Can Tea Consumption Protect against Stroke?
Antioxidant properties of tea that lead to health-protective effects have been reported, mainly in relation to various types of cancer, coronary heart disease, and inflammation (Mukhtar and Ahmad,
1998) . Only a few experimental data are available about the possible neuroprotective effects of tea consumption in human stroke or animal models of ischemia-reperfusion. The purpose of this post is to analyze the available data and the mechanisms by which tea may protect brain areas from stroke and to briefly compare the data on tea with those on coffee and stroke.
TEA CONSUMPTION AND COMPOSITION
The tea plant, Camellia sinensis, also known as Thea sinensis L., originates from southeast Asia but is currently cultivated in more than 30 countries around the world. Tea, the water extract of the dry leaves of Camellia sinensis, is consumed worldwide, although in greatly different quantities; it is generally accepted that, after water, tea is the most consumed beverage in the world, with a per capita consumption of approximately 120 ml/d (Katiyar and Mukhtar, 1996). Of the total amount of tea produced and consumed in the world, 78% is black, 20% is green, and less than 2% is oolong tea. Black tea is mostly consumed in Western countries and in some Asian countries, while green tea is consumed primarily in Japan, China, India, and a few countries in North Africa and the Middle East. This variety of tea has become progressively more popular and is consumed in increasing quantities in Western countries. Oolong tea production and consumption are limited to southeastern China and Taiwan (Katiyar and Mukhtar, 1996).
The different types of tea undergo different manufacturing processes. To produce green tea, freshly harvested leaves are rapidly steamed or pan-fried to inactivate enzymes, thereby preventing fermentation and producing a dry, stable product. Epicatechins are the main compounds in green tea, accounting for its characteristic color and flavor.
For the production of black and oolong teas, the fresh leaves are allowed to wither until their moisture content is reduced to about 55% of the original leaf weight, which results in the concentration of polyphenols in the leaves. The withered leaves are then rolled and crushed, thus initiating the “fermentation” of polyphenols via polyphenol oxidase-catalyzed oxidative polymerization. Oolong tea is prepared by firing the leaves shortly after rolling to terminate the oxidation and dry the leaves. Normal oolong tea is considered to be about half less fermented than black tea.
The composition of tea leaves depends on a variety of factors, including climate, season, horticulture practices, and the type and age of the plant. The chemical composition of green tea is similar to that of the leaf. Green tea contains polyphenolic compounds that include flavanols, flavandiols, flavonoids, and phenolic acids that account for 25 to 30% of the solids in water extracts of green tea leaves. Most of the polyphenols in green tea are (-)-epicatechin, (-)-epicatechin-3- gallate, (-)-epigallocatechin, (-)-epigallocatechin-3-gallate (ECGC), and (+)-catechin. In black tea, the major polyphenols are bisflavanols, theaflavins, and thearubigins that are formed from catechins during the process of polymerization. Theaflavins (about 1 to 2% of the solid in water extracts of black tea leaves) include theaflavin, theaflavin-3-gallate, and theaflavin-3,3′-digallate, and these substances contribute to the typical color and flavor of black tea. A substantial proportion of the solids in water extracts of black tea leaves represent thearubigins that have a wide range of molecular weights and are poorly characterized (Graham, 1992). Thus, it has been assumed that there are significant differences in antioxidant properties between green and black teas.
GENERAL PROTECTIVE PROPERTIES OF TEA
Tea has been consumed by some human populations for many generations and, in some parts of the world, has been considered to have health-promoting properties (Weisburger et al., 1997). Extensive laboratory research and the epidemiological findings of the past 20 years reported that polyphenolic compounds present in tea may reduce the risk of a variety of illnesses. Mainly, green tea catechins display pharmacological properties such as anticarcinogenic activity (Bu-Abbas et al., 1994; Katiyar and Mukhtar, 1996; Xu et al., 1996; Dreosti et al., 1997; Kohlmeier et al., 1997; Weisburger et al., 1997; Mukhtar and Ahmad, 2000), antioxidant activity (Serafini et al., 1996; Uchida et al., 1992), and anti-inflammatory activity (Katiyar et al., 1995a,b; Katiyar and Mukhtar, 1996) and appear able to prevent cardiovascular disease (Yamaguchi et al., 1991; Stensvold et al., 1992; Uchida et al., 1995; Tijburg et al., 1997), stroke (Weisburger, 1996), osteoporosis (Fujita,
1993) , liver disease (Imai and Nakachi, 1995), and bacterial and viral infections (Nakayama et al., 1990; Horiba et al., 1991). Drinking green tea daily would contribute to maintaining plasma levels of catechins sufficient to exert antioxidant activities against oxidative modification of lipoproteins in circulating blood (Nagakawa et al., 1997). Japanese epidemiologists reported that among patients with the highest consumption of green tea (10 or more cups per day), a significant decrease in the risk of gastric cancer was obvious. Moreover, one cup of green tea infusion contains 100 to 200 mg of polyphenolic compounds, which leads to the possible daily consumption of about 1 g of (-)-epigallocatechin-3-gallate in green tea (Kono et al., 1988).
TEA AND ISCHEMIA
In ischemia, the mode of neuronal death is considered to be a continuum between apoptosis and necrosis: ischemic neurons appear cytologically necrotic while exhibiting many biochemical features of apoptosis. Ischemia-induced cell death is active, energy-dependent, and the result of a cascade of detrimental events that include disturbance of calcium homeostasis leading to increased excitotoxicity, dysfunction of the endoplasmic reticulum and mitochondria, elevation of oxidative stress causing DNA damage, lipid peroxidation, alteration of proapoptotic gene expression, and activation of caspases and endonucleases leading to the final degradation of the genome. The purpose of the present post is not to review the whole cascade of the molecular events occurring in ischemia/reperfusion-induced neuronal death, which has been described in detail elsewhere (Chan, 2001; Graham and Chen, 2001; Hou and MacManus, 2002), but rather to focus on the steps of the ischemic cascade that have been considered as targets for the potential protective action of tea and tea extracts.
Ischemia/reperfusion-mediated brain injury results, at least partly, from the oxidation of cellular macromolecules (Siesjo, 1993; Kawase et al., 1999). Indeed, because of the high consumption of oxygen by the brain, the high concentrations of polyunsaturated fatty acids and transition metals, and the low concentration of antioxidants, the brain is very vulnerable to reperfusion-induced reactive oxygen species that lead to oxidative damage to lipids and DNA. Within the molecules most harmful to the brain, eicosanoids (prostaglandins and leukotrienes), thromboxane A2, malon- dialdehyde, and oxygen radicals are considered as mediators of ischemia/reperfusion-induced brain injury (Matsuo et al., 1996; Islekel et al., 1999). Eicosanoids and lipid peroxides are involved in ischemia/reperfusion-induced brain damage because of their ability to alter membrane permeability, induce brain edema, and ultimately lead to neuronal death (Watanabe et al., 1994).
At present, only a limited number of groups have studied the potential neuroprotective effects of tea and tea constituents on ischemia/reperfusion-induced ischemic neuronal damage. In global ischemia, the consumption of 0.5% green tea extracts by rats subjected to a 5-min ligation of the two common carotid arteries followed by 48 h of recirculation allowed a 37% reduction of the infarcted volume compared to animals drinking regular water (Hong et al., 2000). Similarly, 41 and 60% reductions in the infarcted volume were recorded in Mongolian gerbils subjected to a 3- week 0.5 or 2% green tea extract regimen prior to a 60-min focal ischemia induced by the occlusion of the middle cerebral artery, followed by 48 h of blood recirculation (Hong et al., 2001). A similar protection from cerebral infarction induced by global ischemia consecutive to a 3-min bilateral ligation of the common carotid arteries followed by 5 d of recirculation was found in gerbils treated immediately after the induction of the ischemia with 25 or 50 mg/kg of the green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG) (Lee et al., 2000). Likewise, a long-term administration of 0.5% EGCG to spontaneously hypertensive rats decreased the incidence of stroke and prolonged the rats’ life span without affecting blood pressure (Uchida et al., 1995). The protective potency of EGCG on memory function following transient global ischemia induced by the bilateral ligation of the common carotid arteries is, however, weaker than that of two other tea polyphenols, (-)epi- catechin and (+)catechin (Matsuoka et al., 1995).
MECHANISMS OF TEA-INDUCED PROTECTION AGAINST ISCHEMIA
Epidemiological studies suggest that the consumption of tea polyphenols (also called flavonoids) may be associated with reduced risk of coronary heart disease, stroke, and cancer-related deaths (Weisburger et al., 1997; Mukhtar and Ahmad, 2000). Tea polyphenols are rapidly absorbed into the circulation following oral ingestion and are found predominantly after a single administration in the plasma, colon and small intestine, liver, lungs, pancreas, mammary glands, and skin, also in brain, kidneys, and reproductive organs (Nagakawa and Miyazawa, 1997; Suganuma et al., 1998). Moreover, a second administration of the polyphenol EGCG enhances tissue levels in blood, brain, liver, pancreas, bladder, and bones four to six times above those observed after a single administration (Suganuma et al., 1998). These results suggest that frequent consumption of green tea enables the body to maintain a high organic level of tea polyphenols, and these experimental data are in accordance with the report that the antioxidant potential is increased in humans by the consumption of green and black teas (Langley-Evans, 2000; Sung et al., 2000). The antioxidant potential of tea measured in vitro compares to that of beverages from fruits or vegetables.
From calculations of the antioxidant levels of green tea, it appears that a consumption of 150 ml of tea could make a significant contribution to the total daily antioxidant capacity intake (Prior and Cao, 1999). In humans, the antioxidant capacity of plasma is significantly and progressively increased after taking green or black tea in amounts of 300 and 450 ml (Langley-Evans, 2000; Sung et al., 2000). However, the antioxidant potential of black tea appears to be totally negated by the simultaneous consumption of milk in tea (Langley-Evans, 2000). The protective role of different green tea extracts against oxidative damage relates to their polyphenol composition, directly to their amounts of EGCG and (-)-epigallocatechin (Toschi et al., 2000). Tea polyphenols inhibit the liver enzyme xanthine oxidase, which produces reactive oxygen species, and thus act at a quite early level in the oxidative cascade by inhibiting production rather than only by neutralizing already-formed reactive oxygen species (Aucamp et al., 1997; Kondo et al., 1999).
Reactive oxygen species are largely involved in the pathogenesis of ischemia/reperfusion brain injury. These reactive oxygen species lead to oxidative damage to lipids and DNA. Oxygen radicals, eicosanoids (i.e., prostaglandins and leukotrienes) that result from the metabolism of arachidonic acid by lipoxygenase and cyclooxygenase, thromboxane A2, and malondialdehyde are considered as mediators of ischemia/reperfusion-induced brain injury by altering membrane permeability, inducing brain edema, and ultimately leading to neuronal death (Matsuo et al., 1996; Islekel et al., 1999) . A chronic treatment with green tea before experimental global or focal ischemia has been shown to reduce ischemia/reperfusion-induced elevation of reactive oxygen species such as the hydrogen peroxide level; this confirms that green tea can act in ischemia either by preventing or scavenging oxygen-free radicals, as shown in other in vivo or in vitro systems (Lee et al., 1995; Hiramaoto et al., 1996; Wei et al., 1999). This effect may reflect the green tea extract-induced increase in the level of the antioxidant enzyme catalase in liver (Khan et al., 1992; Lee et al., 1995). Thromboxane A2 and platelet-activating factor (PAF) are the mediators of neutrophil activation during cerebral ischemia/reperfusion (Matsuo et al., 1996) that leads to an additional deleterious generation of oxygen radicals during ischemia/reperfusion injury (Matsuo et al., 1995). Green tea polyphenols exhibit antiplatelet activity, which results in antithrombotic activities that may add to the neuroprotective properties of green tea polyphenols (Kang et al., 1999, 2001).
Likewise, the production of eicosanoids (leukotriene C4 and prostaglandin E2), thromboxane A2, lipid peroxidation products (malonaldehyde and 4-hydroxynonenal), and 8-hydroxydeoxygua- nosine, a form of oxidative DNA damage is largely increased after ischemia/reperfusion (Hong et al., 2000, 2001). Chronic exposure to green tea prior to the ischemic insult or the acute administration of the green tea polyphenol EGCG reduces the production of the damaging compounds cited above (Lee et al., 2000). The mechanisms underlying these effects are unknown. Green tea extracts reduce the activities of the enzymes phospholipase A2 and cyclooxygenase in rat platelets that lead to the enhanced synthesis of eicosanoids (Yang et al., 1999). Alternately, green tea could also increase the degradation pathway of eicosanoids (Hong et al., 2000). The green tea-mediated protection against damage to lipids and DNA leads to an attenuation of ischemia/reperfusioninduced brain apoptosis and cell death (Matsuoka et al., 1995; Lee et al., 2000; Hong et al., 2001). Similar protective effects of green tea extracts or polyphenols were observed in other models of oxidative stress-induced neuronal cell death, such as in vitro cell models of Parkinson’s disease (Levites et al., 2001, 2002b; Nie et al., 2002). The neuroprotective mechanisms of tea polyphenols against oxidative stress-induced cell death include the stimulation of protein kinase C and modulation of cell survival/cell cycle genes (Levites et al., 2002a).
Another factor involved in ischemia/reperfusion-induced cell damage is the production of nitric oxide (NO). Brain ischemia leads to a rise in NO3 *NO2 concentrations mainly produced by inducible nitric oxide synthase (iNOS), which forms large amounts of NO in macrophages several hours after an insult. These high concentrations of NO produce large amounts of reactive oxygen species that have been shown to cause deamination of DNA deoxynucleotides and bases. The large energy depletion leading to energy failure that is caused by the activation of the enzyme poly(ADP- ribose) polymerase that repairs strand breakage in DNA appears as a major factor involved in ischemia/reperfusion-induced cell death (Eliasson et al., 1997; Szabo and Dawson, 1998). EGCG from green tea has been shown to serve as an iNOS inhibitor (Chan et al., 1997). EGCG is able to block the early events mediated by iNOS activation by inhibiting the binding of the transcription factor, nuclear factor-kappa B, to the iNOS promoter, thereby inhibiting iNOS transcription (Lin and Lin, 1997). EGCG is also able to directly act as an antioxidant and scavenge reactive oxygen radicals produced by ischemia/reperfusion (Lin and Lin, 1997; Nagai et al., 2002).
CONCLUSION AND FUTURE DIRECTIONS
At this point, only a few experimental studies have concentrated on the potential neuroprotective effects of green tea extracts on neuronal damage induced by global or focal ischemia/reperfusion. As reported, the studies have all been focused on the antioxidant properties of green tea polyphenols, mainly EGCG. By contrast, studies of the neuroprotective effects of coffee in global or focal ischemia/reperfusion-induced damage are fully devoted to the caffeine contained in coffee (for details see this post), although coffee also contains polyphenols and antioxidant compounds such as caffeic acid (for more details, see this post in this book). This would in fact be particularly relevant, since the total antioxidant capacity of coffee appears to be higher than that of tea (Natella et al., 2002). Thus, further studies should examine the potential cumulative neuro- protective effect of polyphenols and caffeine contained in coffee and tea against injuries such as ischemia/reperfusion.
It will also be important to assess whether the amounts of green tea extracts or EGCG given in experimental studies are really representative of the human situation. A recent phase I clinical trial was initiated after allowance from the U.S. Food and Drug Administration in order to examine the safety and efficacy of consuming the equivalent of at least 10 cups (2.4 l) of green tea per day in cancer patients. The results are not known at this point (Mukhtar and Ahmad, 2000). This type of study should be extended to stroke and other neurodegenerative diseases such as Parkinson’s disease, for which the consumption of tea has recently been reported to be preventive (Ascherio et al., 2001; Checkoway et al., 2002).
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