Biomolecules & Therapeutics 2019; 27(6): 584-590  https://doi.org/10.4062/biomolther.2019.149
Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors
Tae-Ho Kim1, Raly James Custodio2, Jae Hoon Cheong2, Hee Jin Kim2,* and Yi-Sook Jung1,3,*
1College of Pharmacy, Ajou University, Suwon 16499,
2Uimyoung Research Institute in Neuroscience, Sahmyook University, Seoul 01795,
3College of Pharmacy, Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 16499, Republic of Korea
E-mail: yisjung@ajou.ac.kr (Jung YS), msheejin@gmail.com (Kim HJ)
Tel: +82-31-219-3444 (Jung YS), +82-2-3399-1609 (Kim HJ)
Fax: +82-31-219-3435 (Jung YS), +82-2-2339-1619 (Kim HJ)
Received: September 16, 2019; Revised: October 2, 2019; Accepted: October 4, 2019; Published online: October 24, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer’s disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptor-benzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC50 of 1.19, 0.84 μg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

Keywords: Luteolin, Sleep, Electroencephalogram, Adenosine A1 receptor, Adenosine A2A receptor, Insomnia
INTRODUCTION

Sleep is essential to maintain human health and well-being, and sleep disturbances can affect negatively both physical and psychological health (Krueger et al., 2008). Studies have shown that the prevalence of sleep disorders increase with age so that almost up to 50% of elderly people (>65 yr) suffer from sleep disturbances (Rashid et al., 2012). Thus, improvement of sleep quality, especially among elderly people, is considered to be essential care issues. The most common case among sleep disturbances that affect elderly people is insomnia worldwide (Neikrug and Ancoli-Israel, 2010). To improve sleep quality, most elderly people with insomnia are known to take hypnotic agents such as benzodiazepines, antidepressants, and antihistamines (Bloom et al., 2009). However, long-term use of these drugs have been demonstrated to often result in tolerance and dependence, thus leading to withdrawal syndrome following their discontinuation (Rudolph and Knoflach, 2011).

To overcome the adverse effects of sleep medications, special attention has been recently focused on alternative sleep aids such as natural and herbal therapies (Cho et al., 2012). According to the recent report, over 1.6 million American people have used alternative medications to manage insomnia (Pearson et al., 2006). In addition, there has been increasing needs for a new class of alternative natural products with sleep improving effects (Adib-Hajbaghery and Mousavi, 2017). Phytochemicals are known as plant-derived biologically active ingredients, and they are responsible for the pharmacological roles of plant extracts (Nabavi et al., 2015a). Among them, especially flavonoids, a large group of plant secondary metabolites, are the most effective chemical classes with various pharmacological effects, such as antioxidant, anti-inflammatory, anticancer and neuroprotective effects (Nabavi et al., 2015b). Flavonoids are ubiquitously found in the human diet and often found abundantly in various medicinal plants (Wasowski and Marder, 2012).

Among various flavonoids, apigenin and chrysin have been known to have hypnotic effects with benzodiazepine (BDZ)-binding mechanisms (Wolfman et al., 1994; Zanoli et al., 2000; Wasowski and Marder, 2012). While luteolin is also a well-known bioactive flavonoid which is structurally very close to apigenin and chrysin, there is little information about its hypnotic effect. In the present study, therefore, we evaluated the hypnotic effect of luteolin in pentobarbital-induced sleep model in mice. We also investigated the effect of luteolin on sleep architectures [wake, non-rapid eye movement (NREM), REM] by recording electroencephalogram (EEG) and electromyogram (EMG). Furthermore, as we were interested whether luteolin can interact with the GABAA receptor BDZ binding site (GABAAR-BDZ), we performed binding assay using [3H] flunitrazepam.

MATERIALS AND METHODS

Chemicals

Pentobarbital and diazepam (DZP, a reference hypnotic drug) was purchased from Hanlim Pharm. Co. Ltd. (Seoul, Korea) and Myungin Pharm. Co. Ltd. (Seoul, Korea), respectively. Luteolin, flumazenil, bicuculline and caffeine were purchased from Sigma–Aldrich Inc (St. Louis, USA). 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), and SCH58261 were purchased from Tocris Biosciences (Avonmouth, UK). In GABAAR binding assay, the radioligand [3H] flunitrazepam (NEN Perkin-Elmer, Ontario, CA, USA) used for GABAAR-BZD agonist, and [3H] muscimol (NEN Perkin-Elmer) were used for GABAAR-GABA binding site (GABAAR-GABA) agonist. For the adenosine 1 receptor (A1R), and adenosine 2A receptor (A2AR) binding assay, the radioligand [3H] CCPA and [3H] CGS21680, respectively, were purchased from NEN Life Science Products (Boston, MA, USA).

Animals

All animals were purchased from Orient Bio Inc (Seongnam, Korea). Male Imprinting Control Region (ICR) mice of 8 weeks old (weigh 25–30 g) were used in pentobarbital-induced sleep.

Male C57BL/6 mice of 4 weeks old (weigh 20–25 g) were used for measurements of EEG architectures. Mice were housed at 24°C and 55% humidity, with food and water were ad libitum. The room maintained 12 h light/dark cycle (light on at 8:00 and off at 20:00). Animals were acclimated for over 1 week before experiments. All animals related study protocols were approved by the Committee on Animal Research at Ajou University (Permission No. 2018-0051).

Pentobarbital-induced sleep test

Pentobarbital-induced sleep test were performed between 13:00 and 17:00. Luteolin, flumazenil, bicuculline, caffeine, and pentobarbital were suspended in saline. DPCPX and SCH58261 were suspended in 1% aqueous solution of Tween 80. Luteolin or saline was orally administered to mice 30 min before pentobarbital injection. Antagonists for GABAAR, A1R and A2AR were orally administered 15 min before luteolin administration. Control and vehicle mice were administered with saline or 1% Tween 80 at the same time for compared to the sample administration group. After pentobarbital injection (45 mg/kg i.p.), mice were placed in individual cages for the test. For sleep latency, the time was recorded from pentobarbital injection to the time when righting reflex disappeared. For sleep duration, the time was recorded until the righting reflex recovered.

Measurement of EEG and EMG

EEG and EMG were recorded from 09:00 to 15:00 according the method described previously (Dela Pena et al., 2016). Briefly, mice were anesthetized with pentobarbital sodium (50 mg/kg, i.p.). Hair was removed, and the skin was disinfected with betadine and alcohol. Head mount (Pinnacle Technology, Inc., Lawrence, KS, USA) was implanted with EEG and EMG electrodes for polysomnographic recordings. The front part of the head mount was placed 3 mm anterior to bregma. After that, four screws were perforated into the skull for EEG recording. Two wire electrodes were inserted into the nuchal muscle for EMG recording. 1 week after surgery for recovery, EEG and EMG recordings were performed in the cage which designed to allow mice to move freely. Recording was performed for 2 days in same animal. Data collected in first day served as a vehicle to compare with second experimental day. Luteolin or saline was administered at 9:00.

The EEG and EMG signals were routed to an 8401 conditioning/acquisition system (Pinnacle Technology, Inc.) via a tether and low-torque commutator (Part #8408, Pinnacle Technology, Inc.). Continuous sections of recorded EEG and EMG data were divided to 10 s (1 epoch). Each epoch was scored as wake, NREM or REM sleep based on which type of waveform occupied >50% of that time. The absolute EEG power recorded wakefulness, NREM and REM in the range of from 0.5 to 20 Hz. NREM, REM and wakefulness were calculated in δ (0.5–4.0 Hz), θ (5.0–9.0 Hz), α (8.0–13.0 Hz). Values measured were calculated in Microsoft Excel (WA, USA).

Binding assay for GABAAR

The radioligand GABAAR binding assay was performed with Eurofins (St. Charles, IL, USA) Pharmacology Services. The cell membrane pellet from brain tissues of mice was obtained by the method described previously (Risa et al., 2004). The final membrane suspensions concentration was 2.5 μg protein per 100 μl binding buffer. Various concentration of luteolin (1, 3, 10, and 30 μM) and 1 nM [3H] flunitrazepam and [3H] muscimol (10 μl) was added in suspension (180 μl) and incubated on the ice for 40 min. For terminating the binding reaction, rapid filtration onto a glass fiber filter (Whatman GF/C) with ice-cold Tris–HCl buffer (30 mM) were performed to remove unbound [3H] flunitrazepam or [3H] msucimol. The amount of filter-bound radioactivity was counted using a liquid scintillation counter (PerkinElmer Life and Analytical Sciences, Waltham, MA, USA).

Binding assay for A1R and A2AR

The radioligand binding assay for A1R and A2AR was performed with Eurofins Pharmacology Services as described by Rivkees et al. (1995). A1R overexpressed CHO cells and A2R overexpressed HEK293 cells were used. Cell were harvested, pelleted and resuspended to a final protein concentration of 0.5 mg/ml for binding assay. Radioligands, [3H] CCPA (33 Ci/mmol) and [3H] CGS21680 (30 Ci/mmol) were used. The concentration of final cell suspension was 75–150 μg protein per 50 μl. Various concentrations of luteolin (0.3, 1, 3, 10, and 30 μM) and 1 nM [3H] CCPA or 6 nM [3H] CGS21680 was added in Multiscreen plates (Millipore, Bedford, MA, USA). After incubated for 1 h in room temperature, vacuum filtration was performed to separate bound radioactivity. Amount of bound radioactivity was counted using liquid scintillation counting.

Statistical analysis

All data are expressed as mean ± SEM. Significance was evaluated by analysis of variance (ANOVA). Differences between two-group with p<0.05 were considered to be statistically significant. For the significance analysis we used the Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA).

RESULTS

Luteolin improved pentobarbital-induced sleeping behaviors

To evaluate hypnotic activity of luteolin, we examined its effect on pentobarbital-induced sleep in mouse. After injection of a hypnotic dose of pentobarbital (45 mg/kg, i.p.), sleep latency and duration of the control group were 248.0 ± 5.8 sec and 49.6 ± 2.7 min, respectively (Fig. 1). As expected, a wellknown GABAAR-BDZ receptor agonist, DZP (1 mg/kg, p.o.) significantly promoted sleep latency and duration (p<0.01) relative to the control group. Luteolin (0.1–3 mg/kg, p.o.) also decreased sleep latency (Fig. 1A) and increased sleep duration in a dose-dependent manner (Fig. 1B). In particularly, oral administration of 3 mg/kg of luteolin was found to increase sleep duration up to 64.8 ± 1.2 min. This result suggests that luteolin has hypnotic effect on pentobarbital-induced sleep in mice.

Luteolin improved sleep architectures and changed power density

After oral administration of luteolin (3 mg/kg, p.o.) to the mice, the sleep architectures (NREM sleep, REM sleep, wake) were recorded. As shown in Fig. 2, compared to control group (Vehicle), luteolin significantly increased NREM sleep (approximately 16.7%). In addition, wake time was significantly decreased by luteolin approximately 40.9%. Luteolin (3 mg/kg) also changed EEG power density so that in NREM sleep, the power density of δ-wave significantly increased about 9.7% (Fig. 3).

Hypnotic mechanism of luteolin did not involve GABAAR

In order to investigate whether GABAAR is involved in the hypnotic mechanisms of luteolin, we used pharmacological antagonists for GABAAR-BDZ (flumazenil), and GABAAR-GABA (bicuculline). As shown in Fig. 4, the GABAAR-BDZ agonist, DZP (1 mg/kg), significantly decreased sleep latency and increased sleep duration–an effect that was blocked by administration of flumazenil. Unlike DZP, the hypnotic effect of luteolin (3 mg/kg) was not affected by either flumazenil or bicuculline. We also evaluated the binding affinity of luteolin for GABAAR-BDZ or GABAAR-GABA. As expected, luteolin was not displace both [3H] flunitrazepam, and [3H] muscimol binding (Table 1). These results suggested that, hypnotic effect of luteolin were not related with GABAAR-BDZ, and GABAAR-GABA.

Hypnotic mechanism of luteolin involved both A1R and A2AR

To test whether the hypnotic effects of luteolin were related with AR, we used caffeine (an A1R, A2AR antagonist), DPCPX (an A1R antagonist), and SCH58261 (an A2AR antagonist). As shown in Fig. 5, the hypnotic effect of luteolin (3 mg/kg) was antagonized by caffeine, DPCPX and SCH58261. We also evaluated the binding affinity of luteolin for A1R, and A2AR. Luteolin was found to displace over 90% of both [3H] CCPA, and [3H] CGS21680 binding at 10 μg/ml. Its IC50 values for A1R and A2AR were 1.19 and 0.84 μg/ml, respectively (Table 1). These results suggest that hypnotic effect of luteolin involves both A1R and A2AR.

DISCUSSION

The major finding of this study is that luteolin improves quantity and quality of sleep, especially NREM, and its underlying mechanisms may involve A1R and A2AR binding, but neither GABAAR-BDZ nor GABAAR-GABA binding.

Sleep disorders can be caused by lack of sleep, excessive amounts of sleep, or abnormal movements during sleep. Among various sleep disorders, insomnia is that the patient reports not only dissatisfaction with sleep (sleep-onset insomnia or sleep-maintenance insomnia) but also other daytime symptoms (sleepiness, attention disorders, mood disorders) for at least 3 nights per week and last for more than 3 months (K. Pavlova and Latreille, 2019). Most epidemiological studies show that about one third (30%–36%) of adults have at least one symptom of insomnia, such as difficulty in starting or maintaining sleep (Ohayon, 2002). Insomnia increases the public health burden and health care costs, and decreased work ability in many people (Atkin et al., 2018). However, this growing burden has not been successfully relieved yet because synthetic chemicals actually failed to prevent efficiently the progress of sleep disorders. Therefore, increasing attentions are focused on the use of natural products and alternative medicine for sleep promotion due to their safety and efficiency (Hu et al., 2018). Indeed, several dietary and plant supplements, such as suanzaoren (Ziziphi Spinosae Semen) and valerian (Valeriana officinalis), are already available in clinic (Choi et al., 2018).

Luteolin, one of the important bioactive flavonoids, has been suggested to be a useful therapeutic constituent for neurodegenerative diseases based on not only its anti-inflammatory effects which has a crucial role in the neuroprotection, but also its lipophilic property indicating the possibility to cross blood brain barrier (Orhan et al., 2015; Theoharides et al., 2015; Zhang et al., 2017). In addition, a recent study has reported that luteolin shows an anti-anxiolytic effect via the low affinity for the GABAAR-BDZ (Coleta et al., 2008). In the present study, we first found a remarkable hypnotic effect of luteolin through a pentobarbital-induced sleep test along with EEG/EMG analysis. Sleep cycle is well known to consist of two parts, NREM and REM. NREM is a relaxed type of sleep that takes a deeper sleep, and REM is an active type of sleep with brain waves activated (Choi et al., 2018). The amount of these two sleep types is known to determine the quality of sleep so that increasing NREM sleep leads to deeper sleep and increased quality of sleep (Meerlo et al., 1997; Meerlo et al., 2001; Kwon et al., 2017). In general, NREM sleep is considered to be the time during which the brain recovers from prior wakefulness (Benington and Heller, 1995; Kamphuis et al., 2015). Among sleep waves of EEG, such as θ, waves are known to increase in REM sleep, while δ waves increase in NREM sleep (Hutchison and Rathore, 2015). Indeed, slow-wave sleep (SWS) refers to phase 3 sleep, which is the deepest phase of NREM sleep, and is characterized by δ waves of EEG. However, many hypnotics acting at GABAAR-BDZ, such as diazepam, are known to reduce EEG δ wave in NREM, which limits the use of diazepam. (Bastien et al., 2003; Ishida et al., 2009). Our results showed that sleep-improving effect of luteolin was not affected by either flumazenil or bicuculline, and that luteolin bound neither with GABAAR-BZD nor GABAAR-GABA, suggesting that the sleep-promoting effect of luteolin is not related with GABAAR. On the other hand, luteolin increased not only NREM sleep time but also δ waves, and thus suggesting a beneficial role of luteolin in promoting sleep quality as well as sleep time.

Adenosine is known as an endogenous sleep-promoting substance (Zhang et al., 2012). Increased adenosine firing in specific areas of the brain during prolonged awakening has been reported to play a very important role such as increasing sleep homeostasis (Greene et al., 2017). Adenosine and stable adenosine analogs were shown to induce sleep when administered to experimental animals (Basheer et al., 2004). In physiological concentration of adenosine, it regulates cell function through membrane receptor binding cascade (Fredholm et al., 1999). There are four subtypes of adenosine receptors expressed in the central nervous system: A1R, A2AR, A2BR and A3R. Among them, A1R and A2AR have been reported to be related to sleep regulation (Fredholm et al., 2001). A1R is known to couple to Gi/o protein which can inhibit adenylyl cyclase (AC), whereas A2AR couples to Gs/olf protein which can activate AC. Following the activation of the A2AR, cAMP production increases leading to the activation of protein kinase A (PKA) and phosphorylation of the cAMP response element binding protein (CREB) (Sheth et al., 2014). A1R has been shown high level in hypocretin/orexin neurons of lateral hypothalamus (LH), where is the center for the maintenance of arousal. Adenosine binding to this A1R may results in the reduction in wakefulness, because the neuropeptides orexin A and B produced in LH neurons, play a crucial role in the promotion and maintenance of wakefulness (Cun et al., 2014). In consistent with these studies, a recent report has just revealed that application of A1R agonist, N6-cyclopentyl-adenosine (CPA), into the perifornical LH area promotes sleep in rats (Alam et al., 2009). In addition, microdialysis of A1R antisense oligonucleotides into the LH has been reported to significantly decrease NREM sleep and increase wakefulness in rats (Thakkar et al., 2003). As for A2AR, it is known to play an important role in sleep promotion, supported by the studies that intracerebroventricular infusion of the A2AR agonist CGS21680 significantly promoted sleep (Satoh et al., 1999). It has also been reported that in urethane-anesthetized rats, CGS21680 increased GABA secretion in histaminergic tuberomammillary nucleus, and that the expression of glutamate decarboxylase 67 (GAD67) was reduced in striatum of A2AR knockout mice (Yin et al., 2017). Thus, A2AR seems to be associated with GABAergic neuron that promotes sleep and plays a role in promoting sleep, although further study is needed to clarify the mechanism between A2AR and GABAergic neuron.

In this study, we found that luteolin directly bound to both A1R and A2AR and with IC50 value of 1.19 μg/ml and 0.84 μg/ml, respectively. We also found that the sleep-improving effect of luteolin was significantly inhibited by DPCPX and SCH58261, suggesting that the sleep-promoting effect of luteolin may be mediated via activation of not only A1R but A2AR. Further study remains to clarify whether the level of GABA or adenosine in brain tissue can be changed by luteolin. In conclusion, this study for the first time demonstrate that luteolin improves quantity and quality of sleep, especially for NREM in mice. As a mechanism for the effect of luteolin, the involvement of both A1R and A2AR activation, but neither GABAAR-BDZ nor GABAAR-GABA binding seems to be very convincing. From these results, it is suggested that luteolin may have a potential for sleep-promoting agent.

ACKNOWLEDGMENTS

This research was supported by the Commercialization Promotion Agency for R&D Outcomes (COMPA) funded by the Ministry of Science and ICT (MSIT) (2018K000277), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI18C0920), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07048729), Republic of Korea.

Figures
Fig. 1. Effects of luteolin on sleep latency (A) and sleep duration (B) in mice administered a hypnotic dose (45 mg/kg, i.p.) of pentobarbital. Mice injected pentobarbital (i.p.) 30 min after oral administration (p.o.) of CTL (saline), DZP (1 mg/kg), or luteolin (0.1, 0.3, 1, and 3 mg/kg). Each column represents mean ± SEM (n=6). *p<0.05, significant as compared to the control group.
Fig. 2. Time courses of changes of Wake (A), NREMS (B), and REMS (C) after the administration of luteolin. Open circles indicate the vehicle and filled circles indicate the luteolin (3 mg/kg). Total time spent in Wake (D), NREMS (E) and REMS (F) for 4 h after administration of luteolin. Each circle represents the hourly mean ± SEM (n=5) of Wake, NREMS, and REMS. Each column represents the mean ± SEM (n=5). *p<0.05 compared with vehicle.
Fig. 3. The effects of luteolin on EEG power density of Wakefulness (A), NREM sleep (B) and REM sleep (C). The power density was classified with δ wave (0.5–4 hz), theta-wave (4–8 hz) and alpha-wave (8–12 hz). Each bar represents mean ± SEM (n=5). *p<0.05, significant as compared to the Vehicle.
Fig. 4. Effects of GABAAR antagonist on the changes in sleep latency (A) and sleep duration (B) in mice treated with luteolin. Mice were injected with pentobarbital (i.p.) 30 min after oral administration (p.o.) of CTL (saline), DZP (1 mg/kg) or luteolin (3 mg/kg). Vehicle (saline), flumazenil (5 mg/kg, p.o.), or bicuculine (2 mg/kg, p.o.) was administered 15 min before luteolin administration. Each column represents mean ± SEM (n=6). *p<0.05, significant as compared to the control group. #p<0.05, significant as compared to each vehicle group. B, bicuculline; CTL, control; DZP, diazepam; F, flumazenil; Veh, vehicle.
Fig. 5. Effects of adenosine receptor antagonist on the changes in sleep latency (A) and sleep duration (B) in mice treated with luteolin. Mice were injected with pentobarbital (i.p.) 30 min after oral administration (p.o.) of CTL (saline), or luteolin (3 mg/kg). Vehicle (1% Tween80), caffeine (10 mg/kg, p.o.), DPCPX (5 mg/kg, p.o.), or SCH58261 (5 mg/kg, p.o.) was administered 15 min before luteolin administration. Each column represents mean ± SEM (n=6). *p<0.05, significant as compared to the control group. #p<0.05, significant as compared to the vehicle group. C, caffeine; CTL, control; D, DPCPX; S, SCH58261; Veh, vehicle.
Tables

Effect of luteolin on radioligands binding to GABA and adenosine receptors

Receptor subtypeLuteolin (μM)IC50 (μM)

0.3131030
GABAAR-BZD-4.3 ± 1.83.3 ± 0.54.0 ± 3.13.9 ± 3.4-
GABAAR-GABA-0.1 ± 4.23.2 ± 8.47.2 ± 0.43.9 ± 3.2-
A1R11.7 ± 2.124.0 ± 1.950.3 ± 3.176.5 ± 1.294.6 ± 0.91.19
A2AR6.8 ± 3.322.9 ± 0.756.2 ± 0.283.8 ± 1.197.6 ± 2.40.84

The results were expressed as mean ± SD (n=3).

References
  1. Adib-Hajbaghery, M, and Mousavi, SN (2017). The effects of chamomile extract on sleep quality among elderly people: a clinical trial. Complement Ther Med. 35, 109-114.
    Pubmed CrossRef
  2. Alam, MN, Kumar, S, Rai, S, Methippara, M, Szymusiak, R, and McGinty, D (2009). Role of adenosine A(1) receptor in the perifornical-lateral hypothalamic area in sleep-wake regulation in rats. Brain Res. 1304, 96-104.
    Pubmed KoreaMed CrossRef
  3. Atkin, T, Comai, S, and Gobbi, G (2018). Drugs for insomnia beyond benzodiazepines: pharmacology, clinical applications, and discovery. Pharmacol Rev. 70, 197-245.
    Pubmed CrossRef
  4. Basheer, R, Strecker, RE, Thakkar, MM, and McCarley, RW (2004). Adenosine and sleep-wake regulation. Prog Neurobiol. 73, 379-396.
    Pubmed CrossRef
  5. Bastien, CH, LeBlanc, M, Carrier, J, and Morin, CM (2003). Sleep EEG power spectra, insomnia, and chronic use of benzodiazepines. Sleep. 26, 313-317.
    Pubmed CrossRef
  6. Benington, JH, and Heller, HC (1995). Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol. 45, 347-360.
    Pubmed CrossRef
  7. Bloom, HG, Ahmed, I, Alessi, CA, Ancoli-Israel, S, Buysse, DJ, Kryger, MH, Phillips, BA, Thorpy, MJ, Vitiello, MV, and Zee, PC (2009). Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am Geriatr Soc. 57, 761-789.
    Pubmed KoreaMed CrossRef
  8. Cho, S, Yang, H, Jeon, YJ, Lee, CJ, Jin, YH, Baek, I, Kim, D, Kang, SM, Yoon, M, Yong, H, Shimizu, M, and Han, D (2012). Phlorotannins of the edible brown seaweed Ecklonia cava Kjellman induce sleep via positive allosteric modulation of gamma-aminobutyric acid type A-benzodiazepine receptor: a novel neurological activity of seaweed polyphenols. Food Chem. 132, 1133-1142.
    Pubmed CrossRef
  9. Choi, HS, Hong, KB, Han, SH, and Suh, HJ (2018). Valerian/Cascade mixture promotes sleep by increasing non-rapid eye movement (NREM) in rodent model. Biomed Pharmacother. 99, 913-920.
    Pubmed CrossRef
  10. Coleta, M, Campos, MG, Cotrim, MD, Lima, TC, and Cunha, AP (2008). Assessment of luteolin (3′,4′,5,7-tetrahydroxyflavone) neuropharmacological activity. Behav Brain Res. 189, 75-82.
    Pubmed CrossRef
  11. Cun, Y, Tang, L, Yan, J, He, C, Li, Y, Hu, Z, and Xia, J (2014). Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats. Neurosci Bull. 30, 877-886.
    Pubmed KoreaMed CrossRef
  12. Dela Pena, IJI, Kim, HJ, de la Peña, JB, Kim, M, Botanas, CJ, You, KY, Woo, T, Lee, YS, Jung, JC, Kim, KM, and Cheong, JH (2016). A tryptic hydrolysate from bovine milk alphas1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor. Behav Brain Res. 313, 184-190.
    Pubmed CrossRef
  13. Fredholm, BB, IJzerman, AP, Jacobson, KA, Klotz, KN, and Linden, J (2001). International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 53, 527-552.
    Pubmed
  14. Fredholm, BB, Bättig, K, Holmén, J, Nehlig, A, and Zvartau, EE (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 51, 83-133.
    Pubmed
  15. Greene, RW, Bjorness, TE, and Suzuki, A (2017). The adenosine-mediated, neuronal-glial, homeostatic sleep response. Curr Opin Neurobiol. 44, 236-242.
    Pubmed KoreaMed CrossRef
  16. Hu, Z, Oh, S, Ha, TW, Hong, JT, and Oh, KW (2018). Sleep-aids derived from natural products. Biomol Ther (Seoul). 26, 343-349.
    Pubmed KoreaMed CrossRef
  17. Hutchison, IC, and Rathore, S (2015). The role of REM sleep theta activity in emotional memory. Front Psychol. 6, 1439.
    Pubmed KoreaMed CrossRef
  18. Ishida, T, Obara, Y, and Kamei, C (2009). Effects of some antipsychotics and a benzodiazepine hypnotic on the sleep-wake pattern in an animal model of schizophrenia. J Pharmacol Sci. 111, 44-52.
    Pubmed CrossRef
  19. Kamphuis, J, Lancel, M, Koolhaas, JM, and Meerlo, P (2015). Deep sleep after social stress: NREM sleep slow-wave activity is enhanced in both winners and losers of a conflict. Brain Behav Immun. 47, 149-154.
    Pubmed CrossRef
  20. Krueger, JM, Rector, DM, Roy, S, Van Dongen, HP, Belenky, G, and Panksepp, J (2008). Sleep as a fundamental property of neuronal assemblies. Nat Rev Neurosci. 9, 910-919.
    Pubmed KoreaMed CrossRef
  21. Kwon, YO, Hong, JT, and Oh, KW (2017). Rosmarinic acid potentiates pentobarbital-induced sleep behaviors and non-rapid eye movement (NREM) sleep through the activation of GABAA-ergic systems. Biomol Ther (Seoul). 25, 105-111.
    Pubmed KoreaMed CrossRef
  22. Pavlova, MK, and Latreille, V (2019). Sleep disorders. Am J Med. 132, 292-299.
    Pubmed CrossRef
  23. Meerlo, P, de Bruin, EA, Strijkstra, AM, and Daan, S (2001). A social conflict increases EEG slow-wave activity during subsequent sleep. Physiol Behav. 73, 331-335.
    Pubmed CrossRef
  24. Meerlo, P, Pragt, BJ, and Daan, S (1997). Social stress induces high intensity sleep in rats. Neurosci Lett. 225, 41-44.
    Pubmed CrossRef
  25. Nabavi, SF, Braidy, N, Gortzi, O, Sobarzo-Sanchez, E, Daglia, M, Skalicka-Woźniak, K, and Nabavi, SM (2015a). Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull. 119, 1-11.
    Pubmed CrossRef
  26. Nabavi, SF, Russo, GL, Daglia, M, and Nabavi, SM (2015b). Role of quercetin as an alternative for obesity treatment: you are what you eat!. Food Chem. 179, 305-310.
    Pubmed CrossRef
  27. Neikrug, AB, and Ancoli-Israel, S (2010). Sleep disorders in the older adult - a mini-review. Gerontology. 56, 181-189.
    Pubmed KoreaMed CrossRef
  28. Ohayon, MM (2002). Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 6, 97-111.
    Pubmed CrossRef
  29. Orhan, IE, Daglia, M, Nabavi, SF, Loizzo, MR, Sobarzo-Sánchez, E, and Nabavi, SM (2015). Flavonoids and dementia: an update. Curr Med Chem. 22, 1004-1015.
    Pubmed CrossRef
  30. Pearson, NJ, Johnson, LL, and Nahin, RL (2006). Insomnia, trouble sleeping, and complementary and alternative medicine: analysis of the 2002 national health interview survey data. Arch Intern Med. 166, 1775-1782.
    Pubmed CrossRef
  31. Rashid, A, Ong, EK, and Yi Wong, ES (2012). Sleep quality among residents of an old folk’s home in Malaysia. Iran J Nurs Midwifery Res. 17, 512-519.
    Pubmed KoreaMed
  32. Risa, J, Risa, A, Adsersen, A, Gauguin, B, Stafford, GI, van Staden, J, and Jäger, AK (2004). Screening of plants used in southern Africa for epilepsy and convulsions in the GABAA-benzodiazepine receptor assay. J Ethnopharmacol. 93, 177-182.
    Pubmed CrossRef
  33. Rivkees, SA, Lasbury, ME, and Barbhaiya, H (1995). Identification of domains of the human A1 adenosine receptor that are important for binding receptor subtype-selective ligands using chimeric A1/A2a adenosine receptors. J Biol Chem. 270, 20485-20490.
    Pubmed CrossRef
  34. Rudolph, U, and Knoflach, F (2011). Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov. 10, 685-697.
    Pubmed KoreaMed CrossRef
  35. Satoh, S, Matsumura, H, Koike, N, Tokunaga, Y, Maeda, T, and Hayaishi, O (1999). Region-dependent difference in the sleep-promoting potency of an adenosine A2A receptor agonist. Eur J Neurosci. 11, 1587-1597.
    Pubmed CrossRef
  36. Sheth, S, Brito, R, Mukherjea, D, Rybak, LP, and Ramkumar, V (2014). Adenosine receptors: expression, function and regulation. Int J Mol Sci. 15, 2024-2052.
    Pubmed KoreaMed CrossRef
  37. Thakkar, MM, Winston, S, and McCarley, RW (2003). A1 receptor and adenosinergic homeostatic regulation of sleep-wakefulness: effects of antisense to the A1 receptor in the cholinergic basal forebrain. J Neurosci. 23, 4278-4287.
    Pubmed KoreaMed CrossRef
  38. Theoharides, TC, Stewart, JM, Hatziagelaki, E, and Kolaitis, G (2015). Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci. 9, 225.
    Pubmed KoreaMed CrossRef
  39. Wasowski, C, and Marder, M (2012). Flavonoids as GABAA receptor ligands: the whole story?. J Exp Pharmacol. 4, 9-24.
    Pubmed KoreaMed CrossRef
  40. Wolfman, C, Viola, H, Paladini, A, Dajas, F, and Medina, JH (1994). Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea. Pharmacol Biochem Behav. 47, 1-4.
    Pubmed CrossRef
  41. Yin, SB, Zhang, XG, Chen, S, Yang, WT, Zheng, XW, and Zheng, GQ (2017). Adenosine A2A receptor gene knockout prevents l-3,4-dihydroxyphenylalanine-induced dyskinesia by down-regulation of striatal GAD67 in 6-OHDA-lesioned Parkinson’s mice. Front Neurol. 8, 88.
    Pubmed KoreaMed CrossRef
  42. Zanoli, P, Avallone, R, and Baraldi, M (2000). Behavioral characterisation of the flavonoids apigenin and chrysin. Fitoterapia. 71, S117-S123.
    Pubmed CrossRef
  43. Zhang, JX, Xing, JG, Wang, LL, Jiang, HL, Guo, SL, and Liu, R (2017). Luteolin inhibits fibrillary β-amyloid1-40-induced inflammation in a human blood-brain barrier model by suppressing the p38 MAPK-mediated NF-κB signaling pathways. Molecules. 22, E334.
    Pubmed KoreaMed CrossRef
  44. Zhang, Y, Li, M, Kang, RX, Shi, JG, Liu, GT, and Zhang, JJ (2012). NHBA isolated from Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital-treated mice. Pharmacol Biochem Behav. 102, 450-457.
    Pubmed CrossRef


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