OXIMED2012-805762.pdf

Hindawi Publishing Corporation

Oxidative Medicine and Cellular Longevity

Volume 2012, Article ID 805762, 14 pages

doi:10.1155/2012/805762

Review Article

Wine Polyphenols: Potential Agents in Neuroprotection

Abdelkader Basli, 1, 2 Stephanie Soulet, 3 Nassima Chaher, 4 Jean-Michel Merillon, 1

Mohamed Chibane, 5 Jean-Pierre Monti, 1 and Tristan Richard 1

1 GESVAB, EA 3675, ISVV, Universite de Bordeaux, 33882 Villenave d’Ornon, France

2 Laboratoire 3BS, Universite de Bejaia, Targa Ouzemour, 06000 Bejaia, Algeria

3 BIOTEM, EA 4239, Universit´edelaPolynesie Fran¸aise, BP 6570, Tahiti, 98702 FAAA, Polynesie Fran¸aise, France

4 Laboratoire de Biochimie Appliquee, Faculte des Sciences de la Nature et de la vie, Universite de Bejaia, 06000 Bejaia, Algeria

5 Laboratoire de Technologie Alimentaire, Faculte des Sciences, Universite AMO Bouira, Bouira, Algeria

Correspondence should be addressed to Tristan Richard, trichard33@gmail.com

Received 10 February 2012; Revised 20 April 2012; Accepted 20 April 2012

Academic Editor: David Vauzour

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

cited.

There are numerous studies indicating that a moderate consumption of red wine provides certain health beneﬁts, such as the

protection against neurodegenerative diseases. This protective e ﬀ ect is most likely due to the presence of phenolic compounds in

wine. Wine polyphenolic compounds are well known for the antioxidant properties. Oxidative stress is involved in many forms

of cellular and molecular deterioration. This damage can lead to cell death and various neurodegenerative disorders, such as

Parkinson’s or Alzheimer’s diseases. Extensive investigations have been undertaken to determine the neuroprotective e

ects of

wine-related polyphenols. In this review we present the neuroprotective abilities of the major classes of wine-related polyphenols.

ﬀ

1. Introduction

tissues, particularly the brain, are highly exposed to oxidative

damages because of their elevated oxygen consumption and

the induced generation of large amounts of reactive oxygen

species [ 7 , 8 ].

Oxidative stress resulting in ROS generation and inﬂam-

mation is responsible for many forms of cellular and mol-

ecular deterioration such as mitochondrial collapsing, DNA

damage, and protein, carbohydrate, and lipid oxidation [ 9 ].

This damage can lead to early cell aging, cell death, and

various chronic pathologies like neurodegenerative disor-

ders, cardiovascular illnesses, cancers, or type 2 diabetes

[ 2 , 6 , 10 , 11 ]. Di

Aging is a risk factor common to a number of neurodege-

nerative diseases, including Alzheimer’s disease (AD) and

Parkinson’s disease. Moreover, associated with the popula-

tion aging, the occurrence of these neurodegenerative disor-

ders is also likely to augment [ 1 ]. In addition to the possible

involvement in aging, the common characteristic of most

degenerative diseases is that they result from neuronal death.

Oxidative stress may play a crucial role in progressive neu-

ronal death [ 2 ].

Free radicals are oxidative molecules that occur naturally

in the environment but can also be generated in vivo .Reactive

oxygen species (ROS) are produced by immune cells in

order to sustain their antibacterial and antifungal functions

[ 3 ]. When ROS are overproduced, they are taken in charge

by various enzymatic pathways for inactivation (superoxide

dismutase, catalase, cytochromes, etc.) [ 4 , 5 ]. Although these

enzymatic pathways can be overstepped, ROS accumulate

and can react with the di

culty in treating these diseases and better

understanding of their development and causes highlight the

usefulness of antioxidants as prevention treatments.

A number of epidemiological studies have shown that the

consumption of a diet rich in antioxidants can inﬂuence the

incidence of neurodegenerative disorders [ 12 ]. Orgogozo et

al. have shown a positive correlation between a moderate

consumption of red wine and a decreased incidence of

dementia [ 13 , 14 ]. This protective e

erent cell molecules such as lipids,

proteins, carbohydrates, and nucleic acids. These interac-

tions with the ROS apply an oxidative stress to cells [ 6 ]. Some

ﬀ

ectismostlikelydue

to the presence of phenolic compounds in wine. Wine and

grape vine polyphenols are mainly ﬂavonoids (ﬂavanols,

ﬀ

Oxidative Medicine and Cellular Longevity

ﬂavonols, and anthocyanins) and nonﬂavonoids (phenolic

acids, hydrolysable tannins, and stilbenes) [ 15 ]. Extensive

investigations have been undertaken to determine the neu-

roprotective e

[ 15 , 30 ]. The condensations of ﬂavanol in wine induce the

formation of oligomers (proanthocyanidins and condensed

tannins).

Flavanol intake has been associated with various bene-

ﬁcial health e

ects of wine polyphenols [ 16 – 19 ]. These

polyphenols have displayed neuroprotective capacities in

numerous in vitro and animal models of neurotoxicities [ 19 ].

Several neuroprotective mechanisms of action have been

proposed, suggesting that polyphenols exert their activities

by reducing the production and the accumulation of ROS,

whose accumulation is likely to play a crucial pathological

role in brain aging, reducing oxidative stress and inﬂam-

mation and modulating the activity of intracellular signal

transduction molecules [ 19 – 21 ].

In this review we investigate the neuroprotective abilities

of the major classes of polyphenols in wine: ﬂavanols, proan-

thocyanins, ﬂavonols, anthocyanins, phenolic acids, tannins,

and stilbenes. Each speciﬁc class of polyphenol has shown

neuroprotective e

ﬀ

ects [ 31 , 32 ], and ﬂavanols are known to be

brain-permeable substances [ 33 ]. Their transport is stereo-

selectiveinvolvingoneormorestereoselectiveentitiesand

metabolizing with glucuronic acid, for example [ 34 ]. Numer-

ous studies indicate that ﬂavanols are of beneﬁt for neuronal

health. Catechin may protect against the brain injuries

produced by endogenous neurotoxins involved in the onset

of Parkinson’s disease [ 35 ]. Catechin and epicatechin gallate

have also shown an ability to suppress neuroinﬂammation

and can attenuate and inhibit activation of microglia and/or

astrocytes associated with the release of the mediators linked

to the apoptotic death of neurons [ 36 ]. In addition, numer-

ous studies indicate that catechin derivatives may delay the

onset of neurodegenerative disorders such as Alzheimer’s

disease through a numerous di

ﬀ

ects against neurodegenerative diseases.

Their neuroprotective activity has been documented, and we

underline the evidence suggesting that their mechanism of

action involves their antioxidant activity.

ﬀ

erent mechanisms such as

iron chelators, radical scavengers, and modulators of pro-

survival genes [ 31 , 37 – 40 ].

3.1.2. Proanthocyanidins. Proanthocyanidins and condensed

tannins are complex ﬂavonoid polymers naturally present in

cereals, legumes, and fruits [ 41 ]. They are mainly formed

by the condensation of ﬂavanol units to generate oligomers

(proanthocyanidins) and polymers (condensed tannins).

Their levels in wine depend on pressing techniques and grape

varieties. Typically they range from 5mg/L in white wines

to 1 g/L or even higher levels in old red wines [ 15 , 41 ].

They are associated with a change in wine quality such as a

modiﬁcation of the hue and a decrease in astringency.

Very few studies have concerned the bioavailability of

proanthocyanidins. Condensed tannins should be degraded

in monomeric phenols, absorbed and metabolized, as has

been shown for other ﬂavonoids [ 1 , 2 ]. Numerous studies

indicate that proanthocyanidins and condensed tannins

might prevent both cancers and cardiovascular diseases [ 42 ,

43 ]. Some reports demonstrate that its biological abilities

to scavenge the reactive oxygen species are associated to

the degree of polyphenol oligomerization. Some of these

polyphenols might have speciﬁc structures that exhibit

neuroprotective e

2. Wine Polyphenols

Products such as wine extract, grape seed, and grape skin

extracts are all known to contain a large variety of potent

antioxidants in the form of polyphenols. Plant phenolic

constituents are produced through two metabolic pathways,

the main being that of shikimic acid which leads to cinnamic

acids, whereas the polyacetate pathway induces the linkage of

a second aromatic ring to the ﬁrst pathway molecules [ 22 –

24 ].

Wines contain various water-soluble polyphenols includ-

ing phenolic acids, stilbenes, tannins, ﬂavanols, ﬂavonols,

and anthocyanins (see Figure 1 ). Wine phenolics are divided

into two groups: ﬂavonoid and nonﬂavonoid. The amounts

of phenolic compounds in wines are highly variable due to

varietal di

erences and process diversities. Indicative levels of

phenolic components in wine are shown in Ta b l e 1 [ 15 ]. Due

to wine processing, red wines containmore polyphenols than

white wines. Red wine has more antioxidant capacity than

white wine due to its phenolic content [ 25 – 27 ] . Phenolic red

wines are mainly composed by ﬂavonoids with 1450mg/L

for young wines and 1285mg/L for aged ones. Phenolic

white wines are composed principally of nonﬂavonoids with

164mg/L for young wines and 245mg/L for aged ones [ 15 ,

24 ].

ﬀ

ects by interacting with putative neuron-

speciﬁc receptors [ 44 ]. Takahashi et al . have shown that pro-

cyanidin oligomers from grape seed exhibit higher growth-

promoting activity than the monomers toward mouse hair

epithelial cells in vitro and in vivo , these results indicating

that

ﬀ

ect might be correlated with their

structure [ 45 ]. Other research on rat brain suggests that

grape seed extract enriched in proanthocyanidins might

protect against pathology age-related oxidative brain damage

[ 46 ].

the speciﬁc e

ﬀ

3. Wine Polyphenols and Neuroprotection

3.1. Flavonoids and Neuroprotection

3.1.1. Flavanols. The ﬂavanols, also called ﬂavan-3-ols or

catechins, are the most reduced form of ﬂavonoids. They are

present in various plants and are associated with the health

beneﬁts of green tea [ 28 , 29 ]. The levels in wine depend on

the di

3.1.3. Flavonols. Flavonols occur in a wide range of vegeta-

bles. There polyphenols are always found in glycoside forms

in plants including grape berries, where they are present

in the skin. Flavonol glycosides and aglycones are found in

grape wine from trace amounts up to 200mg/L in some

erent grape cultivars and are typically in the range of

20–100mg/L. Catechin is usually the major ﬂavanol in wine

ﬀ

Oxidative Medicine and Cellular Longevity

ﬀ

eic acid (hydroxycinnamate)

Gallic acid (benzoic acid)

Vescalagin (hydrolyzable tannin)

Catechin (ﬂavanol)

Resveratrol (stilbene)

Quercetin (ﬂavonol)

OCH 3

O +

OCH 3

Malvidin (anthocyanidin)

Dimer B3 (condensed tannin)

FIGURE 1: Chemical structures of some phenolic compounds from wine.

Oxidative Medicine and Cellular Longevity

TABLE 1: The levels of principal phenolic classes (mg/L) in red and

white table wine [ 15 ].

[ 61 , 63 – 66 ]. Anthocyanins also possess beneﬁcial neuropro-

tective abilities. Some of them have the ability to cross the

blood-brain barrier and di

use through the central nervous

system [ 67 , 68 ]. Anthocyanins have neuroprotective beneﬁts

in reducing age-associated oxidative stress and improving

cognitive brain function [ 61 , 69 – 72 ]. They induce signiﬁcant

neuroprotective e

ﬀ

White wine

Red wine

Phenol class

Young

Aged

Young

Aged

nonﬂavonoids

hydroxycinnamates

154

130

165

ects against oxidative stress, DNA frag-

mentation and lipid peroxidation in mouse brain [ 73 , 74 ].

Thus, it appears that the antioxidant and anti-inﬂammatory

ﬀ

benzoic acids

hydrolyzable tannins

100

250

ﬀ

ects of anthocyanins contribute to its neuroprotective

stilbenes (resveratrol)

0.5

ﬀ

ect.

Total mg/L

164.5

245.5

232

377

ﬂavonoids

ﬂavanol monomers

200

100

3.2. Nonﬂavonoids and Neuroprotection [ 73 , 74 ]

Condensed tannins

750

1000

3.2.1. Phenolic Acids. The benzoic acids are a minor compo-

nent in wines. Whereas the hydroxycinnamates are the most

important class of nonﬂavonoid phenols in grape vine and

the major class of phenolics in white wine [ 15 , 75 ]. The three

important ones in wine are coumaric acid, ca

ﬂavonols

—

100

anthocyanins

—

400

Total mg/L

1450

1285

eic acid, and

ferulic acid. Amount of total hydroxycinnamates in wine are

typically about 60mg/L in reds and 130mg/L in whites [ 15 ].

Hydroxycinnamates have an antioxidant activity by

scavenging free radicals [ 76 , 77 ]. Their strong antioxidant

properties help to explain their beneﬁcial role on health

and in reducing disease risk. Hydroxycinnamates and other

phenolic acids have received less attention. It has been

shown that p-coumaric acid, hydroxycinnamates ca

ﬀ

red wines [ 15 , 47 , 48 ]. Myricetin, quercetin, and kaempferol

conjugates are the major ﬂavonols in wine [ 48 , 49 ].

Primary results indicate that ﬂavonols can pass the

blood-brain barrier [ 50 , 51 ]. Moreover, numerous stud-

ies indicated that ﬂavonols, in addition to many other

health beneﬁts, contribute signiﬁcantly to the protection of

neuronal cells against oxidative-stress-induced neurotoxicty

[ 52 , 53 ]. In Alzheimer’s disease, neuronal loss is preceded

by the extracellular accumulation of amyloid-

eic acid,

and a Champagne wine extract rich in these compounds

have neuroprotective e

ﬀ

peptide

ects against injury induced by 5-

S-cysteinyl-dopamine in vitro [ 78 ]. Ca

ﬀ

). It has been shown that pretreatment of primary

hippocampal cultures with quercetin signiﬁcantly attenuates

ﬀ

eic acid has been

reported to have neuroprotective e

-induced

neurotoxicity in vitro and to inhibit peroxynitrite-induced

neuronal injury [ 78 – 80 ]. Ferulic acid has been showed to

protect primary neuronal cell cultures against hydroxyl- and

peroxyl-radical-mediated oxidative damage [ 81 , 82 ].

ﬀ

ects against A

-induced toxicity, lipid peroxidation, protein oxidation

and apoptosis [ 54 ]. A dose-response study indicated that

quercetin exhibited protective capacities against A

-induced

toxicity by modulating oxidative stress at lower doses [ 54 ].

In cerebral ischemia, calcium dysregulation is one of the

main instigators of neuronal cell death and brain damage.

Quercetin has been shown to exert signiﬁcant protection

against ischemic injury. Indeed, treatment with quercetin

reduced the spectrin breakdown products caused by ischemic

activation of calcium-dependent protease calpoin and inhib-

ited the acid-mediated intracellular calcium level [ 55 ].

3.2.2. Hydrolyzable Tannins. Tannins are water-soluble poly-

phenols. One of the major properties of these molecules is

their capacity to precipitate proteins such as gelatin from

solution [ 83 – 85 ]. In wine, hydrolyzable tannins arise during

maturation and ageing of wines in oak barrels [ 86 ]. Castala-

gin and vescalagine are the main representative compounds

of ellagic tannins [ 87 ]. Their levels are about 100mg/L in

aged white wines, while red wine levels are about 250mg/L

after aging in oak barrels for two or more years [ 15 , 88 ].

They are mainly ellagic acid and gallic acid ester derivatives

with glucose or other sugars. Due to the presence of the ester

linkage, they are described as being hydrolyzable. Hydro-

lyzable tannins are not present in Vitis vinifera but are present

in other fruits such as muscadine grapes and raspberries

[ 89 ]. These polyphenols are excellentantioxidantsand natural

preservatives, also helping give the wine structure and

texture. However, recent research on tannins has focused on

their potential to impact positively on human health. Tan-

nins have demonstrated a host of potent biological activities,

antiperoxidation properties, inhibition of mutagenicity of

carcinogens and tumor promotion, speciﬁc antitumor abil-

ities in relation with tannin structures, antibacterial activity,

3.1.4. Anthocyanins. Anthocyanins act as guard systems in

plants and protect them from UV damage. They form

complex molecules with other phenolic molecules and

strongly contribute to the color and the aging of wine

[ 56 – 58 ]. The aglycone ring of these ﬂavonoids is called

anthocyanidin. However, nonconjugated anthocyanidins are

never found in grapes or wine, except in trace quantities.

In wine there are ﬁve anthocyanidins: malvidin, cyanidin,

delphinidin, peonidin, and petunidin. Malvidin is the most

abundant anthocyanidin in red wines [ 15 ].

Among the wine ﬂavonoids, anthocyanins constitute one

of the higher potent antioxidants correlated to their capacity

to delocalize electrons and form resonating structures [ 59 –

62 ]. Anthocyanins present numerous health beneﬁts such as

anticarcinogenic, anti-inﬂammatory, or antidiabetic e

ﬀ

ects

Oxidative Medicine and Cellular Longevity

and antiviral activity [ 89 – 91 ]. In vivo , ellagitannins are

mainly transformed into ellagic acid and its metabolites. In

fact, they could be the agent responsible for the e

crucial for understanding polyphenol bioactivity. Several

studies indicate that the antioxidant e

ect in vitro of some

polyphenols may not indicate its activity in vivo .Indeed,its

alteration into metabolites and other derivative constituents

constitute the true bioactive molecules [ 113 , 115 – 118 ].

Polyphenols are extensively metabolized in di

ﬀ

ects of

dietary ellagitannins observed in vivo [ 92 , 93 ].

There are few studies whose objective has been the

neuroprotective activity of hydrolyzable tannins. Ellagic acid

has been reported to promote the formation of

erent tissues

such as colon, small intestine, and liver [ 119 ]. Polyphenols

are absorbed through the gut barrier. Some of them who are

not absorbed pass to the large intestine and undergo colonic

biotransformation by the enzymes of the colonic microﬂora

[ 118 ]. Polyphenols metabolized in the gastrointestinal tract

undergo conjugation in the liver after absorption. Then,

polyphenols are present in circulation as sulfated, glucuroni-

dated,methylated,andasmixedforms.Moreover,alarge

proportion of polyphenols ingested are subjected to hydrol-

yses and degradation by colonic microﬂora to simple phe-

nolic compounds. Wine polyphenols are grouped into two

categories: ﬂavonoids and nonﬂavonoids as described before.

Chemical structure of polyphenol is a factor involved in the

gut absorption and the metabolism. We report here data on

the absorption and the metabolism of the main polyphenols

found in wine.

Concerning ﬂavonoids, ﬂavanols were absorbed and eli-

minated at low micromolar amounts of their direct conju-

gates (methylated, sulfated, and glucuronidated derivatives)

[ 120 ]. However, the degradation of ﬂavan structure in colon

leads to the formation of phenolic compounds [ 114 , 121 ].

Because of their hydrosolubility and high molecular weight,

proanthocyanidins are not absorbed in the gut. The large

majority of proanthocyanidins cross without alteration

through the small intestine after which they are transformed

by the colonic microﬂora to produce simple phenolic acids

such as phenylacetic and phenylpropionic derivatives [ 122 ].

However, Tsang et al . reported that administration of grape-

seed procyanidins induce the formation of catechin glu-

curonide derivatives in rat plasma [ 123 ]. Flavonols are nat-

urally occurred as glycosides. Results indicate that ﬂavonols

uptake induce a cleavage of the glycoside part in the small

intestine followed by absorption and metabolism of the agly-

cone [ 124 ]. Aglycones are then conjugated by sulfation and

glucuronidation as well as methylation of the catechol group

[ 118 ]. A large number of colonic metabolites identiﬁed are

simple phenolic acids [ 125 ]. Anthocyanins was absorbed

and excreted at a low proportion of the intact glycosides

after injection of wine extract [ 126 , 127 ]. The anthocyanins

degradation at the pH of the intestine in addition to the

microﬂora activity in the colon are at least in part involved in

the degradation of anthocyanins into more stable compound

such as phenolic acids [ 113 ].

Concerning nonﬂavonoids, ellagitannins are not absorb-

ed due to their large molecular size [ 128 ]. They are princi-

pally hydrolysed to ellagic acid under physiological condi-

tions in small intestine [ 113 ]. Ellagic acid and ellagitannins

reach the distal part of the small intestine and the colon, they

are mainly transformated by gut microﬂora into urolithin

derivatives [ 129 ]. The major stilbene compound found

in wine is resveratrol; thus, bioavailability of resveratrol

was investigated. Many investigations in animal models

and humans have indicated that a low bioavailability of

ﬀ

Aﬁbriland

signiﬁcant oligomer loss, in contradiction to previous results

indicating that polyphenols inhibited A

ﬁbril formation

[ 94 ]. Nevertheless, ellagic acid reduces signiﬁcantly A

induced neurotoxicity in human SH-SY5Y neuroblastoma

cells. These results are in agreement with the hypothesis that

ﬁbril formation may represent a protective mechanism of

local A

clearance. Thus, ellagic acid may have therapeutic

value in Alzheimer’s disease.

3.2.3. Resveratrol and Other Stilbenes. Stilbenes are second-

ary metabolites described as phytoalexins. Stilbenes are

found in grape vine and wine [ 95 – 97 ]. The main charac-

teristic of stilbenes consist of diary groups on either end of

an active double bond that generates the stilbene skeleton,

the so-called resveratrol. Stilbenes can also be found in

oligomeric and polymeric forms in wine [ 98 ]. Resveratrol is

found in wine from trace amounts up to 10mg/L typically

0.1mg/L in white wines and 2.0mg/L in red wines [ 15 , 99 ].

It is a substance with great potential that is being investigated

intensively, and its derivatives exhibit a wide range of phar-

macological and biological properties [ 100 ].

Resveratrol and its derivatives have also been reported

to be active against neuron cell dysfunction and death in

animal models [ 20 , 101 – 104 ]. Resveratrol can cross the

blood–brain barrier and exhibit neuroprotective properties

against cerebral injury [ 105 ]. Numerous mechanisms may

underline resveratrol neuroprotective e

induced neurotoxicity [ 106 ]. Resveratrol can act by reducing

the intracellular A

ﬀ

ects against A

level by inducing protease degradation

of the peptide in Alzheimer’s disease. Resveratrol and other

stilbenes have been shown to inhibit A

ﬁbril formation in

vitro [ 107 , 108 ]. Furthermore, resveratrol has been shown

to exhibit signiﬁcant free-radical scavenging abilities in

numerous cellular models [ 109 – 112 ]. Thus, overall scientiﬁc

data tend to show that among stilbenoids resveratrol has

ﬀ

ects against brain injuries in reducing brain damage in

complex manner including antioxidant properties, regula-

tion on neurovascular system, or ability to inhibit known

neuropathological processes.

4. Mechanisms

4.1. Bioavailability of Wine-Related Polyphenol. It is now

well established that wine polyphenols exhibit some bene-

ﬁcial activities on health, particularly on neurodegenerative

diseases [ 113 ]. Biological activities are often measured on

cultured cells or isolated tissues using polyphenols in their

form present in wine (as aglycone or their sugar derivatives).

However, the question of their achievable concentration after

ingestion as well as the possibility of conjugate formation has

been ignored by many studies [ 114 ]. These data are though

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