10.1. INTRODUCTION

Polyphenols are a large class of colourful, plant-based, phenolic organic compounds (USDA 2007). They are enriched in certain vegetables, fruits, seeds and beverages (e.g. tea and wine) and are regarded as semi-essential nutrients in humans.

Flavonoids, a polyphenolic subgroup, provide many of the colours in fruits and vegetables (Nieman et al. 2010a). As a natural antioxidant, flavonoids constitute significant components of the human diet and exhibit a diverse array of biological effects (Kandaswami and Middleton 1994, Korkina and Afanas’ev 1997, Li et al. 2000, Middleton et al. 2000).

Flavonoids compromise a large group of plant metabolites, 6000 of which have been identified to date (Erdman et al. 2007) and can then be divided into six subgroups. One of these six groups is flavonols, which it contains the abundant and diffuse flavonoid quercetin (Nieman et al. 2010a). Food-based sources of quercetin include tea, onions, apples, peppers, blueberries and dark green vegetables (Chun et al. 2007, USDA 2007).

The intake of these compounds improves an individual’s health and decreases their risk of cardiovascular disease (Korkina and Afanas’ev 1997, Kim et al. 2004, Scalbert et al. 2005).

10.2. ABSORPTION, BIOAVAILABILITY AND METABOLISM OF QUERCETIN

The first investigations on the pharmacokinetics of quercetin in humans were published in 1975 (Gugler et al. 1975), and the amount of research in this area has increased enormously.

The estimated absorption of quercetin glucoside, the naturally occurring form of quercetin, ranges from 3% to 17% in healthy individuals receiving 100 mg. The relatively low bioavailability of quercetin may be attributed to its low absorption, extensive metabolism and/or rapid elimination. Quercetin absorption is affected by differences in its glycosylation, the food matrix from which it is consumed, and the coadministration of dietary components such as fibre. Recent data indicate that the bioavailability of quercetin increases with the co-ingestion of fat (Guo et al. 2013).

The average terminal half-life of quercetin is 3.5 h. The total recovery of C-quercetin in urine, faeces and exhaled air is highly variable, depending on the individual (Moon et al. 2008). These results are consistent with those of other authors who have measured quercetin absorption and appearance in plasma after ingesting the pure quercetin aglycone as well as various glycoside forms contained in foods such as shallots, onions and apples (Egert et al. 2008). Additional literature indicates that isoquercetin (glycosylated quercetin) is more completely absorbed than is quercetin in the aglycone form, and that the simultaneous ingestion of quercetin with vitamin C, folate and additional flavonoids improves bioavailability (Manach et al. 2005, Harwood et al. 2007).

Quercetin accumulates in the outer and aerial tissues (skin and leaves) because biosynthesis is stimulated by exposure to sunlight. Human subjects can absorb significant amounts of quercetin from food or supplements, and elimination is quite slow, with a reported half-life ranging from 11 to 28 h (Conquer et al. 1998, Manach et al. 2005).

A more recent study showed that flavonol intake is about 13 mg/day for U.S. adults, and quercetin represents three-quarters of this amount. The estimated flavonoid intake ranges from 50 to 800 mg/day, both depending on the consumption of fruits and vegetables and the intake of tea (Chun et al. 2007). In Spain, however, the average daily intake of flavonoids is significantly higher than in the United States and was measured at 313 mg/day based on sources like tea, citrus fruits and juice, beers and ales, wines, melon, apples, onions, berries and bananas (Zamora-Ros et al. 2010).

10.3. QUERCETIN AND SAFETY

Quercetin has GRAS status (generally recognised as safe) according to criteria established by the U.S. Food and Drug Administration (Davis et al. 2009a). Not only is quercetin accepted as safe, but the European Food Safety Authority has published a number of health claims finding that quercetin has beneficial physiological effects in the protection of DNA, proteins and lipids from oxidative damage (EFSA 2011).

In studies on both animals and humans, quercetin supplementation is regarded as medically safe and has not been found to cause any adverse symptoms or harmful physiological effects (Harwood et al. 2007, Henson et al. 2008, Utesch et al. 2008, Davis et al. 2009a, Knab et al. 2011).

Long-term feeding of quercetin in rats leads to accumulation in several organs including the lungs, testes, kidneys, heart, liver, thymus and muscle (de Boer et al. 2005). It was not possible to replicate this finding, however, in pigs, where quercetin was found only in organs involved in its metabolism and excretion, namely the small intestine, kidneys and liver (Bieger et al. 2008).

These data question the degree to which quercetin is incorporated into human tissues including the lung, heart and muscle. Further research is needed using tissue biopsies and radiolabelled procedures (Nieman 2010).

10.4. ROLE OF SUPPLEMENTATION TO COUNTER OXIDATIVE STRESS

During strenuous exercise, there is a dramatic increase in oxygen uptake in various organs, particularly the skeletal muscle. The resting body is equipped with both enzymatic and non-enzymatic antioxidant reserves (Morillas-Ruiz et al. 2006). Cells continuously produce free radicals and reactive oxygen species (ROS) as part of metabolic processes. These free radicals develop an antioxidant defence system consisting of enzymes such as catalase, superoxide dismutase, glutathione peroxidase and numerous non-enzymatic antioxidants, including vitamins A, E and C, glutathione, ubiquinone and flavonoids. Exercise, though generally recognised as healthy and advantageous, can also produce an imbalance between ROS and antioxidants, which is referred to as oxidative stress. Physical activity increases the generation of free radicals in several ways and as oxidative phosphorylation increases in response to exercise, there will be a concomitant increase in free radicals. Catecholamines released during exercise can lead to free radical production. Other sources of free radicals increase with exercise-induced prostanoid metabolism, xanthine oxidase, NAD(P)H oxidase and several secondary sources, such as the release of radicals by macrophages recruited to repair damaged tissue (Jackson 2000).

In order to cope with the excess of free radicals produced upon oxidative stress, the human body has developed mechanisms for maintaining redox homeostasis. These protective mechanisms include scavenging or detoxifying ROS, blocking ROS production, sequestering transition metals, as well as enzymatic and non-enzymatic antioxidant defences produced in the body, that is, endogenous (Hayes and McLellan 1999, Masella et al. 2005) and others supplied within the diet, namely, exogenous ones.

Among them, dietary polyphenols have been widely studied for their strong antioxidant capacities and cell regulatory properties (Hollman et al. 1997, Hartman et al. 2006, Landete 2012).

Athletes use antioxidant supplementation as a means to counteract the oxidative stress of exercise. Whether or not strenuous exercise does, in fact, increase the need for additional antioxidants in the diet is not clear. If the increase in free radicals is greater than the ability to neutralise them, the radicals will attack cellular components, especially lipids. The attack on lipids initiates a chain reaction called lipid peroxidation, which leads to the generation of more radicals and ROS that can harm other cellular components. The body appears to be able to withstand a limited increase in free radicals and, in fact, data suggest that an increase in ROS is necessary for muscle adaptation to occur (Jackson 1999, Urso and Clarkson 2003).

As previously discussed, intensive and sustained exercise can create an imbalance between ROS and antioxidant defences, leading to oxidative stress that causes lipid peroxidation and protein oxidation (Nieman et al. 2003, Mastaloudis et al. 2006).

Although pathways between oxidative stress during heavy exertion and immune dysfunction have been described, data support is widely lacking (Nieman et al. 2003). Moreover, the proposed benefits of antioxidant supplementation in attenuating both oxidative stress and exercise-induced immune dysfunction remain unsubstantiated (Petersen et al. 2001, Nieman et al. 2003, Mastaloudis et al. 2006).

Taking into account all of the results of human studies, antioxidant supplementation to counter both oxidative stress and immune dysfunction in endurance athletes during heavy exertion cannot be recommended. The majority of investigations have failed to show that the ingestion of antioxidants such as vitamins E and C has meaningful effects on exercise-induced inflammation and muscle damage, and immune perturbations (Nieman 2008).

Quercetin is a powerful in vitro antioxidant and free radical scavenger (Loke et al. 2008). Quercetin (aglycone form) has several phenolic OH groups that protect against free radical damage via radical scavenging activity (Santos and Mira 2004). However, low bioavailability and metabolic transformation (i.e. conjugation of absorbed quercetin with glucoronic, sulphur and methyl groups) reduce the likelihood of in vivo scavenging activity (Loke et al. 2008). The majority of human studies conclude that supplementation with quercetin in its aglycone form does not exert antioxidant effects even in daily doses of up to 1000 mg over 12 weeks (Boyle et al. 2000, Egert et al. 2008, Knab et al. 2011).

McAnulty et al. (2008), for example, reported no effect of quercetin supplements in countering exercise-induced oxidative stress or other indicators of physiologic stress. Forty athletes were recruited and randomly given either quercetin or a placebo. Subjects consumed either 1000 mg of quercetin or the placebo every day for 3 weeks before and during 3 days of cycling at 57% work maximum for 3 h. The findings from this study indicate that quercetin supplementation increased the circulating plasma values of quercetin; however, the increase in plasma quercetin metabolites did not affect oxidative stress, inflammation or plasma antioxidant capacity (McAnulty et al. 2008).

Quindry et al. (2008) tested quercetin as an antioxidant countermeasure during the 160-km Western States Endurance Run, where oxidative stress is high due to the length and effort involved. In the double-blind study, 63 subjects received either 1000 mg of quercetin or a placebo. Biomarkers of plasma antioxidant status were not influenced by quercetin after three weeks ingestion (Quindry et al. 2008).

Abbey and Rankin (2011) also failed to reduce oxidative stress via the inhibition of the enzyme xanthine oxidase after 1 week of supplementation with 1000 mg of quercetin in a repeated sprint performance (Abbey and Rankin 2011).

Quercetin’s anti-inflammatory and anti-oxidative effects may be augmented by the co-ingestion of N-3 polyunsaturated fatty acids (Camuesco et al. 2006, Mostafavi-Pour et al. 2008) and epigallocatechin 3-gallate (EGCG) (Ivanov et al. 2008). For example, the concurrent administration of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with quercetin resulted in a synergistic anti-inflammatory effect in rats with inflammatory intestinal disorders (Camuesco et al. 2006). In vitro data indicate that quercetin exhibits antiviral activity only when protected against oxidative degradation by ascorbate (Vrijsen et al. 1988). Another potential weakness of these early human studies was the supplementation regimen. Quercetin supplements were ingested 10–24 h prior to doing exercise, a time period that may have been too long, given the half-life of quercetin (Manach et al. 2005, Moon et al. 2008).

Subjects of both sexes in the general population (n = 1002) were recruited and had a quercetin intake of 500 mg or 1000 mg/day or were on placebo, respectively, over 12 weeks’ time. As a consequence, the plasma quercetin level was significantly increased, but there was no influence on several markers of oxidative stress and antioxidant capacity (Shanely et al. 2010). In their serum, total cholesterol was measured between the 500 mg group and the placebo group, and there was a small decrease in high-density lipoprotein cholesterol levels in the 1000 mg group. Both quercetin groups experienced a small decrease in serum creatine and an increase in the glomerular filtration rate. Interestingly, the drop in mean arterial blood pressure occurred through a combined but nonsignificant reduction in both systolic and diastolic blood pressure for both quercetin groups compared with the placebo group (Knab et al. 2011).

In the elderly, those with chronic diseases and obese subjects, oxidative stress is also increased (Voss and Siems 2006). Because plant extracts work, as has been observed in the context of attenuation exercise-induced oxidative stress and inflammation (Hurst et al. 2010, Nieman et al. 2010a), there is also increasing interest in applying this to the attenuation of obesity-induced inflammation, oxidative stress and immune dysfunction. It is also shown in healthy overweight male subjects with a mildly elevated level of inflammation marker that after a supplementation of different food components, modulating inflammation, oxidation was possible and the metabolism status was altered, all detected by a nutrigenomic approach (Bakker et al. 2010).

Quercetin is a powerful antioxidant and free radical scavenger, as demonstrated by in vitro studies (Rice-Evans et al. 1996, Hou et al. 2004, Loke et al. 2008, Duenas et al. 2010).

Loke et al. (2008) showed in an in vitro study that free quercetin provides greater protection from oxidative stress than its conjugated metabolites found in the plasma. There seems to be better evidence to support the intake of foods rich in antioxidants within the diet than there is for supplementation due to the consequence of increased uric acid levels (Lotito and Frei 2006).

Taken together, the results and benefits of pure high-dose quercetin as an antioxidant are very limited, and in contrast, using quercetin as part of an antioxidant-cocktail has been found to be much more efficient and can be generally recommended.

10.5. QUERCETIN AS AN IMMUNE BOOSTER

It is well known from the studies cited below that after the heavy exertion of a marathon, cytokines (interleukin (IL)-6, IL-10, IL-1ra and IL-8) increased strongly in response to the race and remained elevated 1.5 h later. The pattern of change did not differ significantly in terms of either sex or age (Nieman et al. 2001, Suzuki et al. 2002, Croisier et al. 1999). This means that intensive exercise elicits a depression of several aspects of acquired immune function. This depression is temporary and cell numbers and functions usually return to pre-exercise values within 24 h. During prolonged periods of intensified training in elite athletes and if recovery between exercise sessions is insufficient, this temporary decrease in cell function can become a chronic depression of acquired immunity (Walsh et al. 2011b).

In contrast to moderate physical activity, prolonged and intense exercise also causes an increased risk of certain types of infection, for example, an upper respiratory tract infection (URTI) (Nieman 2007). Overtraining or training with insufficient recovery can further exacerbate these effects (Gleeson 2007).

To counter exercise-induced inflammation, muscle damage and soreness, the intake of non-steroidal anti-inflammatory drugs (NSAID) like ibuprofen is widespread among athletes, especially if they engage in ultra-distance sport. Ibuprofen in the context of heavy exertion is ineffective, however, and has been found to be potentially harmful (Nieman et al. 2006). Users compared with non-users experienced the same amount of muscle damage and soreness and, additionally, a small leakage of colon bacteria into the circulation that promoted even more inflammation. Ibuprofen use was associated with 25–88% higher plasma levels of seven cytokines, and significant elevations in blood neutrophil counts and serum CRP, urine F2-isoprostanes, alanine and aspartate aminotransferase, and blood urea nitrogen (Nieman 2009). In addition, the level of oxidative stress rose and the side effects of mild kidney dysfunction were observed (McAnulty et al. 2007). Athletes strongly believe that NSAID help them and only a better substitute would make them discontinue its use (Nieman 2012).

There are several studies in humans investigating the correlation of quercetin and its immunomodulatory effects. Quercetin does indeed reduce illness after intensive exercise. Again, under double-blind conditions, Nieman et al. (2007) showed that a supplement of 1000 mg of quercetin alone 3 weeks before, during and two weeks after a 3-day period of 3 h of cycling in the winter resulted in a markedly lower incidence of URTI in well-trained subjects in the two weeks after the intensified training, but had no effect on exercise-induced immune dysfunction, inflammation and oxidative stress (Nieman et al. 2007).

The literature is supportive of the antipathogenic capacities of quercetin when it is cultured with target cells and a broad spectrum of pathogens including URTI-related rhinoviruses, adenoviruses and coronaviruses. Quercetin blocks viral patterns at an early stage through several mechanisms, including inhibition of proteases by molecular docking, binding of viral capsid proteins and suppression of virulence enzymes such as DNA gyrase and cellular lipase (Chiang et al. 2003, Chen et al. 2006).

The impact of the co-ingestion of two or more flavonoids increases its bioavailability and the outcomes on immunity: Nieman et al. (2009) tested after 2 weeks of supplementation in trained athletes, before and after a period of heavy exertion, with or without 120 mg of EGCG, 400 mg of isoquercetin and 400 mg of EPA-DHA. It resulted in significantly reduced post-exercise measures for both inflammation and oxidative stress, with a chronic augmentation of granulocyte oxidative burst activity (Nieman et al. 2009).

When taken together, the results of a high-dose mixture of flavonoids, including quercetin, showed a successful reduction in the illness rates of exercise-stressed athletes as well as a chronic augmentation of their innate immune function (Nieman 2010).

10.6. DURATION AND AMOUNT OF SUPPLEMENTATION

There are different approaches to determining the appropriate duration of flavonoid supplementation to achieve any positive effect. Powers et al. (2010) contend that the appropriate duration of antioxidant supplementation is a key issue in investigations on exercise performance.

There have been many attempts in human trials to investigate the impact of quercetin on different outcomes; the longest was as many as 60 days between exercise and supplementation, but the majority varied between seven and 21 days (Nieman et al. 2010a), and in the context of polyphenols even a 7-day supplementation of quercetin is regarded as a ‘short-term’ supplementation (Davis et al. 2009a). Most investigations using flavonoid-rich products or extracts in athletic settings have utilised supplementation periods of at least 7 days prior to heavy exertion, and report varying levels of success in attenuating inflammation and oxidative stress (McAnulty et al. 2005, Chang et al. 2010, Nieman et al. 2010a, Trombold et al. 2010, Goldfarb et al. 2011).

Quercetin supplementation covers periods ranging from 2 to 6 weeks in untrained and trained subjects and has been linked to an inconsistent influence on exercise performance (Nieman et al. 2010a,b).

Few studies used an acute dose of a flavonoid-rich product or extract prior to exercise (Wiswedel et al. 2004, Morillas-Ruiz et al. 2006, Lyall et al. 2009, Davison et al. 2012), and the results were not in favour of acute supplementation in vivo (Konrad et al. 2011, Davison et al. 2012). Short-term (48 h) supplementation with EGCG was related to a small but significant increase in maximal exercise performance (Richards et al. 2010), but in general acute supplementation has limited support, which suggests that a longer loading period is necessary (Konrad et al. 2011).

As has been shown, the range of the duration of any supplementation varies a great deal and there are few studies measuring short-term effects. Taken together, there are no consistent recommendations regarding the timing of the supplement. There is little evidence to support any effects of an acute dose of polyphenols on performance and immunological changes in contrast to NSAIDs, which do not need a loading period prior to heavy exertion (Nieman 2012).

10.7. NECESSITY OF SUPPLEMENTATION

Recent evidence suggests that athletes, more so than non-athletes, seem to require increased antioxidants in order to reduce exercise-induced oxidative damage.

Some question whether or not exercise-induced oxidative stress and inflammation due to the higher turnover of oxygen radicals imposed by high-intensity training and competition should be attenuated in athletes, as antioxidant supplementation blocks many of the beneficial effects of exercise on metabolism; however, transiently increased levels of oxidative stress reflect a potentially health-promoting process at least with regard to the prevention of insulin resistance and type 2 diabetes mellitus (Ristow et al. 2009). Yfanti et al. (2010) did not show any effect on training adaptions with a focus on performance after a 12-week supplementation with a mix of antioxidants in highly trained athletes (Yfanti et al. 2010).

It is well known that certain fruits and vegetables can help prevent or treat chronic human diseases and that a broad spectrum of bioactive food can be more effective than any single-component synthetic drug (Raskin et al. 2002, Lila 2007). These natural components accumulate simultaneously in a plant and show a multiple defensive strategy for the human consumer (Lila 2007).

Data are limited and the method and regimens vary widely, but the main conclusion is that flavonoid–nutrient mixtures or any extracts of fruits, vegetables and tea consumed acutely or chronically before exercise diminish post-exercise oxidative stress, inflammation and delayed onset muscle soreness. To avoid the risk of exceeding intake, the most effective way is to consume a varied diet focused on fruit, vegetables and whole grain (Nieman et al. 2010a).

10.8. EFFECTS OF QUERCETIN ON PERFORMANCE

Active skeletal muscle mitochondrial density has been shown to be increased by as much as 20–100% through cardiorespiratory endurance exercise, depending on the level of intensity (Hoppeler and Fluck 2003). This occurrence is mediated by the rise in intracellular calcium levels when muscles contract and includes the harmonised expression of mitochondrial and nuclear genes including the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator-1 (PGC-1α) (Diaz and Moraes 2008).

Researchers who used animal models found that certain adaptions in muscle phenotype provoked by exercise can be replicated partly by energy restriction, genetic manipulation, drug treatment and with some forms of plant polyphenols including soya isoflavone derivatives, resveratrol and EGCG (Lagouge et al. 2006, Civitarese et al. 2007, Narkar et al. 2008, Rasbach and Schnellmann 2008). The indications suggest that supplementation with quercetin will also induce a rise in mitochondrial biogenesis and endurance performance in mice (Davis et al. 2009b). The study using ‘Imprinting Control Region’ male mice revealed an increase in soleus muscle PGC-1α (~100%) and SIRT1 (~200%) messenger RNA (mRNA), cytochrome C concentration (18–32%) and treadmill running time until fatigue (~37%) after a 7-day period of quercetin ingestion of 12.5 and 25 mg/kg. The soleus muscle mitochondrial DNA (mtDNA) of the mouse had roughly doubled after a week of the 25 mg/kg quercetin dose; however, this was not so with the 12.5 mg/kg dose. All of the mice were separately housed in regular cages and did not receive any training by means of forced treadmill running. As a second experiment, mice that were administered quercetin and provided access to running wheels augmented their running distance after 6 days by 35% when compared with the placebo group (Davis et al. 2009b).

There are multiple studies investigating the effects of quercetin supplementation on performance variables in humans as well, but the results are inconsistent.

After a 2-week supplementation with quercetin (1000 mg/day) vs. placebo in untrained male subjects who provided a blood and muscle biopsy, quercetin was associated with a small but significant improvement in a 12-min time trial (15% treadmill with a self-selected speed) and modest but insignificant increases in the relative copy number of mtDNA and mRNA levels of four genes related to mitochondrial biogenesis (Nieman et al. 2010b).

Another study in untrained volunteers did show a modest improvement of their VO_2max (3.9% vs. placebo; p < 0.05) along with a substantial (13.2%) increase in ride time to fatigue (p < 0.05) after a 1-week supplementation with quercetin (1000 mg·d⁻¹) compared with the placebo (Davis et al. 2010).

One study of 11 elite cyclists reported a 1.7% 30-km time trial performance enhancement compared with the placebo group following six weeks of quercetin supplementation mixed with green tea leaf extract and antioxidant vitamins (MacRae and Mefferd 2006).

Another study with trained cyclists showed differing results: 39 trained cyclists were randomised to a placebo or to quercetin (mixed with EGCG), took the supplements for 2 weeks and cycled on 3 consecutive days for 3 h/day. Subjects from both groups were able to maintain a mean power output of 56.9 ± 0.6% W_max. The total time trial duration did not differ between groups, and there was no difference in mRNA expression for genes related to skeletal muscle mitochondrial biogenesis (Nieman et al. 2009).

Similarly, a study of 40 trained cyclists randomly given 1000 mg/day of quercetin or a placebo for 3 weeks failed to show any group differences in measures of cycling efficiency or skeletal muscle mRNA expression for PGC-1α or SIRT1 (Dumke et al. 2009).

There was also no effect in a study wherein 39 trained cyclists took 1000 mg/day of quercetin supplements compared with a placebo in terms of mRNA expression for mitochondrial biogenesis or cycling time trial performance when engaging in 5-, 110- and 20-km time trials at the end of three 3-h cycling bouts (Nieman et al. 2009).

The number of quercetin-induced changes in muscle PGC-1α and SIRT1 mRNA, and endurance performance in mice (Davis et al. 2009b) was found to be significantly higher than in untrained human subjects (p < 0.05) (Nieman et al. 2010b). There could be numerous potential reasons for this, one being the applicability of mouse model findings to humans in quercetin and flavonoid-based research. Supplementation issues that must also be considered include the length of supplementation, the type of supplementation and amount of quercetin ingested.

There is good evidence to support the hypothesis that quercetin may be able to increase endurance exercise capacity, which comes primarily from in vitro and in vivo studies in rodents that show that quercetin has a combination of biological properties known to affect both physical and mental performance and the ability to increase mitochondrial biogenesis in both the muscle and brain of mice. After 7 days of quercetin supplementation, the mice underwent a change in mitochondrial biogenesis resulting in an increase in both maximal endurance capacity and voluntary wheel-running activity (Davis et al. 2009b). After a short period of supplementation (7–8.5 days) with 1000 mg/day of quercetin alone, there was no significant effect on performance during an aerobically demanding exercise (Abbey and Rankin 2011, Sharp et al. 2012), but that might be due to the short supplementation time (McAnulty et al. 2005).

In a meta-analysis on quercetin and its ergogenic effects, data on 254 subjects did show a small but significant benefit. The mean VO²_max ranged among studies from 41 to 64 mL/kg/min, had a median treatment duration of 14 days and a median dosage of 1083 mg/day. Despite variability among studies, quercetin provides a small but significant benefit in physiological measures of human endurance exercise capacity (Kressler et al. 2011).

Interestingly, quercetin may also enhance mental and physical performance with its caffeine-like psycho-stimulant effects. Many studies have shown that psycho-stimulants like caffeine can delay fatigue during endurance exercise, at least partly due to their ability to block adenosine receptors in the brain, and as a consequence the dopamine activity increases (Davis et al. 2003).

Several flavonoids also exhibit adenosine A₁ receptor antagonist activity in vitro. Quercetin had the highest affinity for this receptor, which is similar to caffeine, of all the tested flavonoids (Alexander 2006).

In general, polyphenols appear to be beneficial for athletic performance; however, the exact mechanisms are unknown, as each class is likely to have a different physiological effect (Powers et al. 2004, Braakhuis et al. 2011). The improvement of physical performance in athletes, however, might be due to quercetin’s antioxidant properties (Cureton et al. 2009). Future quercetin performance studies should have a longer supplementation period with quercetin consumed in combination with other nutrients, flavonoids and adjuvants like EGCG, luteolin, tiliroside and isoquercetin. Multiple performance measures should also be utilised and these should be selected to appropriately measure the desired outcome (Nieman 2010).

10.9. SUMMARY

The popularity of endurance and ultra-endurance events is increasing and, as a result, there is an increased interest in improving health and, of course, performance in athletes, as heavy exertion takes a toll on their immune systems. For this reason, many athletes take NSAID to boost their immune system and to help them to deal with the physical pain that results from such heavy exertion. On the downside, however, the utility of NSAIDs is very limited, as they come with the possibility of severe side effects and may be even harmful or counterproductive (Nieman et al. 2006).

Quercetin is a widespread flavonoid and is predominant in tea, onions, apples, peppers, blueberries and dark green vegetables (Nieman et al. 2010a). It is generally regarded as safe (Davis et al. 2009a) and is of increasing interest based on its broad range of biological effects in athletes as well as in the general population. The results of these effects are not consistent, however, and the outcomes need to be carefully evaluated as they are dependent on the type of subject and their level of fitness.

With regard to the immune system, there is a smaller incidence of URTI after supplementation with quercetin alone; however, inflammation markers are not significantly influenced after heavy exercise in vivo (Nieman et al. 2007). On the contrary, quercetin co-ingested with isoquercetin, EGCG, EPA and DHA does reduce post-exercise measures for both inflammation and oxidative stress with a chronic augmentation of granulocyte oxidative burst activity (Nieman et al. 2009). The outcomes of oxidative stress and quercetin supplementation are not entirely clear: there is in vitro evidence, but in vivo the supplementation fails or has little impact.

Overall, the intake of quercetin appears to provide a small but significant benefit for athletes in terms of physical as well as mental performance (Kressler et al. 2011). There is support in recommending the ingestion of quercetin, especially if it is administered together with green tea extract (EGCG) and fish oil, which is reinforced by in vitro studies that report strong anti-inflammatory, anti-oxidative and antipathogenic effects (Walsh et al. 2011b). The potential synergism between the initiation of exercise training and quercetin supplementation should be studied to determine whether untrained subjects achieve amplified performance outcomes.

Taken together, we know definitively that a flavonoid cocktail is much more efficient than a high dose of one single component. In the majority of the literature, we find references to the benefits of prolonged supplementation with quercetin; with either a mix of several components or only a single dose, only very limited utility has been reported.

The future challenge will be to find the mixture of flavonoids that deliver optimal benefits and especially to establish a recommendation for their protracted intake; this could be within a carbohydrate drink, for example, and would have more of an effect than only ingesting a large dose of a single molecule (Walsh et al. 2011a).

The research in this area is continuing in order to determine the proper outcome measures, dosing regimen and adjuvants that may amplify any perceived bioactive effects of quercetin in vivo (Nieman et al. 2012).

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