1088

DOI 10.1002/mnfr.201400567

Mol. Nutr. Food Res. 2015, 59, 1088–1094

RESEARCH ARTICLE

Quercetin and isorhamnetin aglycones are the main metabolites of dietary quercetin in cerebrospinal fluid Wiesław Wiczkowski1 , Janina Skipor2 , Tomasz Misztal3 , Dorota Szawara-Nowak1 , Joanna Topolska1 and Mariusz K. Piskula1 1

Department of Chemistry and Biodynamics of Food, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland 2 Department of Local Physiological Regulations, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland 3 Department of Endocrinology, Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jablonna, Poland Scope: Reports on the protective effect of certain foods on brain functions are numerous; however, the permeability of the brain barriers by food components is still hardly recognised. There have been in vitro studies aimed at demonstrating this possibility, but not much is known about this phenomenon in in vivo systems. The objective of the study was to determine the metabolites of dietary quercetin (Q) in urine, blood plasma and cerebrospinal fluid (CSF) after intra-rumen administration of Q rich onion dry skin in an animal model. Methods and results: Eleven sheep had permanently implanted cannulas in the third ventricle of the brain as the means for CSF collection. The animals were administered Q at the dose of 10 mg/kg bwt. For 12 h the concentration of Q metabolites was measured in urine, blood plasma, and CSF. It was demonstrated that while in blood plasma Q and isorhamnetin monoglucuronides or mono-sulphates were the main metabolites (80%), in CSF their aglycones were the dominating ones (88%). Conclusion: Q and IR aglycones are the main Q metabolites present in CSF after dietary Q intake. Their passive transport through blood–CSF barrier or a de-conjugating mechanism within that barrier may be involved.

Received: August 14, 2014 Revised: November 19, 2014 Accepted: February 23, 2015

Keywords: Brain barriers / Cerebrospinal fluid / Metabolites / Quercetin

 1

Additional supporting information may be found in the online version of this article at the publisher’s web-site

Introduction

Due to their anti-oxidative properties, phytochemicals taken with food, for example quercetin (Q) (3,3 ,4 ,5,7pentahydroxyflavone), may play a protective role in the central nervous system and prevent its being damaged during uncontrolled oxidation processes; in other words, they can have a prophylactic effect in the case of neuro-degradation diseases caused by oxidative stress [1]. Nevertheless, there are also Correspondence: Professor Mariusz K. Piskula, Department of Chemistry and Biodynamics of Food, Institute of Animal Reproduction and Food Research, The Polish Academy of Sciences, Tuwima 10, 10–748 Olsztyn, Poland E-mail: [email protected] Fax: +48 89 524 01 24 Abbreviations: CSF, cerebrospinal fluid; IR, isorhamnetin; IS, internal standard; Q, quercetin  C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

results pointing to other mechanisms than anti-oxidative action that can lie behind the observed beneficial role of flavonoids consumption on brain function [2]. In any case, the knowledge of the metabolites of dietary flavonoids present on the site of action is the basic knowledge necessary for explanation of the phenomena concluded from epidemiological studies. The environment of the central nervous system is protected by the brain barriers, blood–brain barrier and blood– cerebrospinal barrier, whose aim is to ensure its constancy through protecting it against toxic substances as well as the results of sudden changes in the concentration of different blood components, such as hormones or xenobiotics, since in physiological conditions the degree/rate of the substances Colour Online: See the article online to view Fig. 1 in colour. www.mnf-journal.com

1089

Mol. Nutr. Food Res. 2015, 59, 1088–1094

passing from blood to the brain is not constant [3,4]. Changeability increases especially in pathological conditions, for example, HIV, Alzheimer’s and Parkinson’s diseases [5–7]. The choroid plexus of the brain ventricles, in which the blood–cerebrospinal barrier is localised, has already been used for studying the passing of substances to the brain, both in vivo and in vitro [8]. The aim of this work was simultaneous qualitative and quantitative analyses by determining quercetin metabolites in urine, blood plasma and cerebrospinal fluid (CSF) following oral administration of quercetin on an animal model.

2

in the dry skin for calculation of the dose was determined as described in detail previously [10]. After administration, the samples of CSF (about 0.5 mL/30 min), blood (5 mL) and total urine were collected in 30 min intervals throughout 12 h. Collection tubes for CSF and urine were kept in an ice bath during sampling and immediately after measurement of their volumes, aliquots of 500 ␮L of CSF and 50 ␮L of urine were stored at −80⬚C until assayed for quercetin metabolites. Blood samples were collected to heparinised tubes and centrifuged in two stages (500 × g, 15 min, 1000 × g, 10 min at 4⬚C); the obtained plasma was frozen at −80⬚C in 100 ␮L aliquots.

Material and methods

2.1 Animal model All animal procedures were conducted in accordance with the Polish Guide for the Care and Use of Animals (1997) and the study protocol approved by the Ethical Committee of the University of Warmia and Mazury in Olsztyn (No 73/2010/N). The experiment was performed on adult Polish Lowland sheep (3–4 years of age, 35.5–50.0 kg body weight; n=11), which were maintained indoors. Under general anaesthesia (pentobarbital sodium 8–12 mg/kg body mass intravenously (Vetbutal, Biowet, Puławy, Poland), and ketamine 6–10 mg/kg body mass intravenously (Bioketan, Biowet, Puławy, Poland)), stainless steel guide cannulas (1.2 mm od) were implanted under stereotaxic control into the third ventricle of the ewes’ brains 1 month before the experiment [9]. To wash out potential quercetin metabolites, before the experiment, the animals were kept for 3 days on hay with free access to water. Twenty-four hours before the experiment they were transferred to special single cages where they could lie down and have access to silage. To prevent the stress of social isolation, all ewes during the experiment had visual contact.

2.2 Study design and diets In the morning of the experiment day, to collect the CSF samples, a stainless steel catheter (1.0 mm od, 0.8 mm id) was carefully introduced into the previously implanted guide cannula and connected to a cannula–Eppendorf tube system joined to a PHD 2000 infuse/withdrawal pump (Hugo Sachs Elektronik Harvard Apparatus, Germany). The catheters were inserted into the jugular vein and urethra, respectively, to collect blood samples and total urine. Next, after the control samples of urine, blood and CSF were collected, the animals were administered 1 L of suspension of powdered dry onion skins in 5% (v/v) ethanol in water at the dose of 10 mg/kg bwt via intra-rumen intubation. The ethanol was used to improve the dispersion of onion dry skin in water as well the bioaccessibility of quercetin since in onion dry skin quercetin had 87.6% share and in total quercetin content. The content of total quercetin expressed as aglycone  C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

2.3 Determination of quercetin metabolites in urine, blood plasma and CSF 2.3.1 Analysis of quercetin metabolites with HPLC-MS/MS The quercetin metabolites (Q and IR aglycones and their conjugates) analysis was done on HPLC built up from LC20AD system equipped with column oven CTO-10ASVP (Shimadzu, Japan) set at 45⬚C combined with MS/MS mass spectrometer QTRAP 5500 (AB SCIEX, Canada) working in the ESI mode. Five micro-litres samples were loaded on the C18 XBridge 3.5␮m, 150 × 2.1 mm (Waters, USA) column with mobile phase flow set at 0.23 mL/min in a gradient composed of water/formic acid (99.9:0.1, phase A) and ACN/formic acid (99.9:0.1, phase B) as follows: 3–80–95–95–3% of phase B at 0–10–11–19–23 min, respectively. Qualitative analysis was performed based on the scanning of the biological matrix in negative mode within the range of 50–1250 m/z for quadrupoles and 50–1000 m/z for ion trap in the precursor ion scan mode, 301.1 m/z and 315.1 m/z for quercetin and isorhamnetin (IR), respectively. Also, scanning of fragmentation ions derived from the selected parent ions was conducted for the observation of all the ions formed by the disintegration of the parent ion. In addition, scanning of precursor ion and neutral particles was performed. Optimal identification of quercetin metabolites was achieved under the following conditions: curtain gas, 20 L/min; collision gas, 9 L/min; ionspray voltage, −4500 V; temperature, 550⬚C, one ion source gas, 55 L/min; two ion source gas, 70 L/min; de-clustering potential, −50 to 120 V; entrance potential, −10 V; collision energy, −30 to 70 eV, collision cell exit potential: −10 to 45 V. Quantitative analysis was made in accordance with our recent study [11] using multiple reaction monitoring method with appropriate external standards: 3,4’-O-di-beta-Q glucoside for Q and IR di-glucuronide, 3-O-beta-Q glucoside for Q glucuronide and Q sulphate, 3-O-beta-IR glucoside for IR glucuronide and IR sulphate. The calibration curve (the range of 1–100 nM) was linear with a correlation coefficient of 0.97. The results were corrected for the internal standard recovery factor that was within the range of 1.1–1.15. For www.mnf-journal.com

1090

W. Wiczkowski et al.

quantification, the calibration curves for urine (5–100 nM), blood plasma (1–80 nM) and CSF (0.1–50 nM) were used. Detection limits for injected sample with Q and IR were 0.1 nM at accuracy 97.3%. Depending on the type of sample (urine, blood plasma or CSF fluid), concentration of Q in it and the presence of accompanying compounds, different ways of its preparation for the HPLC-MS/MS analysis were applied.

Mol. Nutr. Food Res. 2015, 59, 1088–1094

ments for each animal ± SEM. To measure the differences between means of measurement points, a repeated ANOVA measure with Tukey’s post hoc test was applied. p < 0.05 was considered significant. The statistical analysis was performed using Statistica v. Ten (Stat Soft, USA).

3 2.3.2 Quercetin metabolites in urine After thawing, 50 ␮L urine samples were mixed with 10 ␮L of 50 ␮M fisetin methanol solution as the internal standard (IS), centrifuged at 13 200 × g for 20 min, diluted when necessary and 5 ␮L injected for HPLC analysis. 2.3.3 Quercetin metabolites in blood plasma After thawing, 100 ␮L plasma was mixed with 10 ␮L of 50 ␮M fisetin in methanol (IS), extracted with 400 ␮L methanol/formic acid (99:1; v/v) and 5 ␮L injected for HPLC analysis.

2.3.4 Quercetin metabolites in CSF After thawing, 500 ␮L CSF was mixed with 10 ␮L of 50 ␮M fisetin in methanol as the IS and extracted with 500 ␮L of methanol/formic acid (99:1; v/v) solution. The resulting mixture was subjected to 30 s vortexing and 30 s sonication followed by centrifugation at 13 200 × g for 20 min. Extraction was done in triplicate, each time collecting the supernatants that, after combining, were evaporated until dry in a nitrogen stream. The residue was dissolved in 50 ␮L of 60% (v/v) methanol in water with formic acid (999:1; v/v), centrifuged at 13 200 × g for 20 min and 5 ␮L injected for HPLC analysis.

2.4 Measurement of beta-glucuronidase activity in CSF The activity of beta-glucuronidase in CSF was measured by the rate of ␳-nitrophenol release from ␳-nitrophenyl-␤D-glucuronide, according to the slightly modified method described elsewhere [12]. The reaction mixture contained 0.3 mL of a substrate solution (5 mM) in 100 mM acetate buffer (pH 4.5) and 0.2 mL of the CSF. Incubation was carried out at 37⬚C and ␳-nitrophenol was quantified at ␭ = 400 nm after the addition of 2.5 mL of 0.25 M cold sodium carbonate to stop the reaction.

2.5 Statistical analysis The concentrations of Q metabolites in urine, blood plasma and CSF are expressed as the mean of individual measure C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Results

Analysis of dry onion skin administered to animals as dietary Q source demonstrated the presence of Q and its four derivatives with total content of quercetin calculated to aglycone as 22.18 mg Q/g dm. The main compound was Q aglycone with the share of 87.6% in total quercetin content expressed as aglycone, 4’-O-beta-Q glucoside (11.4%), 3-O-beta-Q glucoside and 4’-O-beta-IR glucoside with 0.4% share each and 3,4 O-di-beta-Q glucoside contributing 0.2% to total Q content. Quercetin from dry onion skin was rapidly absorbed, metabolised and excreted from the ewes’ systemic circulation. Analysing urine, blood plasma and CSF after intra-gastric application of Q to the animals, 16 metabolites were identified: two Q-di-glucuronides, two IR-di-glucuronides, three Qmono-glucuronides, three IR-mono-glucuronides, Q-sulphoglucuronide, IR-sulpho-glucuronide, Q-mono-sulphate, IRmono-sulphate and Q and IR aglycones. Mono-conjugated Q and IR were the main metabolites in urine (on average 96%) and blood plasma (on average 80%), while in CSF they accounted for only 12%, and this was consistent within 12 h of observation. It is worth noting that Q-monoglucuronides dominated in urine (on average 72%), while IR-mono-glucuronides did so in blood plasma (on average 44%; Supporting Information 1). Typical chromatograms of Q metabolites 5 h after Q administration in urine, blood plasma and CSF are shown in Fig. 1. Figure 2 presents the amounts of total Q excreted via the renal route within particular periods of time after the Q intake. The highest amounts of Q metabolites were eliminated between 3 and 6 h after Q administration Fig. 1A. In total, within 12 h the animals excreted 1.16% of administered Q via this route. In Fig. 3, changes in total Q concentration in blood plasma are shown. Q was found already 30 min following dry onion skin ingestion at first sampling time. The maximum concentration of Q (cmax = 33 ± 10 nmol/L) was reached 3.5 h after Q administration and remained at a similar level till 5 h, than continuously decreased till 2 ± 1 nmol/L at 12 h. Most of the metabolites (80%) were IR and Q mono-glucuronides and mono-sulphates (Supporting Information 1). It is worth noting that among mono-glucuronides, IR-mono-glucuronides dominated (Fig. 1B), while Q-mono-sulphate did so among mono-sulphates (data not shown), which points to effective methylation and glucuronidation of Q. Also, it is important to stress that there were in blood plasma free Q and IR, accounting for 14 and 5% of all Q metabolites, respectively. The highest concentration of total Q in CSF was noted at 5.5 h following dry onion skin administration (cmax = 0.30 ± www.mnf-journal.com

1091

Mol. Nutr. Food Res. 2015, 59, 1088–1094

Figure 1. Chromatograms of HPLCMS/MS in multi-reaction monitoring of quercetin metabolites analysis in: (A) urine, (B) blood plasma, (C) CSF – 5 h after oral administration of onion dry skin.

0.1 nmol/L) – 2h later than that in blood plasma (Fig. 4). Most importantly, the profile of quercetin metabolites in CSF differed from that in blood plasma; not Q and IR conjugates, but their aglycones were the main metabolites, with their average share of 55 and 33% in the total Q metabolites, respectively.  C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

4

Discussion

An ageing population together with growing problems with brain functioning and neurodegenerative disorders has directed attention towards the possibility of introducing www.mnf-journal.com

1092

W. Wiczkowski et al.

Figure 2. The amounts of total quercetin metabolites excreted with urine after intra-gastric application of onion dry skin (n = 11, × ± SEM), values labelled with different letters are significantly different (p < 0.05).

Figure 3. Total quercetin metabolites concentration in blood plasma after intra-gastric application of onion dry skin (n = 11, × ± SEM), values labelled with different letters are significantly different (p < 0.05).

preventive measures via food or its particular isolated components. Polyphenols, especially Q, have been the subject of many studies regarding their suitability in this respect. Knowledge of the food components’ metabolites present at action sites on the systemic level is a prerequisite for understanding the mechanisms of their biological activity. In a multiple sclerosis study on humans before blood collection and lumbar puncture to collect CSF, subjects drank 250 mL of green tea. Several catechin metabolites were found in their blood, but not in CSF [13]. The aspect of the dosage might be considered; however, when emodin and resveratrol were administered orally to rats at a dietary non-relevant dosage of 4 g/kg bwt, neither free compounds nor their conjugates were found in the brain [14], the same as for baicalin, baicalein and wogonin in other work [15]. There have been several studies aiming at demonstration of quercetin permeability through brain barriers in indirect ways, in vitro cell models or demonstrating the presence of Q in the brain tissue [16]. It was shown on the cellular model that  C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Mol. Nutr. Food Res. 2015, 59, 1088–1094

Figure 4. Changes of total quercetin metabolites concentration in CSF after intra-gastric application of onion dry skin (n = 11, × ± SEM), values labelled with different letters are significantly different (p < 0.05).

Q and other flavonoids have the potential to traverse blood– brain barrier and this is consistent with their lipophilicity [17]. Therefore, the polarity of catechins could be the reason why in humans, following green tea intake, catechin metabolites could not pass through blood–CSF barrier [13]. Here, to test the possibility of brain barrier penetration by food components, we experimented with Q, a flavonoid more lipophilic than flavan-3-ols in an animal model (sheep). Our model allowed us to continuously monitor Q metabolites’ presence in urine, blood plasma and CSF following oral administration of dry onion skin. The necessary surgical procedures were developed on the basis of stability of skull structures allowing precise cannula placement for longlasting collection of CSF without any side effects for a couple of months [18]. One might claim that pigs, due to their digestive tract similarities to humans, are a better animal model. However, their rapid growth rate makes it difficult to maintain collection apparatus for any length of time, which makes them an unsuitable animal model for a long-lasting collection of CSF [19]. Previous experiments with dietary interventions demonstrated that dry onion skin is a very convenient source of Q [20,21]. The presence of quercetin in urine, blood plasma and CSF was noted after intra-gastric dry onion skin administration already at the first sampling, which proves its efficient absorption, distribution and excretion (Figs. 2 to 4). It has to be stressed that it occurred despite the fact that the model animal used was a ruminant and during rumination there is a strong degrading metabolic activity of residual microbiota. This is probably the main reason why the concentration of quercetin metabolites in blood plasma and subsequently in CSF was on a relatively low level as compared to rats or humans [10, 21]. Paulke et al. [22] noted that after feeding St. John’s Wort extract to rats, the concentration of Q metabolites in the brain tissue was almost 50 times lower than that in plasma. In our study on sheep, the difference in concentrations between blood plasma and CSF was even twice as high. Distribution pattern of absorbed Q was studied in pigs www.mnf-journal.com

1093

Mol. Nutr. Food Res. 2015, 59, 1088–1094

and rats previously; it was also shown that the concentration of Q in the brain is much lower than that in other organs [23, 24]. A high variation in concentrations of Q metabolites was observed in the analysed biological fluids (Figs. 2 to 4). This is most likely due to variation in the microbiota profile among animals, especially when absorption and metabolism of ingested compounds strongly depend on the rumen metabolic capacity. In the work on urolitins, the product of gut microbiota metabolism of ellagic acid, it was demonstrated that volunteers can be stratified into three phenotypes depending on their metabolism [25]. The primary finding in this study was the demonstration that the main metabolites of dietary Q in CSF were aglycones of Q and IR, while in blood plasma their mono-glucuronides. On the basis of the results obtained, two possible mechanisms can be considered. First, that there must be a mechanism that leads to hydrolysis of conjugates towards aglycones, most likely via beta-glucuronidase activity. Recently, it was shown that this feature is common for micro-glial MG6 and brain capillary endothelial RBEC1 cell lines [16]. It suggests that the epithelial cells of the choroid plexus may have de-conjugation potential, however, this requires separate study. Second, passive diffusion of Q through the brain–CSF barrier. The Q partition coefficient [26] suggests the possibility of its blood–brain barrier penetration via passive diffusion [27] that was already demonstrated earlier [28]. Therefore, the presence of Q aglycone in CSF shown here cannot exclude this possibility for blood-CSF barrier. We rather exclude the possibility for de-conjugation of Q glucuronides in the CSF since we did not find beta-glucuronidase activity there. The presence of Q and IR aglycones in CSF implies their potential to interact with brain structures and exhibit their biological activity, including beneficial or toxic. Vafeiadou et al. [29] proposed that conjugation of Q to glutathione via glial cells observed in vitro can be a mechanism reducing its potential neurotoxicity. Also, the results of a dose–response study suggest that Q may be neuroprotective against amyloidbeta(1–42) toxicity by modulating oxidative stress at lower doses, while at higher doses they may also be toxic [30]. Moreover, in the cell model of human blood–brain barrier glucose uptake was decreased by Q, while its mono-glucuronides had no such effect [31]. Finally, the review by Ossola et al. [32] points out that Q aglycone is more neuroprotective and more beneficial in neural disorders than its conjugates, especially in cerebrovascular insults when blood–brain barrier permeability is increased. In this study on an animal model, we demonstrated the presence of Q and IR aglycones in CSF after dietary Q administration. Direct transfer of this finding to humans may be hampered by species differences. Nevertheless, it provides the basis for acceptance of some in vitro studies where Q or IR aglycones instead of their metabolites were used at physiologically relevant doses.

 C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This work was supported by the National Science Centre, Poland (project 798/N-COST/2010/0). The authors have declared no conflict of interest.

5

References

[1] Shirai, M., Kawai, Y., Yamanish, R., Kinoshita, T. et al., Effect of a conjugated quercetin metabolite, quercetin 3glucuronide, on lipid hydroperoxide-dependent formation of reactive oxygen species in differentiated PC-12 cells. Free Radic Res. 2006, 40, 1047–1053. [2] Rendeiro, C., Foley, A., Lau, V.-C., Ring, R. et al., Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLOS ONE. 2013, 8, e63535. [3] Skipor, J., Wasowska, B., Grzegorzewski, W., Zezula-Szpyra, A. et al., Transfer of dopamine by counter-current mechanism in the ewe changes with endocrine stage. Biog. Amines 2001, 16, 431–445. [4] Thiery, J.-C., Lomet, D., Schumacher, M., Liere, P. et al., Concentrations of estradiol in ewe cerebrospinal fluid are modulated by photoperiod through pineal-dependent mechanisms. J. Pineal Res. 2006, 41, 306–312. [5] Strazielle, N., Ghersi-Egea, J.-F., Ghiso, J., Dehouck, M.-P. et al., In vitro evidence that beta-amyloid peptide 1–40 diffuses across the blood-brain barrier and affects its permeability. J. Neuropat. Exp. Neurol. 2000, 59, 29–38. [6] Lippoldt, A., Knie, U., Liebner, S., Kalbacher, H. et al., Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood-brain barrier endothelial cells. Brain Res. 2000, 885, 251–261. [7] Farkas, E., De Jong, G.-I., de Vos, R.-A., Steur, E.-N. et al., Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease. Acta Neuropat. 2000, 100, 395–402. [8] Strazielle, N., Preston, J.-E., Transport cross the choroid plexuses In vivo and In vitro. Methods Mol. Med. 2003, 89, 291–304. [9] Skipor, J., Misztal, T., Piskula, M.-K., Wiczkowski, W. et al., Phytoestrogens and thyroid hormone levels in the cerebrospinal fluid of ewes fed with red clover silage. Small Rumin. Res. 2012, 102, 157–162 [10] Wiczkowski, W., Nemeth, K., Bucinski, A., Piskula, M.-K., Bioavailability of quercetin from fresh scales and dry skin of onion in rats. Pol. J. Food Nutr. Sci. 2003, 53, 95–99. [11] Wiczkowski, W., Szawara-Nowak, D., Topolska, J., Olejarz, K. et al., Metabolites of dietary quercetin: profile, isolation, identification, and antioxidant activity. J. Funct. Foods 2014, 11, 121–129. _ ary-Sikorska, E., Krol, ´ ´ ´ B. et al., [12] Juskiewicz, J., Zdunczyk, Z., Z Effect of the dietary polyphenolic fraction of chicory root, peel, seed and leaf extracts on caecal fermentation and blood parameters in rats fed diets containing prebiotic fructans. Brit. J. Nutr. 2011, 105, 710–720.

www.mnf-journal.com

1094

W. Wiczkowski et al.

Mol. Nutr. Food Res. 2015, 59, 1088–1094

[13] Zini, A., Del Rio, D., Stewart, A.-J., Mandrioli, J. et. al., Do flavan-3-ols from green tea reach the human brain? Nutr. Neuroscience 2006, 9, 57–61.

[23] de Boer, V.-C.-J., Dihal, A.-A., van der Woude, H., Arts, I.-C.W. et al., Tissue distribution of quercetin in rats and pigs. J. Nutr. 2005, 135, 1718–1725.

[14] Lin, S.-P., Chu, P.-M., Tsai, S.-Y., Wu, M.-H. et al., Pharmacokinetics and tissue distribution of resveratrol, emodin and their metabolites after intake of Polygonum cuspidatum in rats. J. Ethnopharmacol. 2012, 144, 671–676.

[24] Ishisaka, A., Ichikawa, S., Sakakibara, H., Piskula, M.-K. et al., Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic. Biol. Med. 2011, 51, 1329–1336.

[15] Hou, Y.-C., Lin, S.-P., Tsai, S.-Y., Ko, M.-H. et al., Flavonoid pharmacokinetics and tissue distribution after repeated dosing of the roots of Scutellaria baicalensis in rats. Planta Med. 2011, 77, 455–460. [16] Ishisaka, A., Muka,i R., Terao, J., Shibata, N. et al., Specific localization of quercetin-3-O-glucuronide in human brain. Arch. Biochem. Biophys. 2014, 557, 11–17. [17] Youdim, K.-A., Dobbie, M.-S., Kuhnle, G., Proteggente, A.R. et al., Interaction between flavonoids and the bloodbrain barrier: in vitro studies. J. Neurochem. 2003, 85, 180–192. [18] Skipor, J., Misztal, T., Szczepkowska, A., Thyroid hormones in third ventricular cerebrospinal fluid of adult female sheep during different periods of reproductive activity. Pol. J. Vet. Sci. 2010, 13, 587–595. [19] Clarke, I.-J., Two decades of measuring GnRH secretion. Reprod. Suppl. 2002, 59, 1–13. [20] Wiczkowski, W., Romaszko, J., Bucinski, A., Szawara-Nowak, D. et al., Quercetin from shallot (Allium cepa var. Aggregatum) is more bioavailable than its glucosides. J. Nutr. 2008, 138, 885–889. [21] Romaszko, E., Wiczkowski, W., Romaszko, J., Honke, J. et al., Exposure of breastfed infants to quercetin after consumption of a single meal rich in quercetin by their mothers. Mol. Nutr. Food Res. 2014, 58, 221–228. [22] Paulke, A., Schubert-Zsilavecz, M., Wurglics, M., Determination of St. John’s wort flavonoid-metabolites in rat brain through high performance liquid chromatography coupled with fluorescence detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2006, 17, 109–113.

 C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

´ ´ F.-A., Garc´ıa-Villalba, R., Gonzalez-Sarr´ [25] Tomas-Barber ´ an, ıas, A., Selma, M.-V. et al., Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric. Food Chem. 2014, 62, 6535– 6538. [26] Rothwell, J. A., Day, A. J., Morgan, M. R. A., Experimental determination of octan-water partition coefficients of quercetin and related flavonoids. J. Agric. Food Chem. 2005, 53, 4355– 4360. [27] Olendorf, W. H., Lipid solubility and drug penetration of the blood-brain-barrier. Proc. Soc. Exp. Biol. Med. 1974, 147, 813–816. [28] Youdim, K. A., Qaiser, M. Z., Begley, D. J., Rice-Evans, C. A. et al., Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic. Biol. Med. 2004, 36, 592–604. [29] Vafeiadou, K., Vauzour, D., Rodriguez-Mateos, A., Whiteman, M. et al., Glial metabolism of quercetin reduces its neurotoxic potential. Arch. Biochem. Biophys. 2008, 478, 195– 200. [30] Ansari, M.-A., Abdul, H.-M., Joshi, G., Opii, W.-O. et al., Protective effect of quercetin in primary neurons against A␤(142): relevance to Alzheimer’s disease. J. Nutr. Biochem. 2009, 20, 269–275. ´ [31] Meireles, M., Martel, F., Araujo, J., Santos-Buelga, C. et al., Characterization and modulation of glucose uptake in a human blood-brain barrier model. J. Membr. Biol. 2013, 246, 669–677. ¨ ainen, ¨ ¨ ¨ P.-T., The multiple [32] Ossola, B., Ka¨ ari T.-M., Mannist o, faces of quercetin in neuroprotection. Expert Opin. Drug Saf. 2009, 8, 397–409.

www.mnf-journal.com

Quercetin and isorhamnetin aglycones are the main metabolites of dietary quercetin in cerebrospinal fluid.

Reports on the protective effect of certain foods on brain functions are numerous; however, the permeability of the brain barriers by food components ...
379KB Sizes 0 Downloads 7 Views