds [16]. More recently, their therapeutic properties have been explored, mainly because grape juices are rich in carbohydrates and wine is an alcoholic beverage, nonrecommended to diabetic or alcoholics individuals, respectively.

2. Bioactive polyphenols in vine leaves

The grapevine (Vitis spp.) is cultivated across the world in different regions, mainly in temperate climate with adequate rain, warm and dry summers, and mild winters [17]. Climate, soil, conventional or organic cultivation method, and different cultivars are determinant to phytochemical constitution of grapevines [18]. These phytochemical compounds include a variety of bioactive organic acids (e.g., malic, oxalic, fumaric, ascorbic, citric, linoleic, and tartaric acids), vitamin E, terpenes, tannins, carotenoids, and polyphenols that have been highlighted for their beneficial effect on human health [19, 20]. The most important grape polyphenols as flavanols (e.g., epicatechin and gallocatechin), flavonols (e.g., quercetin and myricetin), anthocyanins (e.g., pelargonidin and cyanidin), and resveratrol are secondary metabolites synthesized by plants and associated with growth, pigmentation, pollination, environmental stress, and resistance against pathogens and predators [13, 17].

Polyphenols present biological activities, such as antioxidant, anti‐inflammatory, anticancer, antimicrobial, cardioprotective, and antiaging effects [9, 14]. Polyphenols therapeutic properties have been related to their chemical structure and ability to act as radical scavengers of the lipid peroxidation chain reactions, donating electrons, and neutralizing free radicals [21]. Moreover, they are chelators of metals as iron (Fe2+) and copper (Cu2+), preventing oxidation caused by highly reactive hydroxyl radicals [21, 22]. They also inhibit the immune cell recruitment (T lymphocytes and natural killer cells) and decrease the nuclear factor kappa B (NFκB) expression [23, 24].

SpeciesViticulture methodPreparation Total phenolic mg/g gallic acidPhytochemicals detected Reference
Vitis viniferaNIEthanolic extract216.0 ± 5.1Total flavonoids[26]
Vitis viniferaNIAqueous extract149.93 ± 0.35Total proanthocyanidin; total flavonoid[27]
Vitis viniferaNIAqueous extract146.3 ± 4.2Anthocyanin: cyanidin‐3‐O‐glucoside > peonidin‐3‐O‐glucoside
Flavonols: quercetin‐3‐O‐glucuronide
Caffeic acid derivatives: caftaric acid
Vitis viniferaNIEthanolic extract98.84 ± 9.26NI[29]
Vitis labruscaOrganicAqueous extract81.79 ± 2.68Catechin; resveratrol[30]
Vitis viniferaNIEthanolic extract60.4 ± 0.4Flavonols; quercetin‐3‐O‐glucuronide > kaempherol‐3‐O‐glucoside
Anthocyanin: peonidin‐3‐glucoside > cyanidin‐3‐glucoside
Hydroxycinnamic acid: trans‐caftaric acid
Vitis labruscaOrganicEthanolic extract20.2 ± 1.8Catechin; resveratrol; quercetin; rutin; kaempherol[9]
Vitis labruscaConventionalAqueous extract19.83 ± 0.76Catechin; resveratrol[30]
Vitis labruscaConventionalEthanolic extract19.0 ± 1.8Catechin; resveratrol; quercetin; rutin; kaempherol, naringin[9]
Vitis viniferaNIAcetone/methanol extractAnthocyanins: peonidin 3‐glucoside > malvidin > cyaniding 3‐glucoside; flavonols: quercetin 3‐O‐β‐d‐glucuronide > isoquercitrine quercetin 3‐O‐β‐d‐glucoside phenolic acids[16]

Table 1.

Phenolic compounds from different vine leaf extracts.

[i] - NI: not informed.

A study comparing 10 grape cultivars grown in southern Georgia, USA, showed that the total concentration of phenolic compounds was higher in seed (2178.8 mg/g gallic acid equivalent), followed by skin (374.6 mg/g), and leaf (351.6 mg/g) [25], evidencing that the leaf is also an important source of phenolic compounds. Although gallic acid was a dominant phenolic acid in the vine leaf, other constituents may contribute to the beneficial properties of its extract. Table 1 shows the phenolic contend in different extracts from V. vinifera and V. labrusca leaves. It reveals that ethanolic extracts show the highest extraction rate and the V. labrusca varietal shows the highest total phenolic concentration. Optimal or prolonged low‐temperature exposure decreases the phenolic contends in Vitis vinifera leaves from 526 g/g to 458 mg/g of extract [31]. Antioxidant index, measured by trolox equivalent antioxidant capacity (TEAC) assay, showed that, similarly to grape seeds, leaves present 10 times higher antioxidant activity than grape juice or pulp [7]. Moreover, total phenolic levels in leaf are not affected by brining, a method assumed to preserve vine leaves for future use in the Turkish cuisine [32]. Resveratrol, a compound with therapeutic properties, accumulates in the surface of leaves at range of 40–400 μg/g fresh weight in according to environmental conditions [33].

In addition to environmental influences, farming practices, as organic or conventional viticulture, also interfere with the production of polyphenols [34]. In the organic viticulture, grapevine grown in the absence of pesticides, chemicals, or genetic engineering modification, and it is more vulnerable to external attacks from insets or microorganisms, which may contribute to the higher production of phytochemicals, responsible for plant defenses [35]. A study showed that organic vine leaf extract presents higher concentrations of resveratrol than conventional vine extract, although total polyphenols were similar and catechin and quercetin were lower [9, 30] (Table 1). Given the variability in the phenolic composition of the vine leaf, the quantification of the phenolic constituents may estimate the quality and therapeutic potential in vine leaves [16].

3. Effect of vine leaf extract on hepatic and gastrointestinal systems

Alcoholic and nonalcoholic liver diseases have been related to chronic exposition to risk factors as alcohol, tobacco smoking, drugs, environmental pollutants, and irradiation. It is well known that these risk factors promote excessive formation of oxygen and nitrogen reactive species and may lead to oxidative damage in the liver [36]. Although clinical studies are scarce, preclinical studies show that natural antioxidants from products as vine leaves prevent or attenuate the severity of liver diseases induced by oxidative mechanisms. Animal studies have explored some morphological and biochemistry changes by hepatotoxic substances and the protective effect of vine leaf extracts. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ‐glutamyl transferase (GGT), and alkaline phosphatase (ALP) are some biomarkers that predict liver function and explored in these studies. Aqueous extract from Vitis coignetiae Pulliat leaves shows hepatoprotective effect after chronic oral administration in an animal model of nonalcoholic steatohepatitis (NASH), evidenced by decreasing on AST and ALP activity, confirmed by increasing in plasma antioxidants and delaying in the progression of liver fibrosis [37] (Table 2). Similarly, alcoholic or butanolic extract of vine leaves (Vitis vinifera) decreased AST and ALT activity after acute hepatotoxicity induced by carbon tetrachloride (CCl4) in rats [26]. Vine leaves extract also decreased AST, ALT, ALP, and GGT activity after chronic alcohol administration [29]. For both, CCl4 and alcohol‐induced hepatotoxicity models, vine leaves extract decreased biomarkers of serum oxidative stress as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme, as well decreased histopathological lesions [26, 29]. Preincubation with organic and conventional vine leaf (Vitis labrusca) extracts also prevents both lipid and protein oxidative damage in the rat liver after oxidative stress induced by hydrogen peroxide [39]. Moreover, the organic vine leaves extract restored SOD and the conventional vine leaves extract restored CAT activity, both decreased by hydrogen peroxide‐induced stress and related to different phenolic contend in each extract [39] (Table 2). The liver of diabetic individual is also subject to damage due to exposure to self‐oxidation of free glucose and deficiency of antioxidant system [41]. Indeed, chronic oral administration of aqueous extract of organic grape leaves (Vitis labrusca) reduced the AST activity in an experimental model of diabetes in rats [38]. The synergistic effects of different polyphenols in the vine leaf extract reduced the oxidative stress, preventing lipid and protein damage and increasing enzymatic and nonenzymatic antioxidant defenses in the liver of diabetic rats, suggesting a promising therapeutic approach to hepatic complications induced by diabetes [38].

Species Culture methodTreatmentConditionResultsReference
Vitis labruscaOrganicAqueous extract
Diabetes (rats)↓ Lipid peroxidation
↓ Protein damage
↑ Nonenzymatic antioxidant
↑ SOD activity
↓ CAT activity
Vitis labrusca
Vitis labrusca
Aqueous extract
H2O2‐induced stress
(in vitro)
↓ Lipid peroxidation
↓ Protein damage
↑ SOD activity
↓ Lipid peroxidation
↓ Protein damage
↑ CAT activity
Vitis viniferaNIn‐BuOH extract
Cirrhosis (rats)↓ Lipid peroxidation
↑ GSH content
↓ Histopathological injury
Vitis viniferaNIEthanolic extract
Alcohol induced
↓ Lipid peroxidation
↓ Hydroperoxides
↑ Vitamin E
↑ Vitamin C
↑ SOD activity
↑ CAT activity
↑ GPx activity
↑ GST activity
Vitis coignetiaeNIAqueous extract
Nonalcoholic steatohepatitis
↓ Fibrosis area
↓ MPO activity
↓ Mitochondrial ROS
↓ NFκB expression
Vitis coignetiaeNIAqueous extract
Nonalcoholic steatohepatitis
↓ AST and ALP
↓ CYP2E1 induction
↓ Fibrosis

Table 2.

Hepatoprotective effects of vine leaf.

[i] - NI: not informed; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: γ‐glutamyl transferase; ALP: alkaline phosphatase; SOD: superoxide dismutase, CAT: catalase; GPx: glutathione peroxidase; GSH: reduced glutathione; GST: glutathione‐S‐transferase; ROS: reactive oxygen species; MPO: myeloperoxidase; NFκB; factor nuclear kappa B.

Vine leaves extract (Vitis coignetiae Pulliat) decreases the leakage of biliary enzymes and attenuates liver fibrosis after 3 weeks of treatment in a model of nonalcoholic steatohepatitis in rats [40]. Improving on hepatic fibroses or suppression of its progression by the extract was associated to increasing on plasma antioxidant activity, decreasing on reactive species and NFκB activity, a key pathway linking oxidative stress and inflammation [40]. Vine leaves extract from Vitis vinifera preserved the integrity of the membrane of hepatocytes in CCl4‐intoxicated rats, evidenced by the reduction in plasma levels of AST, ALT, and GGT [27]. Additionally, the extract reduced the concentration of bilirubin, lipoproteins, lipid oxidation and, in parallel, preserved histological injuries of the liver [27].

Among the gastrointestinal diseases, the prevalence and incidence of gastritis, peptic ulcers, and inflammatory bowel disease have increased in recent years, associated to the consumption of processed foods and lifestyle [42]. The activation of inflammatory pathways is the common pathological mechanism of these diseases and initiates by the activation of NFκB, which is related with transcriptional control of multiple proinflammatory mediators as IL‐1β, TNF‐α, and IL‐8 in the gastrointestinal tissue [43].

In this context, the biological activity of the aqueous extract of vine leaves (Vitis vinifera) was assessed in vitro in a model of gastric inflammation (human gastric and intestinal epithelial cell) [28]. Vine leaf extracts impaired the NFκB pathway and, consequently, reduced the TNF‐α and IL‐8 secretion and expression by gastric epithelial cells. The anti‐inflammatory effect of the extract decreased significantly after simulation of intestinal digestion, explained by the poor stability and high rate of degradation of anthocyanins and flavonoids present in the aqueous extract of vine leaves in an alkaline pH [28].

4. Effect of vine leaf extract on the cardiovascular system

Cardiovascular diseases are the most common causes of morbidity and mortality worldwide, currently responsible for over 17 million deaths, with growth forecast to 23.6 million per year to 2030 [44]. Hypertension, dyslipidemia, obesity, and smoking are considered the main cardiovascular risk factors [45]. These factors adversely affect the vascular endothelium, reducing the availability of nitric oxide, facilitating the deposition of oxidized LDL cholesterol by activating oxidative and inflammatory cascades leading to atherosclerosis, endothelial dysfunction, and cardiovascular damage [46].

Studies suggest that consumption of grape polyphenols and its derivatives is associated with reduction in cardiovascular risk related to their antioxidant, anti‐inflammatory, and antithrombotic properties [6]. It is well known that there is a correlation between moderate consumption of red wine and the lowest risk of death associated with heart disease [47, 48]. Indeed, the daily consumption of low to moderate doses of wine reduces by half the risk of death compared to individuals who did not drink wine [49]. Aqueous extract of grape leaves has been tested in rodents and evidenced also an antioxidant effect, decreasing lipid and protein damage, as well increasing SOD and CAT activity in a heart homogenates injured by H2O2 in rats [39]. These antioxidant effects were more significant compared to those extracts prepared from organic grape leaves [39] (Table 3).

SpecieViticulture methodTreatmentConditionTarget tissueResultsReference
Vitis labruscaOrganic and conventionalAqueous extract
H2O2‐induced stress
(in vitro)
Heart↓ Lipid peroxidation
↓ Damage protein
↑ CAT activity
Vitis viniferaNIAqueous extract
Diabetic (rats)Heart↑ GSH content[50]
Vitis viniferaNIEthanolic extract
induced toxicity
Kidney↓ TBARS
↓ Hydroperoxides
↑ Vitamin E and
vitamin C
↑ SOD activity
↑ CAT activity
↑ GPx activity
↑ GST activity
Vitis labruscaOrganicAqueous extract preincubationH2O2
(in vitro)
Kidney↓ Lipid peroxidation
↓ Damage protein
↑ SOD activity
Vitis viniferaNIAqueous extract
Toxicity‐induced by CCl4 (rats)Kidney↓ Creatinine, uric acid,
and calcium levels
Vitis labruscaOrganic and conventionalAqueous extract preincubationH2O2
(in vitro)
Cerebral cortex,  cerebellum and  hippocampus↓ Lipid peroxidation: cerebellum, hippocampus
↓ Damage protein: cerebral cortex, cerebellum, hippocampus
↓ Lipid peroxidation: cerebellum
↓ Damage protein: cerebral cortex
Vitis labruscaOrganicAqueous extract
pretreatment (intraperitoneally)
CCl4‐induced stress
(in rats)
Cerebral cortex,  cerebellum and  hippocampus↓ Damage protein: cerebral cortex, cerebellum, hippocampus
↓ SOD activity: cerebral
cortex, hippocampus
↑ SOD activity: cerebellum
↑ SOD/CAT ratio: cerebral cortex, cerebellum

Table 3.

Therapeutic effects of vine leaf in different tissues.

[i] - NI: not informed; CCl4: carbon tetrachloride; MDA: malondialdehyde; NP‐SH: nonprotein sulfhydryl; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; GSH: reduced glutathione; GST: glutathione‐S‐transferase.

Aqueous extract of grape leaves also presents an in vivo antioxidant effect, increasing the GHS levels in the heart of streptozotocin‐induced diabetic rats, at doses of 500 mg/kg [50], although it did not change MDA levels (Table 3).

Vine leaves are rich in polyphenols such as flavonoids and anthocyanins (Table 1). Beside antioxidant activities, polyphenols inhibit pro‐oxidant enzymes (e.g., xanthine oxidase, NADPH oxidase, lipoxygenases), chelate transient metals, interact with some ion channels, reduce platelet aggregation and leukocyte adhesion, and promote vasodilatation, decreasing the resistance to blood flow [51, 52]. Anthocyanins are also responsible for increasing in the strength and vascular permeability, as well as the inhibition of platelet aggregation [53]. Studies suggest that they promote vasorelaxation by increasing nitric oxide levels and by inhibiting the action of phosphodiesterase‐5 enzyme, which metabolizes the cyclic guanosine monophosphate (cGMP), an important vasodilator, reducing the risk of cardiovascular disease [54].

Anti‐inflammatory properties from flavonoids and other grapevine constituents also contribute to the cardioprotective mechanism against injury caused by ischemia‐reperfusion [51, 52]. Flavonoids inhibit phospholipase A2 and cyclooxygenase enzymes, decreasing prostaglandins synthesis and, indirectly, all inflammatory cascade [55]. Studies show that flavonoids inhibit the TNF‐α, IL1‐β, and interferon‐γ synthesis [51]. All these mechanisms contribute to LDL cholesterol reduction and increasing on HDL cholesterol, useful to protect against cardiovascular disease [56].

A commercial standardized red vine leaf aqueous extract (Antistax®, Boehringer Ingelheim Pharma GmbH & Co, Ingelheim am Rhein, Germany) from Vitis vinifera Folium is available for chronic venous insufficiency, improving the cutaneous microcirculation and oxygen supply in humans [57]. A randomized, double blind study showed that this vine leaf extract decreased the lower leg edema and circumference in chronic venous insufficiency patients [58]. Additionally, the vine leaf extract was investigated in women in long‐term hormone replacement therapy with phlebopathy of the lower limbs [59]. After 3 months, leaf extract treatment decreased the calf and ankle circumference, besides the diameter of the great saphenous vein (GSV), relieving venous symptoms, and improving the quality of life of users [59]. Regulation of blood flow by vine left extract has been positively associated to NO (nitric oxide) synthesis by endothelial and red blood cells, adding to its antioxidant properties [60].

5. Effect of vine leaf extract on the renal system

Diseases that affect the renal system are related to progressive and irreversible loss of kidney function, and inability of the kidney to adequately clean waste products from the blood. This condition is characterized by a reduction in glomerular filtration rate, decreased urine output, proteinuria and microalbunuria, common in diabetes, and hypertensive patients [61, 62].

Oxidative stress is considered an important pathogenic mechanism in renal diseases [61]. In diabetic individuals, particularly, high levels of final advanced glycation end products (AGEs), reactive species, and oxidative stress promote protein oxidation, DNA damage, and apoptosis [62, 63]. Glomerular hypertrophy and tubulointerstitial fibrosis in the kidney in diabetic individuals may progress to nephropathy [63]. Buffering the generation of oxidative pathway may represent a nephroprotective effect against oxidative damage by diabetes [62].

In this context, unpublished results from our group (Figure 2) showed the beneficial effects of an organic aqueous vine leaves extract on the kidney of diabetes rats, agreeing with the results from others [62]. In our experimental protocol, nondiabetic (C) and streptozotocin‐induced diabetic (D) rats were daily administered with 50, 100, and 200 mg/kg of an organic vine leaf extract, by oral gavage, for 30 days (design details showed at [38]). The kidney was collected for analysis of oxidative stress parameters and the blood, for urea and creatinine determination. A two‐away ANOVA showed that diabetes significantly increased protein oxidation (carbonyl), and SOD activity (P < 0.05) and decreased the total sulfhydryl levels (P < 0.001) in the kidney of diabetic rats. All three doses prevented the protein carbonylation (P < 0.05) increased by diabetes, but only the dose of 50 mg/kg restored sulfhydryl levels (P < 0.05) and decreased the SOD activity (P < 0.05) (Figure 2).


Figure 2.

Effect of different doses (50, 100, and 200 mg/kg) of an organic aqueous vine leaf extract in the (A) carbonyl levels, (B) total sulfhydryl levels, and (C) SOD activity in the kidney of nondiabetic (C) and diabetic (D) rats. Values were represented as mean ± standard error; n = 10/group; ANOVA two‐way + Bonferroni. (#) Different from C0 group, P < 0.05; (*) different from D0 group, P < 0.001.

We also showed that diabetes increased the relative kidney weight (P < 0.001) and urea (P < 0.05) and decreased creatinine levels (Table 4). The organic vine leaf extract did not change kidney weight, but the dose of 50 mg/kg significantly decreased urea levels in diabetic rats. Moreover, the organic extract decreased creatinine at doses of 50 and 100 mg/kg in diabetic rats and at dose of 50 mg/kg in nondiabetic rats.

The nephroprotective effect of our vine leaf extract is related to its ability to inhibit in vivo oxidative stress. Our results replayed in vitro assays that showed that the organic and conventional vine leaf extracts prevent both lipids and proteins oxidative damages in the kidney after hydrogen peroxide or alcohol‐induced stress [29, 39]. Polyphenols are the main antioxidants from vine leaf, since these compounds undergo redox reactions and hydrogen atoms transfer from the phenolic hydroxyl group to the free radicals, stabilizing them [29, 64]. Bioactive phytochemicals in our extract showed a remarkable antioxidant activity as evidenced by the reduction of protein oxidation and increase in nonenzymatic antioxidants in the renal tissue of diabetic rats. Resveratrol, one of these bioactive compounds, restores the nonenzymatic levels of antioxidants in the kidney of diabetic rats by reducing the availability of reactive species and improving antioxidant status in this tissue [65]. Indeed, flavonoids increase the expression of enzyme γ‐glutamylcysteine synthetase, a rate‐limiting enzyme in the synthesis of glutathione, a potent antioxidant [66].

GroupsKidney weight (g)Urea (mg/dl)Creatinine (mg/dl)
C00.32 ± 0.0331.01 ± 12.580.29 ± 0.04
C500.31 ± 0.0329.20 ± 3.700.25 ± 0.03**
C1000.31 ± 0.0328.05 ± 7.590.28 ± 0.03
C2000.33 ± 0.0827.80 ± 4.080.28 ± 0.07
D00.53 ± 0.08*77.03 ± 25.52*0.29 ± 0.08
D500.52 ± 0.07*40.71 ± 16.78#0.20 ± 0.03*#
D1000.52 ± 0.04*56.02 ± 16.390.25 ± 0.07#
D2000.50 ± 0.06*59.80 ± 22.320.31 ± 0.09

Table 4.

Relative weights of kidney (g/% body weight), as well as urea and creatinine levels, after 30 days of daily oral administration from an organic aqueous vine (Vitis labrusca, L.) leaf extract, in different doses (50, 100, or 200 mg/kg), in diabetic (D) and nondiabetic (C) rats.

[i] - Values are represented as mean ± standard deviation, n = 10/group; ANOVA two‐way + Bonferroni; (*) different from C groups; (**) different from C0 group, (#) different from D0 group.

Regarding the antioxidant enzymes, we found that only the dose of 50 mg/kg prevented the increasing on SOD activity in the kidney by the chronic hyperglycemia. Because SOD catalyzes the dismutation of superoxide to H2O2 and water, we may infer that this was the main reactive species produced in this tissue in our diabetic rats, prevented by polyphenols present in the organic vine leaf extract [38]. We do not discard that diverse effect would be found after chronic treatment with conventional vine leaf extract, since a study showed that only the organic extract from vine leaf (Vitis labrusca) restored SOD activity after in vitro alcohol‐induced stress in the kidney of rats [39].

Lower urea and creatinine in diabetic rats treated with vine leaf extract at the dose of 50 and 100 mg/kg suggested a dose‐related nephroprotective effect and consequently, improving on renal function. These results agree with another study that showed that polyphenols extracts from Hibiscus sabdariffa improved renal function in an experimental model of diabetes [67]. Resveratrol also decreased creatinine and urea levels, protecting against kidney damage caused by chronic hyperglycemia [65]. In nondiabetic rats, our extract decreased creatinine levels at dose of 50 mg/kg, suggesting an improvement on renal function by hemodynamic mechanisms, already evidenced by regulation of blood flow from poliphenols [57]. Indeed, acute aqueous extracts of Vitis indica leaves increased the urine volume, sodium and potassium chloride excretion in rats [68]. Moreover, the pretreatment with epicatechin in rats exposed to an animal model of nephrolithiasis increased creatinine excretion and urine volume, reducing renal calcium and preventing papillary renal tissue from subepithelial calcification [69]. Pretreatment with vine leaf (Vitis vinifera) extract also restored the renal function, evidenced by decreasing on creatinine, urea, uric acid, and calcium plasma levels, associate to lower histopathologic injuries (Table 3) [27]. In addition, all these parameters were related to lower lipid oxidation and restoring on nonenzymatic antioxidant defenses in the kidney. Such nefroprotetive effects were attributed to the antioxidant properties of proanthocyanidins and other flavonoids present in vine leaf [27].

6. Effect of vine leaf extracts on the central nervous system

The brain is susceptible to the oxidative damage and shows high oxygen consumption rate and abundant lipid content. Indeed, evidence shows that oxidative stress and inflammation are associated with Parkinson, Alzheimer, and other neurodegenerative diseases [7072].

Bioactive compounds as flavonols, flavan‐3‐ols, anthocyanins, phenolic acids, or resveratrol, in red wine and other grapevine byproducts have been extensively studied by their central effect. Conventional and organic vines leaf extracts decrease lipid and protein oxidative damage induced by hydrogen peroxide (H2O2) in the rat brain, reestablishing the SOD and CAT activity [9]. The same neuroprotective effect was found after treatment with both conventional and organic vines leaf extracts in the cortex, hippocampus, and cerebellum after carbon tetrachloride‐induced stress in rats [30].

Although poor central bioavailability, resveratrol is effective for the treatment of aging‐related learning and memory deficits [73]. A recent study showed that oral resveratrol (20 and 40 mg/kg) ameliorated learning and memory impairment and prevented memory extinction in mice in an in vivo animal model of Alzheimer disease [74]. Agreeing with these results, resveratrol also improve learning and memory in old mice, related to increasing on CREB (cAMP response element‐binding) and BDNF (brain‐derived neurotrophic factor) proteins in the hippocampus [75]. Adding to these neurochemical mechanisms, the beneficial effect of resveratrol have been related to its anti‐inflammatory and antioxidant properties in different brain areas as in the hippocampus, and frontal cortex of diabetic and nondiabetic rats [76]. Natural products, rich in anthocyanin, as purple sweet potato extracts also exhibit antioxidant properties and memory enhancing effects in rats [77].

Methanolic Vitis amurensis leaf extract (25–100 mg/kg, oral gavage) prevented oxidative stress after cerebral ischemic in rats indicated by increasing on GSH and decreasing on lipid peroxidation, beyond inhibition of cyclooxygenase‐2, and phosphorylated mitogen‐activated protein kinases (MAPKs) [78]. Moreover, that extract inhibited the glutamate‐induced neuronal death in vitro, and changed the apoptosis‐related proteins, suggesting that the neuroprotective effect of this extract is related to its antioxidant, anti‐inflammatory, and anti‐excitotoxic properties, preventing the neurodegeneration in stroke [78]. Glutamate‐induced neural cytotoxicity in vitro was prevented by a V. vinifera seed extract [79]. Grape seed extract also inhibited DNA damage in the CA1 region of gerbil hippocampus after transient forebrain ischemia, evidencing a neuroprotective effect [80].

7. Conclusion

For centuries, the therapeutic benefits of grapevines and other byproducts have been empirically explored. Recently, it has grown the interest in the health benefits from vine leaves. Leaves remain a waste product from many vine farming, although they show 10 times higher antioxidant activity than grape juice or pulp. Vine leaf extracts, for medical use, or freshly/cooked, for eating as a supplement, are devoid of alcohol (as wine) or sugar (as juice) providing an additional advantage from other vine byproducts. Here, we showed the effect of vine leaf extract in different tissues and point the needed of increase the researchers in the area to explore clinical use of this natural product.


1 - Bisson LF, Waterhouse AL, Ebeler SE, Walker MA, Lapsley JT. The present and future of the international wine industry. Nature 2002; 418:696–9. doi:10.1038/nature01018.
2 - Bernal J, Mendiola JA, Ibáñez E, Cifuentes A. Advanced analysis of nutraceuticals. J Pharm Biomed Anal 2011; 55:758–74. doi:10.1016/j.jpba.2010.11.033.
3 - Georgiev V, Ananga A, Tsolova V. Recent advances and uses of grape flavonoids as nutraceuticals. Nutrients 2014; 6:391–415. doi:10.3390/nu6010391.
4 - Giovinazzo G, Grieco F. Functional properties of grape and wine polyphenols. Plant Foods Hum Nutr Dordr Neth 2015; 70:454–62. doi:10.1007/s11130‐015‐0518‐1.
5 - Yang J, Xiao Y‐Y. Grape phytochemicals and associated health benefits. Crit Rev Food Sci Nutr 2013; 53:1202–25. doi:10.1080/10408398.2012.692408.
6 - Dohadwala MM, Vita JA. Grapes and cardiovascular disease. J Nutr 2009; 139:1788S–93S. doi:10.3945/jn.109.107474.
7 - Xia E‐Q, Deng G‐F, Guo Y‐J, Li H‐B. Biological activities of polyphenols from grapes. Int J Mol Sci 2010; 11:622–46. doi:10.3390/ijms11020622.
8 - Dani C, Oliboni LS, Pasquali MAB, Oliveira MR, Umezu FM, Salvador M, et al. Intake of purple grape juice as a hepatoprotective agent in Wistar rats. J Med Food 2008; 11:127–32. doi:10.1089/jmf.2007.558.
9 - Dani C, Oliboni LS, Agostini F, Funchal C, Serafini L, Henriques JA, et al. Phenolic content of grapevine leaves (Vitis labrusca var. Bordo) and its neuroprotective effect against peroxide damage. Toxicol Vitro Int J Publ Assoc BIBRA 2010; 24:148–53. doi:10.1016/j.tiv.2009.08.006.
10 - Monagas M, Hernández‐Ledesma B, Gómez‐Cordovés C, Bartolomé B. Commercial dietary ingredients from Vitis vinifera L. leaves and grape skins: antioxidant and chemical characterization. J Agric Food Chem 2006; 54:319–27. doi:10.1021/jf051807j.
11 - Park E‐J, Bae JH, Kim S‐Y, Lim J‐G, Baek W‐K, Kwon TK, et al. Inhibition of ATP‐sensitive K+ channels by taurine through a benzamido‐binding site on sulfonylurea receptor 1. Biochem Pharmacol 2004; 67:1089–96. doi:10.1016/j.bcp.2003.11.003.
12 - Suwannaphet W, Meeprom A, Yibchok‐Anun S, Adisakwattana S. Preventive effect of grape seed extract against high‐fructose diet‐induced insulin resistance and oxidative stress in rats. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc 2010; 48:1853–7. doi:10.1016/j.fct.2010.04.021.
13 - Duthie GG, Gardner PT, Kyle JAM. Plant polyphenols: are they the new magic bullet? Proc Nutr Soc 2003; 62:599–603. doi:10.1079/PNS2003275.
14 - Nassiri‐Asl M, Hosseinzadeh H. Review of the pharmacological effects of Vitis vinifera (grape) and its bioactive compounds. Phytother Res 2009;23(9):1197–204. doi: 10.1002/ptr.2761.
15 - Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol Aspects Med 2010; 31:435–45. doi:10.1016/j.mam.2010.09.006.
16 - Schneider E, von der Heydt H, Esperester A. Evaluation of polyphenol composition in red leaves from different varieties of Vitis vinifera. Planta Med 2008; 74:565–72. doi:10.1055/s‐2008‐1034370.
17 - Ali K, Maltese F, Choi YH, Verpoorte R. Metabolic constituents of grapevine and grape‐derived products. Phytochem Rev Proc Phytochem Soc Eur 2010; 9:357–78. doi:10.1007/s11101‐009‐9158‐0.
18 - Vivier MA, Pretorius IS. Genetic improvement of grapevine: tailoring grape varieties for the third millennium—a review. Importance Biotechnol South Afr Vitic Wine Ind New Millenium 2000; 21:5–26.
19 - Quiñones M, Miguel M, Aleixandre A. Beneficial effects of polyphenols on cardiovascular disease. Pharmacol Res 2013; 68:125–31. doi:10.1016/j.phrs.2012.10.018.
20 - Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002; 22:19–34. doi:10.1146/annurev.nutr.22.111401.144957.
21 - Corcoran MP, McKay DL, Blumberg JB. Flavonoid basics: chemistry, sources, mechanisms of action, and safety. J Nutr Gerontol Geriatr 2012; 31:176–89. doi:10.1080/21551197.2012.698219.
22 - Perron NR, Brumaghim JL. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding. Cell Biochem Biophys 2009; 53:75–100. doi:10.1007/s12013‐009‐9043‐x.
23 - Canali R, Comitato R, Ambra R, Virgili F. Red wine metabolites modulate NF‐kappaB, activator protein‐1 and cAMP response element‐binding proteins in human endothelial cells. Br J Nutr 2010; 103:807–14. doi:10.1017/S0007114509992479.
24 - Janega P, Klimentová J, Barta A, Kovácsová M, Vranková S, Cebová M, et al. Red wine extract decreases pro‐inflammatory markers, nuclear factor‐kB and inducible NOS, in experimental metabolic syndrome. Food Funct 2014; 5:2202–7. doi:10.1039/c4fo00097h.
25 - Pastrana‐Bonilla E, Akoh CC, Sellappan S, Krewer G. Phenolic content and antioxidant capacity of muscadine grapes. J Agric Food Chem 2003; 51:5497–503. doi:10.1021/jf030113c.
26 - Orhan DD, Orhan N, Ergun E, Ergun F. Hepatoprotective effect of Vitis vinifera L. leaves on carbon tetrachloride‐induced acute liver damage in rats. J Ethnopharmacol 2007; 112:145–51. doi:10.1016/j.jep.2007.02.013.
27 - Ahmed AF, Al‐Yousef HM, Al‐Qahtani JH, Al‐Said MS, Ashour AE, Al‐Sohaibani M, et al. Hepatorenal protective effect of Antistax(®) against chemically‐induced toxicity. Pharmacogn Mag 2015; 11:S173–81. doi:10.4103/0973‐1296.157726.
28 - Sangiovanni E, Di Lorenzo C, Colombo E, Colombo F, Fumagalli M, Frigerio G, et al. The effect of in vitro gastrointestinal digestion on the anti‐inflammatory activity of Vitis vinifera L. leaves. Food Funct 2015; 6:2453–63. doi:10.1039/c5fo00410a.
29 - Pari L, Suresh A. Effect of grape (Vitis vinifera L.) leaf extract on alcohol induced oxidative stress in rats. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc 2008; 46:1627–34. doi:10.1016/j.fct.2008.01.003.
30 - Wohlenberg M, Almeida D, Bokowski L, Medeiros N, Agostini F, Funchal C, et al. Antioxidant activity of grapevine leaf extracts against oxidative stress induced by carbon tetrachloride in cerebral cortex, hippocampus and cerebellum of rats. Antioxid Basel Switz 2014; 3:200–11. doi:10.3390/antiox3020200.
31 - Król A, Amarowicz R, Weidner S. The effects of cold stress on the phenolic compounds and antioxidant capacity of grapevine (Vitis vinifera L.) leaves. J Plant Physiol 2015; 189:97–104. doi:10.1016/j.jplph.2015.10.002.
32 - Kosar M, Küpeli E, Malyer H, Uylaser V, Türkben C, Baser KHC. Effect of brining on biological activity of leaves of Vitis vinifera L. (Cv. Sultani Cekirdeksiz) from Turkey. J Agric Food Chem 2007; 55:4596–603. doi:10.1021/jf070130s.
33 - Jeandet P, Bessis R, Gautheron B. The production of resveratrol (3,5,4′‐trihydroxystilbene) by grape berries in different developmental stages. Am J Enol Vitic 1991; 42:41–6.
34 - Soyer Y, Koca N, Karadeniz F. Organic acid profile of Turkish white grapes and grape juices. J Food Comp Anal 2003; 16(5):629–36.
35 - Herrmann K. Flavonols and flavones in food plants: a review. Int J Food Sci Technol 1976; 11:433–48. doi:10.1111/j.1365‐2621.1976.tb00743.x.
36 - Li S, Tan H‐Y, Wang N, Zhang Z‐J, Lao L, Wong C‐W, et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16:26087–124. doi:10.3390/ijms161125942.
37 - Takayama F, Nakamoto K, Kawasaki H, Mankura M, Egashira T, Ueki K, et al. Beneficial effects of Vitis coignetiae Pulliat leaves on nonalcoholic steatohepatitis in a rat model. Acta Med Okayama 2009; 63:105–11.
38 - Lacerda DdS, Santos CF, Oliveira AS, Zimmermann R, Schneider R, Agostini F, et al. Antioxidant and hepatoprotective effects of an organic grapevine leaf (Vitis labrusca L.) extract in diabetic rats. RSC Adv 2014; 4:52611–9. doi:10.1039/C4RA08396B.
39 - Oliboni LS, Dani C, Funchal C, Henriques JA, Salvador M. Hepatoprotective, cardioprotective, and renal‐protective effects of organic and conventional grapevine leaf extracts (Vitis labrusca var. Bordo) on Wistar rat tissues. An Acad Bras Ciênc 2011; 83:1403–11. doi:10.1590/S0001‐37652011000400027.
40 - Pak W, Takayama F, Hasegawa A, Mankura M, Egashira T, Ueki K, et al. Water extract of Vitis coignetiae Pulliat leaves attenuates oxidative stress and inflammation in progressive NASH rats. Acta Med Okayama 2012; 66:317–27.
41 - Dey A, Lakshmanan J. The role of antioxidants and other agents in alleviating hyperglycemia mediated oxidative stress and injury in liver. Food Funct 2013; 4:1148–84. doi:10.1039/c3fo30317a.
42 - Marco Gasparetto and Graziella Guariso, “Highlights in IBD Epidemiology and Its Natural History in the Paediatric Age,” Gastroenterology Research and Practice, vol. 2013, Article ID 829040, 12 pages, 2013. doi:10.1155/2013/829040.
43 - Lawrence T. The nuclear factor NF‐kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009; 1:a001651. doi:10.1101/cshperspect.a001651.
44 - Wong ND. Epidemiological studies of CHD and the evolution of preventive cardiology. Nat Rev Cardiol 2014; 11:276–89. doi:10.1038/nrcardio.2014.26.
45 - Laslett LJ, Alagona P, Clark BA, Drozda JP, Saldivar F, Wilson SR, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 2012; 60:S1–49. doi:10.1016/j.jacc.2012.11.002.
46 - Widmer RJ, Lerman A. Endothelial dysfunction and cardiovascular disease. Glob Cardiol Sci Pract 2014; 2014:291–308. doi:10.5339/gcsp.2014.43.
47 - Hansen AS, Marckmann P, Dragsted LO, Finné Nielsen I‐L, Nielsen SE, Grønbaek M. Effect of red wine and red grape extract on blood lipids, haemostatic factors, and other risk factors for cardiovascular disease. Eur J Clin Nutr 2005; 59:449–55. doi:10.1038/sj.ejcn.1602107.
48 - Lippi G, Franchini M, Favaloro EJ, Targher G. Moderate red wine consumption and cardiovascular disease risk: beyond the “French paradox”. Semin Thromb Hemost 2010; 36:59–70. doi:10.1055/s‐0030‐1248725.
49 - Grønbaek M, Deis A, Sørensen TI, Becker U, Schnohr P, Jensen G. Mortality associated with moderate intakes of wine, beer, or spirits. BMJ 1995; 10:1165–9.
50 - Orhan N, Aslan M, Orhan DD, Ergun F, Yesilada E. In‐vivo assessment of antidiabetic and antioxidant activities of grapevine leaves (Vitis vinifera) in diabetic rats. J Ethnopharmacol 2006; 108:280–6. doi:10.1016/j.jep.2006.05.010.
51 - Akhlaghi M, Bandy B. Mechanisms of flavonoid protection against myocardial ischemia‐reperfusion injury. J Mol Cell Cardiol 2009; 46:309–17. doi:10.1016/j.yjmcc.2008.12.003.
52 - Mladenka P, Zatloukalová L, Filipský T, Hrdina R. Cardiovascular effects of flavonoids are not caused only by direct antioxidant activity. Free Radic Biol Med 2010; 49:963–75. doi:10.1016/j.freeradbiomed.2010.06.010.
53 - Lila MA. Anthocyanins and human health: an in vitro investigative approach. J Biomed Biotechnol 2004; 2004(5):306–13. doi:10.1155/S111072430440401X.
54 - Dell'Agli M, Galli GV, Vrhovsek U, Mattivi F, Bosisio E. In vitro inhibition of human cGMP‐specific phosphodiesterase‐5 by polyphenols from red grapes. J Agric Food Chem 2005; 53:1960–5. doi:10.1021/jf048497+.
55 - Kim HP, Son KH, Chang HW, Kang SS. Anti‐inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci 2004; 96:229–45.
56 - Castilla P, Echarri R, Dávalos A, Cerrato F, Ortega H, Teruel JL, et al. Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects. Am J Clin Nutr 2006; 84:252–62.
57 - Kalus U, Koscielny J, Grigorov A, Schaefer E, Peil H, Kiesewetter H. Improvement of cutaneous microcirculation and oxygen supply in patients with chronic venous insufficiency by orally administered extract of red vine leaves AS 195: a randomised, double‐blind, placebo‐controlled, crossover study. Drugs RD 2004; 5:63–71.
58 - Kiesewetter H, Koscielny J, Kalus U, Vix JM, Peil H, Petrini O, et al. Efficacy of orally administered extract of red vine leaf AS 195 (folia Vitis viniferae) in chronic venous insufficiency (stages I‐II). A randomized, double‐blind, placebo‐controlled trial. Arzneimittelforschung 2000; 50:109–17. doi:10.1055/s‐0031‐1300174.
59 - Tsukanov IT, Tsukanov AI. Experience with six‐month administration of red vine leaf extract in hormone‐induced phlebopathy. Angiol Sosud Khirurgiia Angiol Vasc Surg 2014; 20:102–7.
60 - Grau M, Bölck B, Bizjak DA, Stabenow CJA, Bloch W. The red‐vine‐leaf extract AS195 increases nitric oxide synthase‐dependent nitric oxide generation and decreases oxidative stress in endothelial and red blood cells. Pharmacol Res Perspect 2016; 4:e00213. doi:10.1002/prp2.213.
61 - Small DM, Coombes JS, Bennett N, Johnson DW, Gobe GC. Oxidative stress, anti‐oxidant therapies and chronic kidney disease. Nephrol Carlton Vic 2012; 17:311–21. doi:10.1111/j.1440‐1797.2012.01572.x.
62 - Ha H, Hwang I‐A, Park JH, Lee HB. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract 2008; 82(Suppl. 1):S42–5. doi:10.1016/j.diabres.2008.09.017.
63 - Kashihara N, Haruna Y, Kondeti VK, Kanwar YS. Oxidative stress in diabetic nephropathy. Curr Med Chem 2010; 17:4256–69.
64 - Goupy P, Dufour C, Loonis M, Dangles O. Quantitative kinetic analysis of hydrogen transfer reactions from dietary polyphenols to the DPPH radical. J Agric Food Chem 2003; 51:615–22. doi:10.1021/jf025938l.
65 - Schmatz R, Perreira LB, Stefanello N, Mazzanti C, Spanevello R, Gutierres J, et al. Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin‐induced diabetic rats. Biochimie 2012; 94:374–83. doi:10.1016/j.biochi.2011.08.005.
66 - Moskaug JØ, Carlsen H, Myhrstad MCW, Blomhoff R. Polyphenols and glutathione synthesis regulation. Am J Clin Nutr 2005; 81:277S–283S.
67 - Lee W‐C, Wang C‐J, Chen Y‐H, Hsu J‐D, Cheng S‐Y, Chen H‐C, et al. Polyphenol extracts from Hibiscus sabdariffa Linnaeus attenuate nephropathy in experimental type 1 diabetes. J Agric Food Chem 2009; 57:2206–10. doi:10.1021/jf802993s.
68 - Shastry CS, Ashok K, Aravind MB, Joshl SD. Diuretic activity of the extracts of Vitis vinifera leaves. Indian Drugs 2002; 39:497–9.
69 - Grases F, Prieto RM, Fernandez‐Cabot RA, Costa‐Bauzá A, Tur F, Torres JJ. Effects of polyphenols from grape seeds on renal lithiasis. Oxid Med Cell Longev 2015; 2015:813737. doi:10.1155/2015/813737.
70 - Sarrafchi A, Bahmani M, Shirzad H, Rafieian‐Kopaei M. Oxidative stress and Parkinson's disease: new hopes in treatment with herbal antioxidants. Curr Pharm Des 2015; 22:238–46.
71 - Chen Z, Zhong C. Oxidative stress in Alzheimer's disease. Neurosci Bull 2014; 30:271–81. doi:10.1007/s12264‐013‐1423‐y.
72 - Chen G, Shi J, Hu Z, Hang C. Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: a potential neuroprotective mechanism of N‐acetylcysteine. Mediators Inflamm 2008; 2008:716458. doi:10.1155/2008/716458.
73 - Ahmed T, Javed S, Javed S, Tariq A, Šamec D, Tejada S, et al. Resveratrol and Alzheimer's disease: mechanistic insights. Mol Neurobiol. 2016. [Epub ahead of print] doi:10.1007/s12035‐016‐9839‐9.
74 - Wang G, Chen L, Pan X, Chen J, Wang L, Wang W, et al. The effect of resveratrol on beta amyloid‐induced memory impairment involves inhibition of phosphodiesterase‐4 related signaling. Oncotarget 2016; 5. doi:10.18632/oncotarget.8041.
75 - Zhao Y‐N, Li W‐F, Li F, Zhang Z, Dai Y‐D, Xu A‐L, et al. Resveratrol improves learning and memory in normally aged mice through microRNA‐CREB pathway. Biochem Biophys Res Commun 2013; 435:597–602. doi:10.1016/j.bbrc.2013.05.025.
76 - Venturini CD, Merlo S, Souto AA, Fernandes MDC, Gomez R, Rhoden CR. Resveratrol and red wine function as antioxidants in the nervous system without cellular proliferative effects during experimental diabetes. Oxid Med Cell Longev 2010; 3:434–41.
77 - Cho J, Kang JS, Long PH, Jing J, Back Y, Chung K‐S. Antioxidant and memory enhancing effects of purple sweet potato anthocyanin and cordyceps mushroom extract. Arch Pharm Res 2003; 26:821–5.
78 - Kim JY, Jeong HY, Lee HK, Kim S, Hwang BY, Bae K, et al. Neuroprotection of the leaf and stem of Vitis amurensis and their active compounds against ischemic brain damage in rats and excitotoxicity in cultured neurons. Phytomedicine Int J Phytother Phytopharm 2012; 19:150–9. doi:10.1016/j.phymed.2011.06.015.
79 - Narita K, Hisamoto M, Okuda T, Takeda S. Differential neuroprotective activity of two different grape seed extracts. PLoS One 2011; 6(1). doi:10.1371/journal.pone.0014575.
80 - Hwang IK, Yoo K‐Y, Kim DS, Jeong Y‐K, Kim JD, Shin H‐K, et al. Neuroprotective effects of grape seed extract on neuronal injury by inhibiting DNA damage in the gerbil hippocampus after transient forebrain ischemia. Life Sci 2004; 75:1989–2001. doi:10.1016/j.lfs.2004.05.013.