Potential Protective Effects of Wine and the Wine-Derived Phenolic Compounds on Brain Function
Damage to DNA, lipids, and proteins by oxidative free radicals has been implicated in accelerated aging, degenerative diseases including cancer (Ames et al. 1995), Alzheimer’s disease and other dementias (Commenges et al. 2000; Smith and Perry 1995), and Parkinson’s disease (Olanow 2007), as well as cardiovascular disease. Population aging is occurring on a global scale, with faster aging projected for the coming decades than has occurred in the past (Lutz et al. 2008). Globally, the population aged 60 years and over is projected to nearly triple by 2050, while the population aged 80 years and over is projected to experience a more than fivefold increase.
These diseases of old age are thus expected to increase significantly over the next few decades as people increasingly survive beyond the age of 80 years (Kelner and Marx 1996). Consequently, there is interest in identifying lifestyle factors and molecular mechanisms that can minimize the risk of these debilitating conditions, including simple dietary measures.
J-SHAPED RELATIONSHIP OF ALCOHOLIC BEVERAGES
From prospective population-based studies, there is a clear J-shaped relationship between the consumption of alcoholic beverages such as wine, and the risk of cardiovascular diseases including myocardial infarction, which has been extended to a reduced risk of certain cancers, type 2 diabetes, and ischemic stroke (Bantle et al. 2008; Barstad et al. 2005; Benedetti et al. 2006; Booyse and Parks 2001; Briggs et al. 2002; Gronbaek et al. 2000; McDougall et al. 2006; Park et al. 2009; Pedersen et al. 2003; Wannamethee et al. 2002, 2003). The moderate consumption of alcoholic beverages may reduce the risk of cardiovascular diseases, for example, by ∼35%, that of type 2 diabetes by ∼30%, and that of ischemic stroke by 20%–28%; the risk of hemorrhagic stroke is relatively unaffected by moderate alcohol consumption. Over the last decade, evidence has accumulated which suggests that this J-shaped relation-ship could also be extended to a reduced risk of cognitive dysfunction, and dementias such as Alzheimer’s disease, and vascular dementia (Dufouil et al. 1997; Huang et al. 2002; Lindsay et al. 2002; Luchsinger et al. 2004; Rasmussen et al. 2006; Simons et al. 2000; Zuccala et al. 2001). Mild cognitive dysfunction or impairment is a prodrome for Alzheimer’s disease.
While the literature defines consistently light-to-moderate consumption as 20–40 g ethanol per day (Jackson et al. 1992; Klatsky 2003; NHMRC 2005; Palomaki and Kaste 1993), several studies have defined moderate consumption as up to 80 g ethanol per day for men (Elias et al. 1999; Zuccala et al. 2001), which may reflect country and cultural differences in alcohol consumption; 10 g ethanol approximates one drink or 100 mL wine. Above moderate consumption, the risk of alcohol-related diseases increases dose-dependently (Corrao et al. 2004).
RELATIONSHIP OF ALCOHOLIC BEVERAGES TO COGNITIVE FUNCTION AND DEMENTIA
Cognitive function is defined as the intellectual or mental processes by which knowledge is acquired, including perception, reasoning, acts of creativity, problem solving, and possible intuition. Cognitive dysfunction or impairment is associated with increased disability and an increased need for institutionalized care. Dementia is a form of cognitive dysfunction whereby an individual loses the ability to think, remember, and reason due to physical changes in the brain.
Prior to a study by Zuccala et al. (2001), there was conflicting evidence on the relationship between alcohol consumption per se and cognitive function (Cervilla et al. 2000; Dent et al. 1997; Dufouil et al. 1997; Elias et al. 1999; Harwood et al. 1999; Hendrie et al. 1996; Leibovici et al. 1999; Teri et al. 1990). Zuccala et al. (2001) analyzed the association between alcohol consumption and cognitive impairment in 15,807 hospitalized older patients who were enrolled in an Italian multicenter pharmacoepidemiology survey. The amount of alcohol use was recorded as daily wine units (100 mL or ∼10 g ethanol), because wine, particularly with meals, represents the major form of alcohol consumption in this Italian population. The probability of cognitive impairment was reduced among male patients who reported an average daily alcohol consumption of 1 L or less of wine, as compared with abstainers, but the prob-ability increased among heavier drinkers. Among women, only the lightest-drinking category (<500 mL/day) showed a decreased probability of cognitive dysfunction when compared with abstainers, whereas heavier drinking was associated with an increased probability of cognitive impairment. The prevalence of alcohol abuse was similar among participants with cognitive impairment and those with normal cognitive functioning. The results of this study indicated that less than four drinks per day for women and less than eight drinks for men was associated with reduced probability of cognitive impairment as compared with abstinence, after adjusting for potential confounders supportive of other studies. This nonlinear association persisted when cerebrovascular diseases and Alzheimer’s disease were considered separately. Such a nonlinear association might explain the conflicting results of previous studies regarding the relationship between alcohol consumption and cognitive functioning.
The observed gender difference in amount of alcohol consumption necessary for improved cognitive function confirms that observed by Elias et al. (1999), who showed that “superior” cognitive performance was found within the range of four to eight drinks per day for men but only two to four drinks per day for women, com-pared to abstainers.
Subsequent studies have also independently assessed the association between alcohol consumption and cognitive function, and have affirmed the observations of Zuccala et al. (2001) but have also provided more detailed data (Ganguli et al. 2005; McDougall et al. 2006; Reid et al. 2006; Stampfer et al. 2005; Wright et al. 2006). For example, both current moderate consumption and cumulative lifetime alcohol consumption are associated with better cognitive function compared to abstainers. This encompasses processing speed, which is the ability to perform tasks requiring rapid visual scanning and mental processing of information, memory such as verbal knowledge or memory including immediate and delayed recall, recognition memory, figural memory, and working memory, as well as motor speed. This has been observed for both men and women (Bond et al. 2005; Cho et al. 2000; Espeland et al. 2006; Stampfer et al. 2005).
As mentioned earlier, mild cognitive dysfunction is a prodrome for dementia, and in particular Alzheimer’s disease, which is a complex, late-onset disorder characterized by the loss of memory and multiple cognitive functions. In patients with mild cognitive dysfunction, consuming up to 15 g ethanol per day now appears to also decrease the rate of progression to dementia by ∼85%, while 10–30 g alcohol per day reduces the risk of Alzheimer’s disease and vascular dementia (Huang et al. 2002; Mukamal et al. 2003; Ruitenberg et al. 2002).
RELATIONSHIP OF WINE TO COGNITIVE FUNCTION AND DEMENTIA
Moderate wine consumption rather than alcohol consumption per se has been specifically associated with a lower risk of developing dementia and specifically Alzheimer’s disease (Deng et al. 2006; Huang et al. 2002; Larrieu et al. 2004; Leibovici et al. 1999; Lindsay et al. 2002; Luchsinger et al. 2004; Mehlig et al. 2008; Mukamal et al. 2003; Orgogozo et al. 1997; Ruitenberg et al. 2002; Simons et al. 2006; Truelsen et al. 2002). From the PAQUID study of 3777 subjects aged 65 years and older who were followed for 3 years, in the 922 subjects drinking between 125 and 250 mL/day the odds ratio was 0.55 for Alzheimer’s disease. In the 318 subjects drinking between 250 and 500 mL/day, however, the odds ratio was 0.19 for incident dementia and 0.28 for Alzheimer’s disease compared to the 971 nondrinkers after adjusting for age, sex, education, occupation, and other possible confounders. In the Washington Heights Inwood-Columbia Aging Project, 980 community-dwelling individuals aged 65 and older without dementia at baseline were recruited between 1991 and 1996 and followed annually (Luchsinger et al. 2004). After 4 years of follow-up, 260 individuals developed dementia and, of these, 199 developed Alzheimer’s disease. After adjusting for age, sex, apolipoprotein E (APOE)-epsilon 4 status, education, and other alcoholic beverages, only consumption of up to 33 g ethanol per day as wine was associated with a lower risk of Alzheimer’s disease.
A primary difference between wine and the other alcoholic beverages is that wine contains phenolic compounds similar to those contained in fruits, vegetables, and teas, the consumption of which has also been associated a lower incidence of both mild cognitive dysfunction, dementias such as Alzheimer’s disease, and other cerebrovascular/neurodegenerative diseases (Frisardi et al. 2010; Solfrizzi et al. 2011).
POTENTIAL MECHANISMS OF ACTION FOR ETHANOL AND WINE-DERIVED PHENOLIC COMPOUNDS
More than 500 compounds have been identified in Vitis vinifera grapes and wine to date (Rapp and Pretorius 1989; Schreier 1979). Wine typically contains alcohols such as methyl, ethyl, n-propyl, isopropyl, isobutyl, isoamyl, act-amyl, 2-phenethanol, n-hexanol as well as detectable amounts of ∼18 other alcohols, where the most abun-dant alcohol is ethyl alcohol or ethanol (Rapp and Mandery 1986). The concentration of ethanol in “table” wine generally ranges between 8% and 15% v/v (Rankine 1989). Wine also typically contains phenolic compounds and their polymeric forms and the total amount of phenolic compounds in a 100 mL glass of red wine is ∼200 mg versus 40 mg in a glass of white wine (Rankine 1989). Chemically, phe-nolic compounds are cyclic benzene compounds possessing one or more hydroxyl groups associated directly with an aromatic ring structure. Wine-derived phenolic compounds include the nonflavonoid classes of compounds such as hydroxycinnamates, hydroxybenzoates, and stilbenes such as resveratrol, as well as the more abundant flavonoid classes of compounds: flavan-3-ols such as catechin, flavonols such as quercetin, and anthocyanins. Of these, resveratrol appears to have been the most widely examined phenolic compound over the past decade. While polymeric condensed tannins and pigmented tannins constitute the majority of red wine phenolic compounds, their large size precludes absorption and they are thus unlikely to contribute to any biological mechanism (Waterhouse 2002). Data from animal studies suggest that grape- and wine-derived phenolic compounds are absorbed and accumulate in the brain in measurable amounts after multiple or repeated oral doses (Ferruzzi et al. 2009; Passamonti et al. 2005). Wine-derived phenolic compounds, and particularly resveratrol, have been shown to be cerebero- or neuroprotective in various models, in vitro and in vivo, and potential mechanisms have been proposed as follows. Data from similar studies using different varieties of red wines with different profiles of phenolic compounds, as well as studies compar-ing different phenolic compounds, suggest that the individual classes of phenolic compounds may exhibit differential effects in the brain (Hamaguchi et al. 2009; Ho et al. 2009).
HEMOSTASIS AND OXIDATIVE STRESS
The beneficial effects of alcoholic beverages such as wine on the risk of cardio-vascular and cerebrovascular diseases have been partly attributed to changes in lipid and hemostatic or blood flow factors. These changes include ethanol-induced increases in the concentration of high-density lipoprotein-cholesterol, and ethanol- and phenolic-induced increases in the thrombolyic proteins tissue-type plasmino-gen activator activity and tissue-type plasminogen activator antigen, and induced reductions in fibrinogen, and clotting cofactors factor VII and von Willebrand factor. These changes are also associated with atherosclerosis which is the accumulation of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large- and medium-sized arteries. As atherosclerosis has been associ-ated with both Alzheimer’s disease and vascular dementia, it had been suggested that any beneficial effect of wine on atherosclerosis could be expected to benefit these dementias by preserving brain vasculature, consequently resulting in better cognitive function (Wright et al. 2006), however, showed that the appearance of plaque on the carotid artery which carries blood to the brain was not associated with consumption of an alcoholic beverage and associated improvements in cog-nitive function. This suggests then that ethanol and phenolic compounds such as resveratrol may impact cognition through a separate vascular or degenerative path-way (Kennedy et al. 2010). Vasoactive amyloid-O (AP), associated with Alzheimer’s disease and other related neurodegenerative diseases, may also interact with cerebral blood vessels to promote free radical production and reduce local blood flow which precede other neuropathological changes in dementias, and subsequently up-regulate Ap production (Thomas et al. 1996). Indeed, among older persons without cerebro-vascular and neurodegenerative diseases, those who moderately consume alcoholic beverages such as wine have been shown to have fewer white-matter abnormalities and infarcts on magnetic resonance imaging than abstainers (Mukamal et al. 2001), where pronounced reductions in the risk of both vascular dementia and Alzheimer’s disease have been shown among persons consuming one to six standard drinks per week (Mukamal et al. 2003).
A lack of heme oxygenase 1, an endogenous enzyme that is induced in neurons in response to oxidative and other stress and stimulates the degradation of prooxidant heme into free iron, carbon monoxide, and biliverdin and/or the antioxidative bilirubin, may also be associated with increased neural damage from ischemic strokes (Li et al. 2009), as well with Alzheimer’s disease and Parkinson’s disease (Ma et al. 2010). Heme oxygenase 1 is dose- and time-dependently induced by res-veratrol, which may provide another cerebrovascular and neuroprotective effect for phenolic compounds.
Indeed, Parkinson’s disease has been linked to increased levels of oxidative and nitrosative stress (Chung et al. 2003; Dawson and Dawson 2003) and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain and the appearance of Lewy bodies and neurites, which comprise insoluble amyloid-like fibrils that contain the protein a-synuclein. Oxidative stress apparently promotes the aggregation of a-synuclein (Maguire-Zeiss et al. 2005). An inverse relationship between amount of wine consumed and risk has been observed where the lowest risk was observed for wine consumers of ∼140–420 g/week (Fall et al. 1999). Wine-derived phenolic compounds such as catechin and epicatechin have recently been observed in vitro to inhibit the formation of a-synuclein fibrils, and to destabilize preformed fibrils (Ono et al. 2008).
Cognition is also associated with acetylcholine. Cognitive decline associated with dementias, Huntington’s disease, and Parkinson’s disease, as well as with Down’s syndrome and multiple sclerosis, is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, in particular in the cholinergic neurons in the basal forebrain. Inhibition of acetylcholinesterase which restores cholinergic neurotransmission also appears to prevent the aggregation of Ap peptides and for-mation of amyloid fibrillar plaques (Munoz et al. 1999).
Ethanol may stimulate the release of acetylcholine in the hippocampus leading to improved cognitive function, such that a light amount of an alcoholic beverage in normal subjects appears to improve memory for events experienced before consump-tion (Fadda and Rossetti 1998). In contrast, quercetin inhibits acetylcholinesterase (Orhan et al. 2007). Indeed, acetylcholinesterase inhibitors which reversibly bind and inactivate the enzyme that degrades acetylcholine are the primary medications prescribed associated with mild improvements in cognitive function. The impair-ment of memory performance by chronic and heavy consumption, however, parallels the reduction of acetylcholine neurotransmission.
Concerning Alzheimer’s disease, which is associated with the presence of intra-cellular neurofibrillary tau tangles, extracellular Ap peptides, synaptic failure, mitochondrial dysfunction, and depletion of acetylcholine (Anekonda and Reddy 2006), it has been suggested that ethanol may directly stimulate the release of ace-tylcholine in the hippocampus; synaptic levels of acetylcholine decrease as a result of cholinergic neuron involvement. In a rat model, a moderate concentration of etha-nol (0.8 g/kg) stimulated the release of acetylcholine while a higher concentration (2.4 g/kg) inhibited its release. The formation of amyloid fibrillar plaques is also common in diseases such as Parkinson’s disease, prion diseases, Down’s syndrome, and type II diabetes.
Another important intracellular signaling system involved in learning and mem-ory is protein kinase C (PKC), a family of 12 serine/threonine kinases. PKC modu-lates cell viability which protects certain neuronal cells against AB-induced toxicity.
Resveratrol has been observed to protect hippocampal cells against AB-induced toxicity by activating PKC (Han et al. 2004), and specific binding sites for resvera-trol have been identified in the rat brain (Han et al. 2006), as have receptors for the green tea catechin gallates.
AMYLOID-β FACTORS AND ALZHEIMER’S DISEASE
Ap is a core component of the plaque or lesion found in the neocortex and hip-pocampus of diseased brains. It is formed after sequential proteolytic cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein. APP can be processed by a, p, and y secretases. Unlike a secretase which cleaves APP into nontoxic amyloid-a, the toxic amyloid-p protein is generated by successive action of the p and y secretases. The y secretase, which produces the C-terminal end of the Ap peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 39–43 amino acid residues in length. The most common isoforms are Ap40 and Ap42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the longer form is produced by cleav-age in the trans-Golgi network. The Ap40 form is the more common of the two, but Ap42 is the more fibrillogenic or polymeric and is thus associated with disease states, promoting proinflammatory responses and activating neurotoxic pathways leading to neuronal dysfunction, and the death and loss of neurons. Inhibition of the accumulation of amyloid-p peptides and the formation of Ap fibrils/plaques from amyloid-p peptides, as well as the destabilization of preformed Ap fibrils/ plaques in the brain would, therefore, be attractive therapeutic targets for the treatment of Alzheimer’s disease and other related neurodegenerative diseases.
As mutations in APP associated with early-onset Alzheimer’s disease have been noted to increase the relative production of Ap42, a potential therapy may involve modulating the activity of p and y secretases to produce mainly Ap40. Administration of a red wine to Tg2576 mice equivalent to two standard drinks, which model Alzheimer’s disease Ap neuropathology and corresponding cognitive deterioration, has been shown to promote the nonamyloidogenic processing of the APP, which acts to prevent the generation of the Ap peptide (Wang et al. 2006). For example, administration of red wine reduced amyloidogenic Ap(1–40) and Ap(1–42) peptides in the neocortex and hippocampus of Tg2576 mice and correspondingly decreased the neocortical Alzheimer’s disease–associated amyloid fibrils/plaque. Subsequent examination of APP processing and Ap peptide generation increased the concentra-tion of membrane-bound a-carboxyl terminal fragments of APP in the neocortex and a secretase activity was also increased, while there was no significant change in the neocortical concentration of p and y carboxyl terminal fragments of APP or in p and y secretases activity.
The typical red wine–derived phenolic compounds catechin, quercetin, epi-catechin, myricetin, and tannic acid have, however, been shown in vitro to dose-dependently inhibit the formation of Ap fibrils from fresh Ap(1–40) and Ap(1–42), as well as their extension, and also dose-dependently destabilized preformed Ap fibrils (Ono et al. 2003, 2004; Roth et al. 1999). Only resveratrol, however, has been shown to decrease the level of intracellular Ap produced by different cell lines expressing the wild type of Swedish mutant Aâ precursor protein (APP695) by promoting its intracellular degradation (Marambaud et al. 2005). This mechanism was proteasome-dependent, that is, resveratrol appears to activate the proteasome involved in the degradation of Aâ, as the resveratrol-induced decrease of Aâ could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit â5. Resveratrol does not inhibit the production of Aâ because it has no effect on â and ã secretase activity.
Another potential therapy may involve preventing the aggregation of Aâ, as stud-ies have suggested that only when aggregated in the fibrillar form Aâ is neurotoxic, although some studies alternatively suggest that the toxicity lies in soluble oligomeric intermediates rather than in the insoluble fibrils that accumulate. Grape-seed phenolic compound extract, which comprises primarily catechin and epicatechin in monomeric, oligomeric, and polymeric forms, has been shown in vitro and in animal studies to inhibit Aâ aggregation into high-molecular-weight oligomers (Wang et al. 2008). This inhibition coincided with attenuation of Alzheimer’s disease–type cognitive impair-ment. Resveratrol and its glucoside, piceid, have, however, been shown in vitro to dose-dependently inhibit the formation of Aâ fibrils (Riviere et al. 2007, 2010); other stilbene monomers examined are less potent inhibitors. Binding may be induced by hydropho-bic interactions between the phenolic rings and the hydrophobic region of Aâ, thus blocking associations between Aâ molecules and inhibiting fibril formation. These interactions may then be reinforced by the H-bond between the hydroxyl group of the phenolic rings and some donor/acceptor groups of Aâ, as observed for other peptides.
AMYLOID-β AND APOE-EPSILON 4 ALLELE
In the Washington Heights Inwood-Columbia Aging Project (1991−1996), however, a lower risk was confined to wine consumers without the APOE-epsilon 4 allele (Luchsinger et al. 2004). This allele is implicated in atherosclerosis, Alzheimer’s disease, and impaired cognitive function, possibly influencing the increased depo-sition of Aâ in the brain as it is less effective compared to other alleles at facili-tating the proteolytic breakdown of this peptide, both within and between cells (Selkoe 1997).
Indeed, the most important genetic risk factor is the ApoE genotype. ApoE is a protein that carries lipids in and out of cells. It occurs in three isoforms: ApoE2, ApoE3, and ApoE4. The gene for ApoE is on chromosome 19. One copy is inher-ited from each parent. The most common ApoE allele is ApoE3. Persons who are homozygous for the ApoE4 allele develop Alzheimer’s disease earlier at a mean age of 70 years. The ApoE4 allele is also a risk factor for hypercholesterolemia. ApoE4 has been detected in neurofibrillary tangles and in Aâ (Luchsinger et al. 2004). This suggests that ApoE lipoproteins participate in some way in the processing of APP, perhaps by modulating APP secretases, and may also play a role in the assembly of the neuronal cytoskeleton. High cholesterol levels during midlife increase the risk of Alzheimer’s disease and lipid-lowering therapies including the consumption of wine-derived phenolic compounds can lower this risk which may accordingly lower the risk of developing Alzheimer’s disease (Andrade et al. 2009; Broncel et al. 2007; Franiak-Pietryga et al. 2009).
Plausible biological mechanisms in various animal models in vitro and in vivo for the wine-derived phenolic compounds support a cerebro- or neuroprotective role for catechin, quercetin, and resveratrol, in particular, which go beyond their antioxidant activity and attenuation of oxidative stress. More research is required on their intracellular and molecular targets and hence protection, and it would be unwise to extrapolate these results to humans without longer-term clinical studies in patients experiencing extensive neuronal loss associated with dementias and other neuro-degenerative diseases. Considering the extensive plausible biological mechanisms, these compounds provide promise as therapeutic or prophylactic agents in neurodegenerative diseases.