Arch. Pharm. Res. DOI 10.1007/s12272-014-0409-2

RESEARCH ARTICLE

Differential effects of quercetin glycosides on GABAC receptor channel activity Hyeon-Joong Kim • Byung-Hwan Lee • Sun-Hye Choi • Seok-Won Jung • Hyun-Sook Kim • Joon-Hee Lee • Sung-Hee Hwang Mi-Kyung Pyo • Hyoung-Chun Kim • Seung-Yeol Nah



Received: 17 January 2014 / Accepted: 6 May 2014 Ó The Pharmaceutical Society of Korea 2014

Abstract Quercetin, a representative flavonoid, is a compound of low molecular weight found in various colored plants and vegetables. Quercetin shows a wide range of neuropharmacological activities. In fact, quercetin naturally exists as monomer-(quercetin-3-O-rhamnoside) (Rham1), dimer-(Rutin), or trimer-glycosides [quercetin-3(2G-rhamnosylrutinoside)] (Rham2) at carbon-3 in fruits and vegetables. The carbohydrate components are removed after ingestion into gastrointestinal systems. The role of the glycosides attached to quercetin in the regulation of caminobutyric acid class C (GABAC) receptor channel activity has not been determined. In the present study, we Electronic supplementary material The online version of this article (doi:10.1007/s12272-014-0409-2) contains supplementary material, which is available to authorized users. H.-J. Kim  B.-H. Lee  S.-H. Choi  S.-W. Jung  H.-S. Kim  S.-Y. Nah (&) Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University, Seoul 143-701, Korea e-mail: [email protected] J.-H. Lee Department of Physical Therapy, College of Health Science, Cheongju University, Chungbuk 360-764, Korea S.-H. Hwang Department of Pharmaceutical Engineering, Sangji University, Wonju 220-702, Korea M.-K. Pyo International Ginseng and Herb Research Institute, Geumsan 312-804, Korea H.-C. Kim Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea

examined the effects of quercetin glycosides on GABAC receptor channel activity by expressing human GABAC alone in Xenopus oocytes using a two-electrode voltage clamp technique and also compared the effects of quercetin glycosides with quercetin. We found that GABA-induced inward current (IGABA) was inhibited by quercetin or quercetin glycosides. The inhibitory effects of quercetin and its glycosides on IGABA were concentration-dependent and reversible in the order of Rutin & quercetin & Rham 1 [ Rham 2. The inhibitory effects of quercetin and its glycosides on IGABA were noncompetitive and membrane voltage-insensitive. These results indicate that quercetin and its glycosides regulate GABAC receptor channel activity through interaction with a different site from that of GABA, and that the number of carbohydrate attached to quercetin might play an important role in the regulation of GABAC receptor channel activity. Keywords Quercetin glycosides  GABAC receptor  Differential regulations

Introduction Three classes of c-aminobutyric acid (GABA) receptors have been typified based on their pharmacology, namely GABAA, GABAB, and GABAC receptors (Macdonald and Olsen 1994). GABAA and GABAC receptors are ligandgated chloride (Cl-) channels, while GABAB receptors are one of the metabotropic receptors coupled to G proteins (Bormann and Feigenspan 1995). GABAA receptors consist of heteromeric proteins formed by different subunits: a1-6, b1-4, c1-3, d, e, p, and h (Bormann and Feigenspan 1995), whereas GABAC receptors, which are also known as the GABAA-q receptors, can be homomeric or heteromeric,

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H.-J. Kim et al. Fig. 1 Chemical structures of quercetin and its glycosides. a Quercetin b quercetin-3-Orhamnoside (Rham 1), c Rutin, and d quercetin-3-(2Grhamnosylrutinoside) (Rham 2)

and might be exclusively composed of q subunits (q1, q2, and q3) (Polenzani et al. 1991). GABAC receptors are located primarily on the axon terminals of the bipolar cells of the retina (Enz et al. 1996). GABA acts on GABAC receptors of the bipolar cells to regulate the release of excitatory neurotransmitter from these cells (Lukasiewicz and Werblin 1994). Quercetin, one of the flavonoids, and quercetin glycosides are compounds of low molecular weight that are mainly found in apples, tomatoes, gingko, other red fruits, and vegetables (Havsteen 2002). In fruit and vegetables, quercetin naturally exists as monomer- (quercetin-3-Orhamoside) (Rham 1), dimer-(Rutin), or trimer-glycosides [quercetin-3-(2G-rhamnosylrutinoside)] (Rham 2) at carbon-3, and in other glycosidic forms (Azevedo et al. 2013). A line of evidence suggests that quercetin glycosides, in addition to quercetin, also exert physiological or pharmacological effects (Azevedo et al. 2013). Although it has been reported in previous report that various flavonoids including quercetin regulate GABAc q1 receptor channel activity (Goutman et al. 2003), it is unknown how quercetin glycosides affect GABAC receptor channel activity. Therefore, in the present study we examined the effects of

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quercetin glycosides and also compared quercetin with that of quercetin glycosides on the regulation of human GABAC q1 receptor channel activity expressed in Xenopus oocytes using a two-electrode voltage clamp technique. We observed that applications of quercetin or its glycosides reversibly inhibited GABA-induced current (IGABA) in oocytes expressing human GABAC q1 receptor in the order of Rutin & quercetin & Rham 1 [ Rham 2. The inhibition of IGABA by quercetin and quercetin glycosides was noncompetitive and voltage-insensitive. These results indicate that quercetin glycosides might regulate human GABAC in different ways. We further discuss the role of the carbohydrate components of quercetin glycosides in the regulation of GABAC q1 receptor channel activity.

Materials and methods Materials Figure 1 shows the structures of quercetin and its glycosides used in this study. They were dissolved in dimethyl sulfoxide (DMSO) and were diluted with bath medium

Differential effects of quercetin glycosides

before use; the final DMSO concentration was less than 0.01 %. cDNAs containing human GABA q1 receptor were kindly provided by Dr. H. Betz (Max-Plank-Institute, Germany). Quercetin and other chemical agents were purchased from Sigma-Aldrich (St. Louis, MO, USA). Quercetin glycosides were purified from Magnolia obovata (Pyo et al. 2002). Oocyte preparation Xenopus laevis frogs were purchased from Xenopus I (Ann Arbor, MI, USA). Xenopus laevis care and handling were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, USA. Frogs underwent surgery only twice, separated by at least 3 weeks. To isolate oocytes, frogs were anesthetized with an aerated solution of 3-amino benzoic acid ethyl ester. Oocytes were separated by treatment with collagenase with gentle shaking for 2 h in CaCl2-free medium containing 82.5 mM NaCl, 2 mM KCl, 1 mM MgCl2, 5 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 2.5 mM sodium pyruvate, 100 units penicillin/mL, and 100 lg streptomycin/ mL. Only stage 5 or 6 oocytes were collected and maintained at 18 °C with continuous gentle shaking in ND96 medium (96 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, and 5 mM HEPES, pH 7.5) supplemented with 0.5 mM theophylline and 50 lg gentamycin/mL. All solutions were changed every day. All experiments were performed within 2–4 d following isolation of the oocytes.

templates with an in vitro transcription kit (mMessage mMachine; Ambion; Austin, TX, USA) using a T3 polymerase. The cRNA was dissolved in RNase-free water at a final concentration of approximately 1 lg/lL and stored at -70 °C until use. Oocytes were injected with H2O and human GABAC q1 receptor cRNAs (5–10 ng) by using a Nanoject Automatic Oocyte Injector (Drummond Scientific; Broomall, PA, USA). The injection pipette was pulled from the glass capillary tubing used for recording electrodes and the tip was broken to ca. 20-mm-OD. Data analysis To obtain the concentration–response curve for GABAinduced current in the presence of quercetin or its glycosides, the observed peak amplitudes were normalized and plotted and then fitted to the following Hill equation using Origin software (Northampton, MA, USA): y/ymax = [A]n/ ([A]n ? [IC50]n), where y, % inhibition at given concentration of quercetin or its glycosides; ymax, % of maximal inhibition; IC50 is the concentration of quercetin producing half-maximum inhibition of the control response to GABA; [A] is the concentration of quercetin or its glycosides; and n is the interaction coefficient. All values are presented as mean ± standard error of the mean (SEM). The differences between means of control and quercetin or its glycosides treatment data were analyzed using unpaired Student’s ttests. A value of p \ 0.05 was considered statistically significant.

Oocyte recording

Results

A single oocyte was placed in a small Plexiglas net chamber (0.5 mL) and was constantly superfused with ND96 medium. The microelectrodes were filled with 3 M KCl and had a resistance of 0.2–0.7 MX. Two-electrode voltage-clamp recordings were taken at room temperature with Oocyte Clamp (OC-725C; Warner Instrument; Hamden, CT, U.S.A.) with Digidata 1200A (Axon Instruments; Union City, CA, USA). For most of the electrophysiological experiments, the oocytes were clamped at a holding potential of -80 mV and 300-ms voltage steps for the current–voltage relationship were applied from -100 to ?40 and ?60 mV for the GABAC receptor [Lee et al. 2005, 2007].

Effects of quercetin glycosides on human GABAC receptor-mediated currents

cRNA preparation of the GABAC q1 receptor and microinjection The cDNAs encoding the human GABAC q1 receptor were linearized by digestion with appropriate restriction enzymes. The cRNAs were transcribed from linearized

As previously reported, we observed that application of GABA (1.5 lM) to bathing medium induced a large inward current (IGABA) in oocytes injected with cRNAs encoding the GABAC q1 receptor (Fig. 2a). Picrotoxin (10 lM), which is a GABAC receptor antagonist, almost blocked the GABAC channel activity (data not shown), indicating that the GABAC q1 receptors were functionally expressed in this system, as previously reported (Enz et al. 1996, Lukasiewicz and Werblin 1994). Next, we examined the effects of quercetin or quercetin glycosides on IGABA. Quercetin and its glycosides (100 lM each) themselves had no effect on oocytes expressing the GABAC q1 receptor at a holding potential of ?80 mV. However, coapplication of quercetin or its glycosides with GABA inhibited IGABA in a reversible manner (Fig. 2a, n = 15 from three different frogs) (Fig. 2a, b) by 79.6 ± 9.4, 83.8 ± 7.1 %, 90.8 ± 4.3 %, and 48.7 ± 14.5 % for

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Fig. 2 Effects of Quercetin and its glycosides on the human caminobutyric acid class C (GABAC) receptor channel in Xenopus oocytes after GABAC receptor subunit cRNA injection. a The inward currents were recorded at a holding potential of -80 mV. GABA (1.5 lM) induced a large inward current in oocytes expressing the GABAC receptor. Co-treatment of 100 lM of quercetin, quercetin-3O-rhamnoside (Rham 1), Rutin (Rutin), and quercetin-3-(2Grhamnosylrutinoside) (Rham 2) with GABA inhibited GABA-induced inward current (IGABA) in the representative trace. The representative trace shows that both quercetin and its glycosides inhibit IGABA. b Cotreatment of quercetin and its glycosides with GABA exhibits differential inhibitory effects in summary histograms. *p \ 0.01, compared to quercetin and other quercetin glycosides. Each point represents the mean ± SEM (n = 9–12 oocytes/group)

quercetin, Rham1, Rutin, and Rham2, respectively (Fig. 2b). Thus, the inhibitory potency for IGABA was in the order of Rutin & quercetin & Rham 1 [ Rham 2, and the degree of glycosylation of quercetin affected the GABAC q1 receptor channel current inhibition (Fig. 2b). Concentration-dependent effect of quercetin glycosides on IGABA Quercetin and its glycosides inhibited IGABA in a concentration-dependent manner (Fig. 3a). The IC50 values for IGABA were 3.9 ± 0.2, 4.0 ± 0.1, 3.2 ± 0.2, and 4.7 ± 0.5 lM for quercetin, Rham1, Rutin, and Rham2, respectively (n = 8 from three different frogs for each

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Fig. 3 Concentration-dependent effects of quercetin and its glycosides on the human c-aminobutyric acid class C (GABAC) receptor. a IGABA in oocytes expressing the GABAC receptor was elicited at a holding potential of -80 mV for 30 s in the presence of 1.5 lM GABA, and then the indicated concentrations of quercetin and its glycosides were co-applied with GABA. The solid lines were fit by using the Hill equation. Each point represents the mean ± SEM (n = 9–12 oocytes/group). *p \ 0.05; **p \ 0.01, compared to quercetin, Rhim 1, and Rutin. b Dose–response relationship for caminobutyric acid (GABA) and its glycosides in oocytes expressing the human GABAC receptor. Co-treatment of 100 lM of quercetin, quercetin-3-O-rhamnoside (Rham1), Rutin (Rutin), and quercetin-3(2G-rhamnosylrutinoside) (Rham2) with GABA shows each graph. Concentration-dependent effects of GABA on quercetin- and its glycosides-mediated inhibition of IGABA. Each point represents the mean ± SEM (n = 10–11 oocytes/group). *p \ 0.05; **p \ 0.01, compared to quercetin alone at indicated concentration

point) (Fig. 3a). The IC50 value for Rham 2 on the GABAC q1 receptor channel regulation was significantly higher than that of quercetin (*p \ 0.05, compared to quercetin alone). Interestingly, it appears that the increase in the IC50 value was related to the extent of quercetin glycosylation. In addition, it seems that the co-application of quercetin or quercetin glycosides with GABA reduces the efficacy for

Differential effects of quercetin glycosides

GABA-mediated GABAC q1 receptor activations. These results demonstrate the possibility that quercetin, rather than quercetin glycosides, is the main regulator of GABAC q1 receptor channel activity, indicating that quercetin glycosylation did affect GABAC q1 receptor channel regulation. Quercetin glycosides inhibit IGABA non-competitively To further study the mechanism by which quercetin and quercetin glycosides inhibit IGABA, we first analyzed the effects of quercetin and its glycosides on IGABA evoked by different GABA concentrations in oocytes expressing the GABAC q1 receptors (Fig. 3b). Co-application of quercetin or its glycosides for 30 s with different concentrations of GABA did not significantly shift the dose–response curve of GABA. The EC50 values were 1.1 ± 0.1, 2.1 ± 0.2, 2.0 ± 0.2, 2.4 ± 0.1, and 1.8 ± 0.2 lM for GABA alone, GABA ? quercetin, GABA ? Rham1, GABA ? Rutin, and GABA ? Rham2, respectively, and the Hill coefficients were 1.7 ± 0.1, 1.7 ± 0.2, 1.8 ± 0.3, 1.5 ± 0.1, and 2.0 ± 0.3, respectively. Thus, quercetin, Rham1, Rutin, and Rham2 significantly inhibited the IGABA elicited by 69.1 ± 2.2, 61.8 ± 2.3, 49.0 ± 1.1 and 87.3 ± 2.7 lM of GABA, which are independent of the GABA concentrations (n = 9–12 from three different frogs) (Fig. 3b). These results indicate that quercetin and quercetin glycosides inhibit the IGABA in a non-competitive manner. Current–voltage relationships in quercetin glycosides mediated human GABAC receptor regulations In experiments of the current–voltage relationship, the membrane potential was held at -80 mV, and 300 ms voltage ramps were applied from -100 to ?40 mV for the GABAC q1 receptor. In the absence of GABA, the inward current at -100 mV was 0.1 lA and the outward current at ?40 mV was 0.1–0.4 lA in the GABAC q1 receptor (data not shown). The addition of GABA to the bathing medium resulted in an increase of the inward current at an approximately 20 mV more negative potential. In contrast, at an approximately 20 mV more positive potential, GABA led to a large increase in outward current. Co-application of quercetin and quercetin glycosides with GABA inhibited both the inward and outward currents more than those induced by GABA treatment alone. The reversal potential was also near -20 mV in the GABA alone, GABA ? quercetin, or GABA ? quercetin glycosides treatments (Fig. 4a). The inhibitory effects of quercetin and its glycosides on IGABA in oocytes expressing the GABAC q1 receptor were not membrane voltage-sensitive. Thus, quercetin, Rham1, Rutin, and Rham2 inhibited IGABA by 76.4 ± 3.8 %, 80.5 ± 4.6 %, 84.8 ± 3.7 %, and 45.1 ± 3.6 %, respectively, at

Fig. 4 Current-voltage relationship and voltage-independent inhibition by quercetin and its glycosides. a The representative current– voltage relationship was obtained using voltage ramps from -100 and ?40 mV for a 300-ms duration. Voltage steps were applied before and after application of 1.5 lM GABA in the absence or presence of 30 lM quercetin, Rham1, Rutin, and Rham2. Each point represents the mean ± SEM (n = 10–12 oocytes in three different frogs). b Voltage-independent inhibition of IGABA in the GABAC receptors by quercetin and its glycosides (30 lM each). The values were obtained from the receptors in the presence of 1.5 lM GABA at the indicated membrane holding potentials. Each point represents the mean ± SEM (n = 8–12/group)

-120 mV, and by 7.9 ± 3.1 %, 77 ± 3.9 %, 83.5 ± 4.7 %, and 45.1 ± 3.4 %, respectively, at -30 mV (n = 10–12, from three different frogs). These results indicate that quercetin and its glycosides inhibit IGABA in a voltageinsensitive manner.

Discussion Quercetin glycosides, which are natural forms of quercetin, are flavonoids mainly found in colored fruit and vegetables (Fig. 1) (Miksicek 1993). Quercetin exhibits a variety of in vivo biological effects (Kandaswami and Middleton 1994, Harborne and Williams 2000), including analgesia,

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motility and sleep (Speroni and Minghetti 1988; Picq et al. 1991; Oyama et al. 1994), anticonvulsant, sedative, and anxiolytic effects (Marder et al. 1996; Medina et al. 1997; Griebel et al. 1999; Sine and Taylor 1982). However, the in vitro cellular mechanisms underlying the in vivo actions of quercetin glycosides are not well studied. Most of quercetin in fruit and vegetables exist as quercetin glycosides. In addition, the in vitro and in vivo pharmacological and physiological roles of quercetin glycosides in nervous systems are relatively unknown. Here, we demonstrated that: (1) Rutin with two carbohydrates was a more potent inhibitor of IGABA than other quercetin glycosides and Rutin action was comparable to quercetin, whereas Rham2, which has three carbohydrates, was a less potent inhibitor of IGABA than quercetin, Rham1, and Rutin; (2) quercetin glycosides inhibited IGABA in a concentration-dependent and reversible manner; and (3) quercetin glycoside-induced inhibition of IGABA was non-competitive and was voltage insensitive in oocytes expressing human GABAC receptors. Dietary quercetin glycosides are usually metabolized in three ways. First, they remain in intact quercetin or are conjugated with glucoses or sulfates to produce quercetin glucuronides or quercetin sulfates in the blood stream; second, quercetin glycosides are deglycosylated to quercetin aglycone; and third, they remain as quercetin glycosides without further metabolism (Havsteen 2002; Azevedo et al. 2013). Interestingly, quercetin glucuronides or quercetin sulfates keep their biological activity as antioxidants if they are conjugated with carbon-3 but not carbon-4. These results indicate that the antioxidant effects of quercetin and its metabolites arise from the catechol ring of quercetin’s backbone structure (Fig. 1) (Havsteen 2002). However, it is unknown whether the unmodified backbone structure of quercetin is also involved in ligand-gated ion channel activity regulation. In previous reports, we demonstrated that quercetin and quercetin glycosides regulate glycine and 5-hydroxytryptamine receptor channel (5-HT3) activity in a differential manner. Applications of quercetin and its glycosides inhibited the glycine-induced current (IGly) in the order quercetin [ Rutin [ Rham 1 [ Rham 2. Applications of quercetin and its glycosides inhibited the 5-HT-induced current (I5-HT) in the order Rham 2 [ quercetin [ Rutin [ Rham 1. In the present study, we found that Rutin, which has two carbohydrates, was more potent than quercetin and other quercetin glycosides in the inhibition of IGABA. The previous and present studies show that the backbone structure of quercetin is required for ligand-gated ion channel regulation, and that carbohydrates attached to the backbone structure of quercetin might also be necessary for the differential regulation of ligand-gated ion channel activity. Thus, Rutin could be one of the main candidates for the regulation of GABAC q1 receptor channel activity if it is not deglycosylated after intake.

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It has been reported that picrotoxin, a GABAA receptor antagonist, also blocked GABAC q1 receptor channel activity (Goutman and Calvo 2004). Picrotoxin causes the convulsion by inhibition of GABAA receptor (Nilsson and Eyrich 1950). Comparing with picrotoxin, it is unlikely that quercetin glycosides-induced inhibition of IGABA induces the convulsion like picrotoxin, since quercetin glycosides are not a full glycine receptor antagonist compared to alkaloid picrotoxin (Nilsson and Eyrich 1950) and there is no report that quercetin glycosides including quercetin induces a convulsion. However, quercetin glycosidesmediated inhibition of IGABA might be coupled to depolarization in neurons that express GABACq1 receptors and affect the synaptic transmissions. The GABAC receptor is expressed in certain limited areas of the brain such as the retina and the thalamus, hippocampus, and pituitary glands (Enz et al. 1996, Lukasiewicz and Werblin 1994; Boue-Grabot et al. 2000, Jansen et al. 2000; Chebib 2004). GABAC receptors are abundant in the eye (Enz et al. 1996). In the retina, a major role of the GABAC receptor may be visual processing. It is known that GABAs released in the absence of light from cones or rods of the retina regulate retinal bipolar neurons, which are located at postsynaptic sites (Enz et al. 1996). Currently, there is no report on effects of quercetin or quercetin glycosides in visual processing. Recent reports show that quercetin attenuate diabetic cataract (Kyselova et al. 2004, Stefek and Karasu 2011). In addition, quercetin increased non-rapid eye movement (non-REM) sleep during dark period in rats via GABAA receptor regulations, while it significantly decreased REM sleep (Kambe et al. 2010). Thus, although quercetin’s role in visual systems is rudimentary, we firs show a possibility that quercetin glycosides-mediated regulation of IGABA via GABAC receptor is directly or indirectly linked to regulation of visual systems including visual processing. Further studies will be required to determine how in vitro quercetin glycosides-mediated inhibition of IGABA is coupled to GABAC receptor-related beneficial effects in eye. In summary, we have revealed that quercetin glycosides inhibit IGABA in oocytes expressing the human GABAC receptor. Rutin was a more potent inhibitor of IGABA than Rham2, indicating that the number of glycosylated carbohydrates attached to quercetin might significantly influence its differential effects on IGABA. Acknowledgments This work was supported by the Basic Science Research Program (2011-0021144) and the Priority Research Centers Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education, Science, and Technology (2012-0006686) and by the BK21 plus project fund to S.-Y. Nah.

References Azevedo, M.I., A.F. Pereira, R.B. Nogueira, F.E. Rolim, G.A. Brito, D.V. Wong, R.C. Lima-Ju´nior, R. de Albuquerque Ribeiro, and

Differential effects of quercetin glycosides M.L. Vale. 2013. The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Molecular Pain 9(1): 53. Bormann, J., and A. Feigenspan. 1995. GABAC receptors. Trends in Neurosciences 18(12): 9–515. Boue-Grabot, E., A. Taupignon, G. Tramu, and M. Garret. 2000. Molecular and electrophysiological evidence for a GABAc receptor in thyrotropin-secreting cells. Endocrinology 141: 1627–1632. Chebib, M. 2004. GABAC receptor ion channels. Clinical and Experimental Pharmacology and Physiology 31: 800–804. Enz, R., J.H. Brandsta¨tter, H. Wa¨ssle, and J. Bormann. 1996. Immunocytochemical localization of the GABAc receptor rho subunits in the mammalian retina. Journal of Neuroscience 16(14): 90–4479. Goutman, J.D., and D.J. Calvo. 2004. Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA rho 1 receptor. British Journal of Pharmacology 141(4): 27–717. Goutman, J.D., M.D. Waxemberg, F. Don˜ate-Oliver, P.E. Pomata, and D.J. Calvo. 2003. Flavonoid modulation of ionic currents mediated by GABAA and GABAC receptors. European Journal of Pharmacology 461(2–3): 79–87. Griebel, G., G. Perrault, S. Tan, H. Schoemaker, and D.J. Sanger. 1999. Pharmacological studies on synthetic flavonoids: comparison with diazepam. Neuropharmacology 38(7): 77–965. Harborne, J.B., and C.A. Williams. 2000. Advances in flavonoid research since 1992. Phytochemistry 55(6): 481–504. Havsteen, B.H. 2002. The biochemistry and medical significance of the flavonoids. Pharmacology and Therapeutics 96(2–3): 67–202. Jansen, A., M. Hoepfner, K.H. Herzig, E.O. Riecken, and H. Scheru¨bl. 2000. GABA(C) receptors in neuroendocrine gut cells: a new GABA-binding site in the gut. Pflugers Archiv. European Journal of Physiology 441: 294–300. Kambe, D., M. Kotani, M. Yoshimoto, S. Kaku, S. Chaki, and K. Honda. 2010. Effects of quercetin on the sleep–wake cycle in rats: involvement of gamma-aminobutyric acid receptor type A in regulation of rapid eye movement sleep. Brain Research 1330: 8–83. Kandaswami, C., and E. Middleton Jr. 1994. Free radical scavenging and antioxidant activity of plant flavonoids. Advances in Experimental Medicine and Biology 66: 76–351. Kyselova, Z., M. Stefek, and V. Bauer. 2004. Pharmacological prevention of diabetic cataract. Journal of Diabetes and Its Complications 18(2): 40–129. Lee, B.H., S.M. Jeong, J.H. Lee, J.H. Kim, I.S. Yoon, J.H. Lee, S.H. Choi, S.M. Lee, C.G. Chang, H.C. Kim, Y. Han, H.D. Paik, Y. Kim, and S.Y. Nah. 2005. Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I. Molecules and Cells 20(1): 69–73.

Lee, B.H., J.H. Lee, I.S. Yoon, J.H. Lee, S.H. Choi, M.K. Pyo, S.M. Jeong, W.S. Choi, T.J. Shin, S.M. Lee, H. Rhim, Y.S. Park, Y.S. Han, H.D. Paik, S.G. Cho, C.H. Kim, Y.H. Lim, and S.Y. Nah. 2007. Human glycine alpha1 receptor inhibition by quercetin is abolished or inversed by alpha267 mutations in transmembrane domain 2. Brain Research 1161: 1–10. Lukasiewicz, P.D., and F.S. Werblin. 1994. A novel GABA receptor modulates synaptic transmission from bipolar to ganglion and amacrine cells in the tiger salamander retina. Journal of Neuroscience 14: 23–1213. Macdonald, R.L., and R.W. Olsen. 1994. GABAA receptor channels. Annual Review of Neuroscience 17: 569–602. Marder, M., H. Viola, C. Wasowski, C. Wolfman, P.G. Waterman, B.K. Cassels, J.G. Medina, and A.C. Paladini. 1996. 6-Bromoflavone, a high affinity ligand for the central benzodiazepine receptors is a member of a family of active flavonoids. Biochemical and Biophysical Research Communications 223(2): 9–384. Medina, J.H., H. Viola, C. Wolfman, M. Marder, C. Wasowski, D. Calvo, and A.C. Paladini. 1997. Overview—flavonoids: a new family of benzodiazepine receptor ligands. Neurochemical Research 22(4): 25–419. Miksicek, R.J. 1993. In situ localization of the estrogen receptor in living cells with the fluorescent phytoestrogen coumestrol. Journal of Histochemistry and Cytochemistry 41(6): 10–801. Nilsson, E., and B. Eyrich. 1950. On treatment of barbiturate poisoning. Acta Medica Scandinavica 137(6): 381–389. Oyama, Y., P.A. Fuchs, N. Katayama, and K. Noda. 1994. Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca2?-loaded brain neurons. Brain Research 635(1–2): 9–125. Picq, M., S.L. Cheav, and A.F. Prigent. 1991. Effect of two flavonoid compounds on central nervous system. Analgesic activity. Life Sciences 49(26): 88–1979. Polenzani, L., R.M. Woodward, and R. Miledi. 1991. Expression of mammalian gamma-aminobutyric acid receptors with distinct pharmacology in Xenopus oocytes. Proceedings of the National Academy of Sciences of the United States of America 88(10): 22–4318. Pyo, M.K., Y.K. Koo, and H.S. Yun-Choi. 2002. Anti-platelet effect of the phenolic constituents isolated from the leaves of Magnolia obovata. Nat Prod Sci 8(4): 147–151. Sine, S.M., and P. Taylor. 1982. Local anesthetics and histrionicotoxin are allosteric inhibitors of the acetylcholine receptor. Studies of clonal muscle cells. Journal of Biological Chemistry 257(14): 104–8106. Speroni, E., and A. Minghetti. 1988. Neuropharmacological activity of extracts from Passiflora incarnata. Planta Medica 54(6): 91–488. Stefek, M., and C. Karasu. 2011. Eye lens in aging and diabetes: effect of quercetin. Rejuvenation Res 14(5): 34–525.

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Differential effects of quercetin glycosides on GABAC receptor channel activity.

Quercetin, a representative flavonoid, is a compound of low molecular weight found in various colored plants and vegetables. Quercetin shows a wide ra...
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