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Natural Sleep Aids and Polyphenols as Treatments for Insomnia
Abstract
Sleep is vital for maintaining health and well-being; however, insomnia is currently a widespread health complaint. According to a report from the National Sleep Foundation in the United States, 87% of American adults experience sleeping problems. Recently, natural sleep aids have become increasingly popular as an alternative to prescription sleep medications for the treatment of insomnia. Various dietary and herbal supplements, such as valerian, suanzaoren, kava kava, and 5-hydroxytryptophan are used for treating insomnia. Polyphenols are a major type of hypnotic phytochemicals present in these supplements, and the gamma-aminobutyric acid type A (GABAA) receptor has been extensively studied as a molecular target of hypnotic polyphenols. Terrestrial plant polyphenols, such as magnolol, honokiol, and glabrol, reportedly have hypnotic effects via positive allosteric modulation of the GABAA-benzodiazepine (BZD) receptor. Marine plant polyphenol phlorotannins also have sleep-promoting effects via the GABAA-BZD receptor. This chapter discusses information related to the properties and potential mechanisms of natural sleep aids and hypnotic polyphenols.
... This disorder is marked by difficulties in initiating and maintaining sleep, as well as non-restorative sleep patterns. Statistical estimates indicate that around 10-15% of adults experience chronic insomnia, while an additional 25-35% encounter intermittent episodes of sleeplessness (Cho and Shimizu, 2015). The consequences of insomnia are profound, leading to impairments in daily performance, cognitive deficits, and increased risks of physical and neurological issues (Javaheri and Redline, 2017;Li et al., 2016). ...
... Insomnia is a prevalent sleep disorder that affects a significant segment of the population. Chronic insomnia affects around 10-15% of the adult population, while 25-35% experience occasional episodes of sleep disturbance (Doghramji, 2006;Cho and Shimizu, 2015). It is characterized by difficulties in initiating and maintaining sleep as well as non-restorative sleep (Mendelson et al., 2004;Roth, 2007). ...
Insomnia, a prevalent health challenge, often requires pharmacological interventions to improve sleep onset, maintenance, and quality. Benzodiazepines and Z-drugs, like other positive modulators, enhance the inhibitory effects of gamma-aminobutyric acid (GABA) by stabilizing the open conformation of the GABAA receptor (GABAAR) chloride ion channels, facilitating the transition to sleep. However, prolonged use raises concerns, including dependence and cognitive issues. Among herbal alternatives, Humulus lupulus (hops) is gaining attention due to its role as a natural relaxant, sleep aid, and brewing component. Neuroactive phytochemicals in hops may modulate GABAARs differently from benzodiazepines. This research uncovers these hop constituents and potential therapeutic mechanisms.
The α-acid humulone and hop prenylflavonoids (PFs), including xanthohumol/isoxanthohumol, 6/8-prenylnaringenin, enhanced GABA-induced displacement of [3H]EBOB, a GABAAR function marker, in the low micromolar range. These potent effects were flumazenil-insensitive and α6β3δ subtype-selective. Molecular docking at the α1β2γ2 isoform identified the extracellular α+/β− interface as the PF binding site. An additional 6-prenylnaringenin site was recognized at the extracellular α+/γ2− interface, aligning with its inhibition of [3H]flunitrazepam and [3H]Ro 15-4513 binding. Given humulone’s prominence and relatively high potency, its activity was confirmed electrophysiologically, where it enhanced GABA-evoked currents in the sedation-mediating α1β3γ2 subtype. In mice, humulone reduced locomotor activity, shortened sleep onset induced by pentobarbital, and prolonged sleep duration induced by either pentobarbital or ethanol. Moreover, [3H]EBOB binding assays showed synergies between humulone and ethanol, and additive interactions with PFs, suggesting enhanced alcohol intoxication in hop-rich beers.
In summary, we revealed positive modulators of GABAARs that act independently of the classical benzodiazepine site. 6-prenylnaringenin also acts as a silent modulator with the potential to block benzodiazepine responses. Humulone plays a pivotal role in the sedative and sleep-promoting properties of hops. These findings offer novel mechanistic insights into hop neuroactive constituents and potential avenues for sleep aid optimization.
... As insomnia becomes more common, herbal sleep aids are gaining popularity worldwide as alternatives to prescription drugs to treat insomnia or improve sleep quality [21,22]. Most sedative-hypnotic drugs have numerous side effects, such as impairment of memory, cognitive function, and general daytime performance; therefore, their use is generally not recommended beyond 4 weeks [23,24]. In addition, long-term administration typically results in dependence and tolerance [25]. ...
... In addition, long-term administration typically results in dependence and tolerance [25]. Thus, sedative-hypnotic effects of herbal plants or their phytochemicals have been widely reported, such as valerian (Valeriana officinalis), St. John's wort (Hypericum perforatum), kava kava (Piper methysticum), passion flower (Passiflora incarnata), and hops (Humulus lupulus) [19,24]. Although numerous studies have been conducted on the hypnotic effects of herbal plants, few studies have investigated marine polyphenol phlorotannins. ...
Insomnia is a common sleep disorder. Natural sleep aids are gaining worldwide popularity as alternatives to prescription drugs for improving sleep. Recently, numerous studies have investigated the sedative–hypnotic effects of the polyphenols of terrestrial plants. The hypnotic effects of marine polyphenols have also been studied in recent years. Phlorotannins are marine polyphenols that are found only in brown algae. Phlorotannins exert sedative–hypnotic effects via the gamma-aminobutyric acid type A-benzodiazepine receptor. In addition, the brown seaweed Ecklonia cava supplement containing phlorotannins has been approved by the Ministry of Food and Drug Safety as a health-functional ingredient that helps improve sleep quality. Currently, it is meaningful to deal with the sedative–hypnotic effects of phlorotannins as natural sleep aids. The current review comprehensively presents the sedative–hypnotic effects in animal models and human clinical trials as well as their mechanism of action, extraction, purification, and safety.
... Although apparently safe, over the counter melatonin has come under scrutiny due to wide variability in the actual melatonin content of tablets 40 . Moreover, there is a concerning rise in chronic insomnia combined with chronic prescription sleep aid use (e.g., Ambien/Zolpidem, Gabapentin) which may contribute to cognitive impairment and dementia [41][42][43][44] . These concerning effects highlight the importance for . ...
Purpose
Sleep aids derived from traditional plant medicines are strong candidates for safely improving insomnia but require wider validation in patient populations.
Methods
We conducted an open label trial of the impact of a compound, Sip2Sleep ® , containing Montmorency tart cherry ( prunus cerasus ) extract and Venetron ® ( apocynum venetum ) on subjective sleep quality, subjective daytime alertness, sleep duration, sleep latency, anxiety, and insomnia in 43 adults with moderate to severe insomnia. Participants collected data over four weeks, with the sleep aid consumed prior to bed during weeks two and four.
Results
The Montmorency tart cherry and Venetron ® mixture statistically improved subjective sleep quality, daytime alertness, insomnia symptoms, and anxiety without impacting sleep duration and latency. Subjective improvements in sleep quality exhibited a statistical upward trend across the entire study window, suggesting potential persistence of the compounds days after consumption and greater improvement with longer-term consumption.
Conclusions
The combination of Montmorency tart cherry and Venetron ® in this commercially available tincture is a promising sleep aid warranting further investigation in larger trials.
... Flavonoids have an active role in the sleep mechanism by affecting gamma-aminobutyric acid (GABA) receptors 1 in the brain [11,14] and binding to these receptors [15]. GABA and its receptors can have an effective role in improving sleep disorders [16][17][18][19]. ...
Purpose
The present study aimed to assess the effects of Viola odorata syrup on the sleep quality of postmenopausal women.
Methods
This triple-blinded randomized clinical trial was conducted on menopausal women presenting to the healthcare centers in Mashhad, Iran, in 2019. The participants were selected using simple random sampling. Participants received 5 ml syrup V. odorata or placebo twice a day for 1 month. Data were collected using the Pittsburgh Sleep Quality Index. The data were analyzed using SPSS version 25.
Results
The 118 eligible women enrolled in the study were divided into two groups of V. odorata syrup and placebo (n = 59 each). The analysis was conducted on only 84 menopausal women (42 in each group) due to exclusions. Exclusions consisted of 12 participants who withdrew from the study due to unwillingness to cooperate, 8 who had irregular consumption of the therapeutic syrup, 6 with inaccurate completion of the questionnaire, and 8 due to lack of accessibility. The two study groups were homogenous in terms of demographic characteristics. Before the intervention, no significant difference was observed in the mean PSQI score between the two groups (9.2 ± 2.9 vs. 8.4 ± 2.5) (P = 0.18). However, a significant difference was seen in the mean PSQI score between the two groups (4.9 ± 1.9 vs. 8.1 ± 2.1, P < 0.001) after the intervention.
Conclusions
The findings of this study suggest that V. odorata syrup may be a useful therapeutic agent to improve the sleep quality of menopausal women.
Registration code
IRCT20180514039660N1.
... Седативное, снотворное, противотревожное действие пассифлоры обеспечивается за счет алкалоида пассифлорин и ряда флавоноидов -магнолола, хонокиола, глаброла, кризина. Данные клинические эффекты достигаются в результате ГАМКергического воздействия биологически активных веществ растения, что приводит к снижению возбудимости клеток головного мозга [10][11][12]. Легкое антидепрессивное действие растения обеспечивается за счет алкалоида гарман, который способен ингибировать энзим моноаминооксидазу, что приводит к повышению содержания моноаминов (норадреналин, серотонин, дофамин) в синаптической щели [13]. ...
Тревожные расстройства являются наиболее часто встречающейся группой психических расстройств. Вопросы своевременной диагностики и эффективного лечения этих заболеваний приобретают особую актуальность, прежде всего в первичном звене здравоохранения. Законом Республики Беларусь от 11.11.2019 № 255-З определены полномочия врачей общей практики в лечении психических расстройств. Среди ряда психотропных препаратов, которые применяются для лечения тревожных расстройств, отдельную группу представляют лекарственные растения с анксиолитическим эффектом. Одним из таких растений является пассифлора (Passiflora incarnata). В статье приведен анализ литературных данных по проблеме тревожных расстройств и использованию пассифлоры для их лечения. Описаны характеристика пассифлоры, ее состав, клинические эффекты и показания для применения в общей врачебной практике.
Anxiety disorders are the most common group of mental disorders. The issues of timely diagnosis and effective treatment of these diseases are of particular relevance, primarily in primary health care. The Law of the Republic of Belarus No. 255-3 of 11.11.2019 defines the powers of general practitioners in the treatment of mental disorders. Among a number of psychotropic drugs that are used to treat anxiety disorders, medicinal plants with anxiolytic effect represent a separate group. One of these plants is Passiflora (Passiflora incarnata). The article provides an analysis of the literature data on the problem of anxiety disorders and the use of passionflora for their treatment. The characteristics of passionflower, its composition, clinical effects and indications for use in general medical practice are described.
... Valerenic acid inhibits GABA breakdown and this in return leads to sedation. [24][25][26][27] Flavonoids: are natural compounds with the function to control the activity of cells and to combat free radicals. Due to the antioxidant effect of flavonoids, free molecules can be destroyed which can be harmful for the body. ...
Introduction and aim. "Valeriana officinalis" has been recognized in traditional medicine and used since ancient times for a variety of health ailments. It is mainly appreciated for its sedative and sleeping properties. Currently, scientists are conducting numerous studies on the exact chemical composition of valerian and the properties they carry in the human body. Material and methods. This paper presents a narrative review on valerian. Analysis of the literature. The desire to summarize information on the uses and properties of V. officinalis is presented. V. officinalis exhibits sedative, sleep-inducing and antidepressant properties. Studies show broad effects on the human nervous system, for example, reducing stress. Conclusion. By discovering new properties of valerian, its properties are expanding significantly day by day. Its main use is primarily in the treatment of sleep disorders and nervous system disorders. However, it is also used in headaches, depression, anti-cancer therapy, urinary and digestive disorders. More and more people are turning to valerian as an alternative to drugs that have more side effects.
... However, it has the limitation that the hypnotic effects may be exhibited even when the sample has toxic or adverse effects [20]. In addition, this method can evaluate sleep quantity, such as sleep duration and latency, but not sleep quality [21]. Taking into consideration the limitations of the pentobarbital-induced sleep test, the hypnotic effects of GKPEE in mice treated with pentobarbital do not confirm that it has sleep-promoting or sleep-enhancing effects. ...
In the previous study, it was reported that green kiwifruit peel ethanol extract (GKPEE) increases sleep duration and decreases sleep latency in pentobarbital-treated mice. The pentobarbital-induced sleep test can be used to verify sleep quantity, which includes factors such as sleep duration and latency, but not sleep quality. In the present study, the sleep-promoting effects of GKPEE were investigated by the analysis of electroencephalogram (EEG) and electromyogram in mice and were compared with the results of diazepam (DZP), a representative sedative-hypnotic agent. The acute administration of GKPEE (250, 500 and 1000 mg/kg) increased the amount of non-rapid eye movement sleep (NREMS) and decreased sleep latency in a dose-dependent manner. The effect of GKPEE at 1000 mg/kg produced persistently significantly different results until the second hour of time-course changes. In particular, GKPEE did not produce any change in delta activity compared to DZP. Furthermore, sub-chronic administration (15 days) of GKPEE (500 mg/kg) continued sleep-promoting effects, whilst the EEG power density of NREMS did not show significant differences, indicating that there were no tolerance phenomena. Our findings suggest that GKPEE may be a promising natural sleep aid for treating sleep disorders. In addition, considering the number of by-products discarded each year by the food industry, the application of GKPEE here contributes to the utilization of processed kiwifruit by-products and can help to solve environmental problems.
... Moreover, various phlorotannin derivatives were extracted from a range of brown algae: Ecklonia kurome, Ecklonia cava, Ecklonia bicyclis, and Ecklonia radiate [27]. Phlorotannins are reported to have sleep-promoting [28], antibacterial [29], antioxidant [30,31], and algicidal effects [32]. It has been found to have inhibitory action against HIV-1 reverse transcriptase [33]. ...
Marine-derived natural products are rich source of secondary metabolites with huge potentials including novel therapeutic agents. Marine algae considered good source of secondary metabolites with versatile bioactivities. During few last decades, researches related to natural products obtained from brown algae have remarkably escalated as they contain active compounds with varied biologically activities like antimicrobial, anticancer, antioxidant, anti-inflammatory, antidiabetic, and antiparasitic properties. The main bioactive components such as phlorotannin, fucoxanthin, alginic acid, Fucoidan and laminarin have been briefly discussed here, together with their composition and biological activities. In this review, the biological function of extracts and the metabolites of brown algae as well as their pharmacological impacts with the description of the possible mechanism of their action are described and discussed. Also, this study is expected to examine the multifunctional properties of brown algae that facilitate natural algal products, including the ability to integrate these functional properties in a variety of applications.
... The effect of phenolic compounds in fast-growing algae on the gel properties of surimi gel has attracted considerable attention. The phenolic compound in brown algae is mainly phlorotannins, a polymer of phloroglucinol [10]. For example, phlorotannins were exclusively possessed in brown algae, with content more than 20% of the dry weight [11]. ...
The cross-linking degree between myosin affected the surimi gel properties in the hairtail. In this study, the effects of phlorotannin extracts (PE) derived from brown algae (Sargassum horneri) with different concentrations (0.05%, 0.3%, 1% w/w) on the hairtail surimi gel-forming properties were investigated in comparison with the commercial phloroglucinol (PG). The breaking forces of surimi gel with 1% PE and 0.05% PG were increased by 14.80% and 2.73%, respectively. The increase in deformation was 9.66% with 1% PE compared with the control added with water, but there was no increase in deformation of surimi gel with 0.05% PG. The improved surimi gel structure with PE as a bridge for the three-dimensional network forming of protein was observed in the microstructure. Moreover, PE could significantly shorten the water relaxation time (p < 0.05), reduce free water content (p < 0.05), and increase the hydrogen proton density of the hairtail surimi according to the results of NMR, dielectric properties, and MRI map, respectively. Our findings suggest that the extracts from the brown algae could be a potential economical gel structure enhancer to improve the myosin network.
... Polyphenolic compounds, also known as phenolics, are typically isolated from brown algae. They differ from simple molecules, including phenolic acids and other simple polyphenolic compounds, as well as more complex compounds such as phlorotannins, which are made up of phloroglucinol (1,3,5-trihydroxybenzene) units of polymeric structures [36]. Main compounds belonging to the group of polyphenolic compounds include eckols, fucols, fuhalols, phlorethols, fucophlorethols, bromophenols, terpenoids, phlorotannins and flavonoid. ...
Air pollution has recently become a subject of increasing concern in many parts of the world. The World Health Organization (WHO) estimated that nearly 4.2 million early deaths are due to exposure to fine particles in polluted air, which causes multiple respiratory diseases. Algae, as a natural product, can be an alternative treatment due to potential biofunctional properties and advantages. This systematic review aims to summarize and evaluate the evidence of metabolites derived from algae as potential anti-inflammatory agents against respiratory disorders induced by atmospheric particulate matter (PM). Databases such as Scopus, Web of Science, and PubMed were systematically searched for relevant published full articles from 2016 to 2020. The main key search terms were limited to “algae”, “anti-inflammation”, and “air pollutant”. The search activity resulted in the retrieval of a total of 36 publications. Nine publications are eligible for inclusion in this systematic review. A total of four brown algae (Ecklonia cava, Ishige okamurae, Sargassum binderi and Sargassum horneri) with phytosterol, polysaccharides and polyphenols were reported in the nine studies. The review sheds light on the pathways of particulate matter travelling into respiratory systems and causing inflammation, and on the mechanisms of actions of algae in inhibiting inflammation. Limitations and future directions are also discussed. More research is needed to investigate the potential of algae as anti-inflammatory agents against PM in in vivo and in vitro experimental models, as well as clinically.
... Glabrol, which is licorice component, has been characterized as a GABA A -BZD receptor ligand that exhibits hypnotic effects (Cho et al., 2012a). Although many studies have been conducted to reveal the hypnotic effects of polyphenols, they have all been limited to terrestrial plants (Cho and Shimizu, 2015). Recently, we reported for the first time that phlorotannins, which are marine polyphenols, enhance sleep in mice via the GABA A -BZD receptor (Cho et al., 2014). ...
We had previously demonstrated that phlorotannins, which are marine polyphenols, enhance sleep in mice via the GABAA-benzodiazepine (BZD) receptor. Among the constituents of phlorotannin, dieckol is a major marine polyphenol from the brown alga Ecklonia cava. Although phlorotannins are known to exert hypnotic effects, the sleep-enhancing effect of dieckol has not yet been determined. We evaluated the effect of dieckol on sleep-wake state of mice by analyzing electroencephalograms (EEGs) and electromyograms. Flumazenil, a GABAA-BZD antagonist, was used to investigate the molecular mechanism underlying the effects of dieckol on sleep. The polygraphic recordings and corresponding hypnograms revealed that dieckol accelerated the initiation of non-rapid eye movement sleep (NREMS); it shortened sleep latency and increased NREMS duration. According to the change in time-course, dieckol showed sleep-enhancing effects by increasing the amount of NREMS and decreasing wakefulness during the same hours. Additionally, sleep quality was evaluated by analyzing the EEG power density, and dieckol was found to not affect sleep intensity while zolpidem was found to reduce it. Finally, we treated mice with zolpidem or dieckol in combination with flumazenil and found the latter to inhibit the sleep-enhancing effect of dieckol and zolpidem, thereby indicating that dieckol exerts sleep-enhancing effects by activating the GABAA-BZD receptor, similar to zolpidem. These results implied that dieckol can be used as a promising herbal sleep aid with minimal side effects, unlike the existing hypnotics.
... For the last two decades, the sedative-hypnotic effects of medicinal plants and their constituents have been extensively investigated [6]. In particular, polyphenols have been considered as major sedative-hypnotic phytochemicals. ...
In our previous studies, we have demonstrated that marine polyphenol phlorotannins promote sleep through the benzodiazepine site of the gamma-aminobutyric acid type A (GABAA) receptors. In this follow-up study, the sleep-promoting effects of triphlorethol A, one of the major phlorotannin constituents, were investigated. The effect of triphlorethol A on sleep-wake architecture and profiles was evaluated based on electroencephalogram and electromyogram data from C57BL/6N mice and compared with the well-known hypnotic drug zolpidem. Oral administration of triphlorethol A (5, 10, 25, and 50 mg/kg) dose-dependently decreased sleep latency and increased sleep duration during pentobarbital-induced sleep in imprinting control region mice. Triphlorethol A (50 mg/kg) significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in C57BL/6N mice, without affecting rapid eye movement sleep (REMS). There was no significant difference between the effects of triphlorethol A at 50 mg/kg and zolpidem at 10 mg/kg. Triphlorethol A had no effect on delta activity (0.5–4 Hz) of NREMS, whereas zolpidem significantly decreased it. These results not only support the sleep-promoting effects of marine polyphenol phlorotannins, but also suggest that the marine polyphenol compound triphlorethol A is a promising structure for developing novel sedative hypnotics.
... With respect to pharmacological studies on natural sleep aids, terrestrial polyphenols have been considered as important sedative-hypnotic phytochemicals (Cho & Shimizu, 2015). Although marine plants have polyphenols, known as phlorotannins, they have not been recognized as potential sources of natural sleep aids, unlike terrestrial plants. ...
Our previous study demonstrated that phlorotannin supplement had a sleep-promoting effect in rodents. In the present study, we investigated whether the phlorotannin supplement could improve sleep in subjects with self-reported sleep disturbances. In a randomized, double-blind, placebo-controlled trial, 24 subjects consumed either a placebo or phlorotannin supplement (500 mg/day) for 1 week, 30–60 min prior to bedtime. Sleep parameters were assessed at baseline and at 1 week with sleep questionnaires and polysomnography. At the end of the treatment period, the complete sets of sleep parameters from 20 subjects. Phlorotannin resulted in a significant increase in “Sleep duration” scores compared to the placebo (p = .044), although there were no significant differences on the total PSQI scores. Polysomnography revealed that wakefulness after sleep onset was significantly lower in the phlorotannin group compared to the placebo group (phlorotannin vs. placebo, −25.5 ± 30.5 vs. −1.7 ± 14.9; p = .045) as well as total wake time (phlorotannin vs. placebo, −0.9 ± 3.0 vs. −6.1 ± 6.8; p = .048). Additionally, the respiratory disturbance index during supine rapid eye movement sleep was significantly lower in the phlorotannin group (p = .035). There were no serious adverse effects in either group. Our data suggest that the phlorotannin supplement improved sleep maintenance (WHO ICTRP: KCT0001892).
One of the complications of menopause is sleep disorders, which affect women's health. Ocimum basilicum contains compounds that may affect sleep. The aim of this study was to determine the effect of an oral capsule of O. basilicum leaf extract on sleep quality and the severity of insomnia in menopausal women. This triple‐blind, randomized clinical trial study was performed on 60 Iranian menopausal women aged 40 to 65 years. Subjects were randomly assigned into two groups of intervention (each capsule containing 250 mg of O. basilicum extract and 250 mg Avicel) per day for 1 month and placebo. The Pittsburgh Sleep Quality and Insomnia Intensity Index were used to assess sleep quality and severity of insomnia before, 2 weeks after and 1 month after the intervention. There was no statistically significant difference in the baseline variables between the intervention and placebo groups (p > .05). The total sleep quality scores in the two groups of intervention and placebo were 6.2 ± 0.3 versus 9.3 ± 0.3 (p < .001) and 3.7 ± 0.3 versus 9.1 ± 0.3 (p = .015) 2 weeks and 1 month after the intervention, respectively. The total insomnia severity scores in the two groups of intervention and placebo were 9.0 ± 0.3 versus 12.1 ± 0.3 (p < .001) and 5.6 ± 0.5 versus 11.0 ± 0.5 (p < .001) 2 weeks and 1 month after the intervention, respectively. Consumption of O. basilicum capsules improved sleep quality and insomnia in menopausal women. This study was approved (code IR.MUMS.NURSE.REC.1398.070) by the Ethic committee of Mashhad University of Medical Sciences and registered at the Iranian Registry of Clinical Trials, with the No. IRCT20200104046001N1 in January 2020.
Seaweed is the general term for marine algae. It is the algae growing in the sea. There are various of bioactive substances in the seaweed which have been proved to have acceptable neuroprotective functions. Among studies to date, drugs for neurodegenerative diseases treatment have detrimental side effects in vivo. Furthermore, in recent years, insomnia is afflicting people of different ages as a intractable precursory problem of neurasthenia and neurodegenerative. In this review, we first summarized the effects and mechanisms of different seaweed bioactive compounds on neurodegenerative disorders, then discussed the effects on insomnia. The various seaweed bioactive compounds were finally confirmed to be effective on neuroprotection, which in turn may provide thoughts for further research on potential dietary therapeutic strategy for insomnia.
Sleep is vital to maintain health and well-being; however, insomnia is currently a widespread health complaint worldwide. In particular, caffeine, a psychoactive component of coffee, tea, and caffeine beverages may lead to sleep disorders such as insomnia. In this study, our primary objective was to investigate the inhibitory effect of high-purity phlorotannin preparation (HP-PRT) on caffeine-induced wakefulness. The sleep test of pentobarbital-induced mice was used as an in vivo animal model. Caffeine (50 and 100 mg/kg) showed significant arousal effects (an increase in sleep latency and a decrease in sleep duration). Co-administration of caffeine (50 mg/kg) and the sedative-hypnotic diazepam (DZP, 1 mg/kg) did not result in similar arousal activity. HP-PRT (500 mg/kg) also inhibited caffeine-induced wakefulness. Our results suggest that HP-PRT would be a useful additive for developing coffee products without the arousal effect.
We investigated the effects of Ecklonia cava ethanol extract (ECE) on sleep architecture and sleep profiles. ECE was orally administered at a dose of 100, 250, or 500 mg/kg to C57BL/6N mice and its effects were measured by recording electroencephalogram (EEG) and electromyogram. Administration of ECE (250 and 500 mg/kg) significantly induced non-rapid eye movement sleep (NREMS) without affecting rapid eye movement sleep. The increase in NREMS by ECE (500 mg/kg) was significant (P < 0.05) during the first 2 h after administration. In addition, ECE had no effect on EEG power density (an indicator of sleep quality) in NREMS. These results suggest that ECE induces NREMS in a manner similar to physiological sleep.
In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs.
The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep-wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated.
The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep-wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism.
PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil.
We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative-hypnotics.
The sleep-promoting effect of isoliquiritigenin (ILTG) was investigated by analyzing the sleep architecture in mice. A hypnotic diazepam (DZP, 2 mg/kg) significantly decreased sleep latency by 39.7% and increased the amount of non-rapid eye movement sleep (NREMS) by 103.8% for the first 3 h after administration. ILTG (50 mg/kg) also produced a significant decrease in sleep latency (30.7%) and an increase in the amount of NREMS (61.1%). DZP significantly decreased delta (0.5-4 Hz) activity as compared with the vehicle; however, ILTG did not alter the delta activity. These results mean that ILTG induces sleep similar to physiological sleep without a decline in sleep quality.
In the 70s, reports began to appear of phenolic metabolites of brown algae with the characteristics of tannins; these compounds, initially termed phaeophyte tannins, marine algal polyphenols or polyphloroglucinols, are known as phlorotannins, the youngest group of plant polyphenolics. Despite over 40 years of research in phlorotannins, this area is still in the exponential growth phase; however, several reviews have appeared, primarily concerning their biological activity. This review focuses on techniques for the extraction, isolation and chromatographic purification of approximately 150 phlorotannins during these four decades. Due to the high structural diversity of these polyphenols and the difficulty of classification, these topics are also reviewed: structural diversity and classification, extraction and preparative chromatography, thin-layer chromatography, and analytical high-performance liquid chromatography (HPLC) and HPLC-mass spectrometry. These techniques have primarily been used for separation monitoring and qualitative profiles, and not too many reports have been published on the development of quantification or quality control.
Benzodiazepines are the most widely prescribed class of psychoactive drugs in current therapeutic use, despite the important unwanted side effects that they produce, such as sedation, myorelaxation, ataxia, amnesia, and ethanol and barbiturate potentiation and tolerance. They exert their therapeutic effects via binding to the benzodiazepine binding site of gamma-aminobutyric acid (GABA) type A receptors, and allosterically modulating the chloride flux through the ion channel complex. First isolated from plants used as tranquilizers in folkloric medicine, some natural flavonoids have been shown to possess selective affinity for the benzodiazepine binding site with a broad spectrum of central nervous system effects. Since the initial search for alternative benzodiazepine ligands amongst the flavonoids, a list of successful synthetic derivatives has been generated with enhanced activities. This review provides an update on research developments that have established the activity of natural and synthetic flavonoids on GABA type A receptors. Flavonoids are prominent drugs in the treat-ment of mental disorders, and can also be used as tools to study modulatory sites at GABA type A receptors and to develop GABA type A selective agents further.
Background and purpose:
Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved.
Experimental approach:
Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c-Fos expression and in vitro electrophysiology.
Key results:
Honokiol (10 and 20 mg·kg⁻¹) significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c-Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep-promoting neurons in the VLPO by whole-cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol.
Conclusion and implications:
Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep.
Marine plants have been reported to possess various pharmacological properties; however, there have been few reports on their neuropharmacological effects. Terrestrial plants have depressive effects on the central nervous system (CNS) because of their polyphenols which make them effective as anticonvulsants and sleep inducers. We investigated in this study the depressive effects of the polyphenol-rich brown seaweed, Ecklonia cava (EC), on CNS. An EC enzymatic extract (ECEE) showed significant anticonvulsive (>500 mg/kg) and sleep-inducing (>500 mg/kg) effects on the respective mice seizure induced by picrotoxin and on the mice sleep induced by pentobarbital. The phlorotannin-rich fraction (PTRF) from ECEE significantly potentiated the pentobarbital-induced sleep at >50 mg/kg. PTRF had binding activity to the gamma aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptors. The sleep-inducing effects of diazepam (DZP, a well-known GABA(A)-BZD agonist), ECEE, and PTRF were completely blocked by flumazenil, a well-known antagonist of GABA(A)-BZD receptors. These results imply that ECEE produced depressive effects on CNS by positive allosteric modulation of its phlorotannins on GABA(A)-BZD receptors like DZP. Our study proposes EC as a candidate for the effective treatment of neuropsychiatric disorders such as anxiety and insomnia.
Little scientific evidence supports the efficacy of herbal medicines in the treatment of women with sleep difficulty during the climacteric period. The purpose of this study is to evaluate the efficacy and safety of Suan Zao Ren Tang (SZRT) in reducing the impact of sleep disturbance on climacteric women, as measured by Pittsburg sleep quality index (PSQI) and the World Health Organization quality of life (WHOQOL). Sixty-seven climacteric women with sleep difficulty intending to treat received SZRT at a rate of 4.0 g, thrice daily for four weeks (MRS < 16, n = 34; MRS ≥ 16, n = 33). After taking into account potential confounding factors, the mean PSQI total scores had fallen from 13.0 (±2.9) to 9.0 (±3.2) (95% confidence interval -4.93, -3.10). Further analyses showed that SZRT produced superior benefit of daytime dysfunction in women with severe menopausal symptoms (MRS ≥ 16). There were three of the withdrawals involved treatment-related adverse events (stomachache, diarrhea, and dizziness). Excluding women with a past history of stomachache, diarrhea, or dizziness, four weeks of therapy with SZRT appears to be a relatively safe and effective short-term therapeutic option in improving daytime function of climacteric women with poor sleep quality.
Flavonoids are present in almost all terrestrial plants, where they provide UV-protection and colour. Flavonoids have a fused ring system consisting of an aromatic ring and a benzopyran ring with a phenyl substituent. The flavonoids can be divided into several classes depending on their structure. Flavonoids are present in food and medicinal plants and are thus consumed by humans. They are found in plants as glycosides. Before oral absorption, flavonoids undergo deglycosylation either by lactase phloridzin hydrolase or cytosolic β-glucosidase. The absorbed aglycone is then conjugated by methylation, sulphatation or glucuronidation. Both the aglycones and the conjugates can pass the blood-brain barrier. In the CNS several flavones bind to the benzodiazepine site on the GABA(A)-receptor resulting in sedation, anxiolytic or anti-convulsive effects. Flavonoids of several classes are inhibitors of monoamine oxidase A or B, thereby working as anti-depressants or to improve the conditions of Parkinson's patients. Flavanols, flavanones and anthocyanidins have protective effects preventing inflammatory processes leading to nerve injury. Flavonoids seem capable of influencing health and mood.
Chronic insomnia afflicts up to 10% of the population in Western industrialized countries. It is characterized by delayed sleep onset, problems in maintaining sleep, early morning awakening or the feeling of non-restorative sleep coupled with significant daytime impairments on an emotional, social or professional level. It can occur as a co-morbid condition in any other medical or mental disorder, but also as a primary condition. Within the last decade new diagnostic and differential diagnostic approaches have been suggested that enhance diagnostic precision. Epidemiological data and data relating to the health care and cost situation of chronic insomnia suggest a huge burden for society. Chronic insomnia leads to a clear-cut increased risk for psychopathology (i. e., affective disorders) and probably also for cardiovascular and metabolic dysfunction. The pathophysiology of the condition is still poorly understood and will profit from integrating modern neuroscientific approaches (animal studies, molecular biology, neuroimaging, neurophysiology, etc.). Current treatment strategies are mainly based on cognitive behavioural interventions (CBT-I) and hypnotic treatment with benzodiazepine receptor agonists and sedating antidepressants. Although the effectiveness of these treatments has been clearly demonstrated, a substantial proportion of patients proves to be treatment-resistant or profits only poorly. The question of long-term pharmaceutical treatment of chronic insomnia, at least in Europe, is unresolved and urgently needs answers. Novel rational treatment avenues require clues on causes and mechanisms from integrated neuroscientific approaches. The important issues concerning insomnia treatment in the future especially in Europe will be reviewed and discussed critically.
To unravel mechanisms of action of dietary flavonoids in their potential role in disease prevention, it is crucial to know the factors that determine their release from foods, their extent of absorption, and their fate in the organism. Research on absorption, metabolism, and bioavailability of flavonoids will answer these questions. The subclass, flavonols, with quercetin as the major dietary flavonol, was the first to be studied, and information on other subclasses of flavonoids is emerging. Most flavonoids, except for the subclass of catechins, are present in plants bound to sugars as beta-glycosides. This structural feature determines whether the flavonoid can be absorbed from the small intestine or has to go to the colon before absorption can occur. Generally, but exceptions have been described, glucosides are the only glycosides that can be absorbed from the small intestine. Absorption from the small intestine is more efficient than from the colon and will lead to higher plasma values. After absorption from the small intestine, flavonoids are conjugated with glucuronic acid or sulfate or O-methylation may occur. The conjugation reactions, which occur in the small intestine upon absorption, are very efficient. As a result, no free flavonoid aglycones can be found in plasma or urine, except for catechins. Plasma concentrations due to a normal diet will be less than 1 microM. Flavonoids that cannot be absorbed from the small intestine, and absorbed flavonoids secreted with bile, will be degraded in the colon by microorganisms, which will break down the flavonoid ring structure. The resulting phenolic acids have partly been characterised. These phenolic acids can be absorbed and have been measured in plasma and urine. Future research will need to address tissue distribution, cellular uptake, and cellular metabolism.
Good sleep is necessary for physical and mental health. For example, sleep loss impairs immune function, and sleep is altered during infection. Immune signalling molecules are present in the healthy brain, where they interact with neurochemical systems to contribute to the regulation of normal sleep. Animal studies have shown that interactions between immune signalling molecules (such as the cytokine interleukin 1) and brain neurochemical systems (such as the serotonin system) are amplified during infection, indicating that these interactions might underlie the changes in sleep that occur during infection. Why should the immune system cause us to sleep differently when we are sick? We propose that the alterations in sleep architecture during infection are exquisitely tailored to support the generation of fever, which in turn imparts survival value.
Sleep is vital to cognitive performance, productivity, health and well-being. Earlier theories of sleep presumed that it occurred at the level of the whole organism and that it was governed by central control mechanisms. However, evidence now indicates that sleep might be regulated at a more local level in the brain: it seems to be a fundamental property of neuronal networks and is dependent on prior activity in each network. Such local-network sleep might be initiated by metabolically driven changes in the production of sleep-regulatory substances. We discuss a mathematical model which illustrates that the sleep-like states of individual cortical columns can be synchronized through humoral and electrical connections, and that whole-organism sleep occurs as an emergent property of local-network interactions.
St. John's Wort (Hypericum perforatum), a perennial flowering plant, has been used medicinally for thousands of years, and has most recently been identified as an effective treatment for mild to moderate depression. Clinical studies on the use of this plant for depression have utilized liquid tinctures and standardized solid extracts (0.3% hypericin--300 mg three times a day). Severe depression may also respond to this botanical, although it appears a larger dose is needed (600 mg solid extract three times a day). Hypericum has been favorably compared to numerous antidepressant drugs, the studies having revealed equivalent results and a much more favorable incidence of side effects. Studies have also demonstrated its efficacy in treating seasonal affective disorder. In vitro investigations of Hypericum show antiviral activity, although there is evidence these promising results might not occur in vivo. Traditional actions and uses include enhancement of wound healing, as well as anti-inflammatory and analgesic activity.
We studied the effect of two doses (0.9 mg and 1.8 mg) of Hypericum perforatum (St John's wort) on the sleep polysomnogram of healthy subjects using a placebo-controlled, cross-over design. Both doses of hypericum significantly increased the latency to rapid eye movement (REM) sleep without producing any other effect on sleep architecture. Our data are consistent with the proposed clinical antidepressant efficacy of hypericum, and raise the possibility that its pharmacological mechanism of action may be similar to that of conventional antidepressant medication.
Hypericum perforatum L. (St. John's wort; SJW) is one of the leading psychotherapeutic phytomedicines and great effort has been devoted to clarifying its mechanism of action.
We have undertaken a comprehensive analysis of several pure compounds isolated from the crude extract to gain further insight into the molecular actions of various substituents of SJW.
We characterized the in vitro pharmacology of the naphthodianthrones hypericin and pseudohypericin, the phloroglucinol derivative hyperforin, and several flavonoids at 42 biogenic amine receptors and transporters using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program.
The biflavonoid amentoflavone significantly inhibited binding at serotonin (5-HT(1D), 5-HT(2C)), D(3)-dopamine, delta-opiate, and benzodiazepine receptors. The naphthodianthrone hypericin had significant activity at D(3)- and D(4)-dopamine receptors and beta-adrenergic receptors. With the exception of the D(1)-dopamine receptor, the phloroglucinol derivative hyperforin was less active than other SJW constituents tested on all screened receptors.
Our present in vitro data clearly show that several pure substances in SJW are potential CNS psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner. Our data also reveal novel and heretofore unexpected interactions of pure compounds in SJW at a number of GPCRs, transporters, and ion channels. We hypothesize that additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW. These results and this general approach may impact our understanding of phytomedicines in general and H. perforatum specifically.
We examined the effects of ornithine on the sleep–wake cycle by monitoring the electroencephalogram, electromyogram, and locomotor activity of freely moving mice after oral administration of it at lights‐off time (18:00). Ornithine (1.0 and 3.0 g/kg of body weight) increased the amount of non–rapid eye movement (non‐REM, NREM) sleep for 2 h after its administration, with a peak at 60 min post administration, to 164% and 198%, respectively, of that of the vehicle‐administered mice, without changing the amount of REM sleep. The administration of ornithine at a lower dose (0.3 g/kg of body weight) did not increase the amount of NREM sleep compared with the vehicle administration. Ornithine did not affect the power spectrum density of NREM sleep but increased the number of episodes of wakefulness and NREM sleep and that of transitions between wakefulness and NREM sleep, and decreased the mean duration of wake episodes in a dose‐dependent manner for 2 h after the oral administration. These results indicate that ornithine increased the amount of NREM sleep without reducing the power spectrum density of NREM sleep.
Flavonoids are a group of polyphenolic compounds, diverse in chemical structure and characteristics, found ubiquitously in plants. Therefore, flavonoids are part of the human diet. Over 4,000 different flavonoids have been identified within the major flavonoid classes which include flavonols, flavones, flavanones, catechins, anthocyanidins, isoflavones, dihydroflavonols, and chalcones. Flavonoids are absorbed from the gastrointestinal tracts of humans and animals and are excreted either unchanged or as flavonoid metabolites in the urine and feces. Flavonoids are potent antioxidants, free radical scavengers, and metal chelators and inhibit lipid peroxidation. The structural requirements for the antioxidant and free radical scavenging functions of flavonoids include a hydroxyl group in carbon position three, a double bond between carbon positions two and three, a carbonyl group in carbon position four, and polyhydroxylation of the A and B aromatic rings. Epidemiological studies show an inverse correlation between dietary flavonoid intake and mortality from coronary heart disease (CHD) which is explained in part by the inhibition of low density lipoprotein oxidation and reduced platelet aggregability. Dietary intake of flavonoids range between 23 mg/day estimated in The Netherlands and 170 mg/day estimated in the USA. Major dietary sources of flavonoids determined from studies and analyses conducted in The Netherlands include tea, onions, apples, and red wine. More research is needed for further elucidation of the mechanisms of flavonoid absorption, metabolism, biochemical action, and association with CHD.
Sleep is an essential part of life. It is not a passive state of unconsciousness, but rather a dynamic brain processthat is the result of the interaction between two largely independent basic mechanisms: the circadian rhythm and the homeostatic drive to sleep. Its exact role has yet to be elucidated but it is known that sleep plays an important role in the restoration of physical and mental functioning.Sleep can be described both quantitatively and qualitatively, subjectively and objectively. Recent research hasled to a substantially improved understanding of both normal and altered sleep patterns, and their impact on health. A large diversity of factors has been described that can either favourably or adversely influence sleep, including sleep deprivation, sleep fragmentation, medical conditions and external stimuli. Normal sleep patterns vary significantly across the life-course, with more disrupted and less efficient sleep seeming to occur in the elderly. Sleep disorders are frequent and diverse in their origin, and commonly result in excessive daytime somnolence, which can have a major impact on daytime performance and safety in the individual. Also, chronic sleep disturbance is associated with increased morbidity and mortality. It is thus important that the quality of sleep is maintained, and situations and conditions known to have a negative impact on sleep initiation and maintenance should be prevented or treated.
In a randomized, placebo-controlled double-blind study two groups of 29 patients each with anxiety syndromes not caused by mental disorders were treated for four weeks with three daily doses of 100 mg of Kava extract WS 1490 (Laitan®) from Piper methysticum rhizoma or a placebo preparation. Therapeutic efficacy was assessed by the Hamilton Anxiety Scale (main outcome variable), the Adjectives Check List and the Clinical Global Impression Scale (secondary target variables) after 1, 2, and 4 weeks of treatment. The HAMA overall score of anxiety symptomatology revealed a significant reduction in the drug group compared with the placebo group after one week of treatment. The difference between the two groups of patients increased during the course of the study. The results of the secondary target variables were in agreement with the HAMA score and demonstrated the efficacy of WS 1490 in patients with anxiety disorders. No adverse reactions caused by the medication were noted during the four weeks WS 1490 was administered.
a b s t r a c t The primary objective was to investigate whether seaweeds have hypnotic activity. Methanol extracts of 30 seaweeds were screened for their binding activity at the GABA type A–benzodiazepine (GABA A –BZD) receptor, a well-characterised molecular target for sedative–hypnotics. The most active seaweed was Ecklonia cava Kjellman (ECK). An ethanol extract of ECK (ECK-E) significantly potentiated pentobarbi-tal-induced sleep in mice. In four solvent fractions separated from ECK-E, hypnotic activity was propor-tional to contents of total phenols and total phlorotannins, known as seaweed polyphenols. Major phlorotannins of the ethyl acetate (EtOAc) fraction with the highest activity were eckol, eckstolonol, dieckol, and triphlorethol-A, and their K i (binding affinity, lM) values for [ 3 H]-flumazenil binding were 1.070, 1.491, 3.072, and 4.419, respectively. Hypnotic effects of ECK-E and the EtOAc fraction were fully inhibited by flumazenil, a specific GABA A –BZD receptor antagonist. These results imply that phlorotan-nins of ECK induce sleep by positive allosteric modulation of the GABA A –BZD receptor. Ó 2011 Published by Elsevier Ltd.
Magnolol (6,6',7,12-tetramethoxy-2,2'-dimethyl-1-beta-berbaman, C(18)H(18)O(2)), an active ingredient of the bark of Magnolia officinalis, has been reported to exert potent anti-epileptic effects via the GABA(A) receptor. The receptor also mediates sleep in humans and animals. The aim of this study was to determine whether magnolol could modulate sleep behaviors by recording EEG and electromyogram in mice. The results showed that magnolol administered i.p. at a dose of 5 or 25 mg/kg could significantly shorten the sleep latency, increase the amount of non-rapid eye movement (non-REM, NREM) and rapid eye movement (REM) sleep for 3 h after administration with an increase in the number of NREM and REM sleep episodes. Magnolol at doses of 5 and 25 mg/kg increased the number of bouts of wakefulness but decreased their duration. On the other hand, magnolol increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. Immunohistochemical study showed that magnolol increased c-Fos expression in the neurons of ventrolateral preoptic area, a sleep center in the anterior hypothalamus, and decreased c-Fos expression in the arousal tuberomammillary nucleus, which was located in the caudolateral hypothalamus. The sleep-promoting effects and changes in c-Fos induced by magnolol were reversed by flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor. These results indicate that magnolol increased NREM and REM sleep via the GABA(A) receptor.
As part of this study on the isolation of cholinesterase inhibitors from natural marine products, the bioactivity of the ethanolic extracts from 27 Korean seaweeds were screened using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory assays. Ecklonia stolonifera exhibited promising inhibitory properties against both AChE and BChE. Bioassay-guided fractionation of the active n-hexane and ethyl acetate (EtOAc) soluble fractions, obtained from the ethanolic extract of E. stolonifera, resulted in the isolation of the sterols; fucosterol (1) and 24-hydroperoxy 24-vinylcholesterol (2), from the n-hexane fraction and the phlorotannins; phloroglucinol (3), eckstolonol (4), eckol (5), phlorofucofuroeckol-A (6), dieckol (7), triphlorethol-A (8), 2-phloroeckol (9) and 7-phloroeckol (10), from the EtOAc fraction. Of these, compounds 2, 9 and 10 were isolated from E. stolonifera for the first time. Compounds 4–7, 9 and 10 exhibited inhibitory potential against AChE, with 50% inhibition concentration (IC50) values of 42.66 ± 8.48, 20.56 ± 5.61, 4.89 ± 2.28, 17.11 ± 3.24, 38.13 ± 4.95 and 21.11 ± 4.16 μM, respectively; whereas, compounds 1, 2, 4 and 6 were found to be active against BChE, with IC50 values of 421.72 ± 1.43, 176.46 ± 2.51, 230.27 ± 3.52 and 136.71 ± 3.33 μM, respectively. It has been suggested that the inhibition of these enzymes by the sterols and phlorotannins derived from marine brown algae could be a useful approach for the treatment of Alzheimer's disease.
OBJECTIVE: To measure the prevalence of sleep problems in a working population and examine their association with health problems, health-related
quality-of-life measures, work-related problems, and medical expenditures. Also, to explore the usefulness of a sleep-problems
screen for mental health conditions and underlying sleep disorders.
DESIGN: Cross-sectional survey administered via voice mail and telephone interview.
SETTING: A San Francisco Bay Area telecommunications firm.
PARTICIPANTS: Volunteer sample of 588 employees who worked for a minimum of six months at the company and were enrolled in its fee-for-service
health plan.
MEASUREMENTS AND MAIN RESULTS: Thirty percent of respondents reported currently experiencing sleep problems and were found to have worse functioning and
well-being (general health, cognitive functioning, energy), more work-related problems (decreased job performance and lower
satisfaction, increased absenteeism), and a greater likelihood of comorbid physical and mental health conditions than were
the respondents who did not have sleep problems. They also demonstrated a trend toward higher medical expenditures.
CONCLUSIONS: Self-perceived sleep problems were common among the respondents and were associated with poorer health and health-related
quality of life. A single question about sleep problems may serve as an effective screen for identifying primary care patients
with mental health problems, as well as underlying sleep disorders.
The local and chemical distribution of phlorotannins among the Japanese Laminariaceae, Eisenia bicyclis, Ecklonia cava and Ecklonia kurome, was investigated. As a result of light microscopy observations with vanillin-HCl staining, phlorotannins were found to be accumulated within the vegetative cells of the outer cortical layer of the thalli, regardless of the species, stage of growth or organ. Crude phlorotannins comprised about 3.0% of the algal powder for each of the algae. High-performance liquid chromatography (HPLC) showed that the phlorotannins of E. bicyclis were composed of phloroglucinol (0.9%), phloroglucinol tetramer (4.4%), eckol (7.5%), phlorofucofuroeckol A (21.9%), dieckol (23.4%), and 8,8''-bieckol (24.6%), plus some other unknown phenolic compounds (17.3%). The composition of the phlorotannins differed little among the Laminariaceae, except for a significantly larger amount of the tetramer, MW 478, in E. bicyclis.
This experiment was performed to investigate whether apigenin has hypnotic effects and/or enhances pentobarbital-induced sleep behaviors through the GABAergic systems. Apigenin prolonged sleep time induced by pentobarbital similar to muscimol, a GABA(A) receptors agonist. Apigenin also increased sleep rate and sleep time in the combined administration with pentobarbital at the sub-hypnotic dosage, and showed synergic effects with muscimol in potentiating sleep onset and enhancing sleep time induced by pentobarbital. In addition, both of apigeinin and pentobarbital increased chloride influx in primary cultured cerebellar granule cells. Apigenin increased glutamate decarboxylase (GAD) and had no effect on the expression of GABA(A) receptor α-, β-, γ-subunits in n hippocampus of mouse brain, showing different expression of subunits from pentobarbital treatment group. In conclusion, it is suggested that apigenin augments pentobarbital-induced sleep behaviors through chloride ion channel activation.
Introduction:
The imidazopyridine derivative zolpidem , which acts as a benzodiazepine (BZ) receptor agonist, is the most widely prescribed hypnotic drug in the US.
Areas covered:
This review addresses the neuroreceptor properties of zolpidem; clinical pharmacokinetics, pharmacodynamics and drug interactions; efficacy as a hypnotic; adverse effects; tolerance, dependence and withdrawal; relation to motor vehicle accidents and complex sleep behaviors; and new dosage forms.
Expert opinion:
Approved doses of zolpidem (10 mg for adults, 5 mg for the elderly) are consistently effective in reducing sleep latency and consequently increasing sleep duration in patients with insomnia. However, favorable effects on sleep maintenance are observed less consistently. Residual daytime effects are unlikely with recommended doses, and provided that at least 8 h elapse prior to arising. Hypnotic efficacy is maintained with repeated nightly use, and the risk of rebound insomnia is low. Dependence and abuse of zolpidem are no more likely to occur than with typical benzodiazepines. Newly available novel dosage forms of zolpidem have increased therapeutic options for patients with insomnia variants such as sleep maintenance insomnia and middle-of-the-night awakening.
Crocus sativus L. (saffron) has been traditionally used for the treatment of insomnia and other diseases of the nervous systems. Two carotenoid pigments, crocin and crocetin, are the major components responsible for the various pharmacological activities of C. sativus L. In this study, we examined the sleep-promoting activity of crocin and crocetin by monitoring the locomotor activity and electroencephalogram after administration of these components to mice. Crocin (30 and 100 mg/kg) increased the total time of non-rapid eye movement (non-REM) sleep by 60 and 170%, respectively, during a 4-h period from 20:00 to 24:00 after its intraperitoneal administration at a lights-off time of 20:00. Crocetin (100 mg/kg) also increased the total time of non-REM sleep by 50% after the administration. These compounds did not change the amount of REM sleep or show any adverse effects, such as rebound insomnia, after the induction of sleep.
Isoliquiritigenin (ILTG) is a chalcone compound and has valuable pharmacological properties such as antioxidant, anti-inflammatory, anticancer, and antiallergic activities. Recently, the anxiolytic effect of ILTG has been reported; however, its action mechanism and hypnotic activity have not yet been demonstrated. Therefore, we investigated the hypnotic effect and action mechanism of ILTG. ILTG significantly potentiated the pentobarbital-induced sleep in mice at doses of 25 and 50mg/kg. The hypnotic activity of ILTG was fully inhibited by flumazenil (FLU), a specific gamma-aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptor antagonist. The binding affinity of ILTG was 0.453 μM and was found to be higher than that of the reference compound, diazepam (DZP, 0.012 μM). ILTG (10(-5)M) potentiated GABA-evoked currents to 151% of the control level on isolated dorsal raphe neurons. ILTG has 65 times higher affinity for GABA(A)-BZD receptors than DZP, and the dissociation constant for ILTG was 4.0 × 10(-10)M. The effect of ILTG on GABA currents was blocked by 10(-7)M FLU and ZK-93426. These results suggest that ILTG produces hypnotic effects by positive allosteric modulation of GABA(A)-BZD receptors.
This experiment investigated whether (-)-epigallocatechin-3-O-gallate (EGCG) (5-20 mg/kg, p.o.) has hypnotic effects and/or enhances pentobarbital-induced sleeping behaviors and whether these effects are mediated by γ-aminobutyric acid (GABA) receptors. EGCG prolonged sleeping time induced by pentobarbital (42 mg/kg, i.p.) and reduced sleeping latency induced by pentobarbital similarly to muscimol (0.2 mg/kg, i.p.), a GABA(A) receptor agonist in mice. EGCG also increased sleeping rate and sleeping time when co-administered with pentobarbital (28 mg/kg, i.p.) at a subhypnotic dosage. In addition, EGCG and pentobarbital increased chloride (Cl(-)) influx in primary cultured cerebellar cells. EGCG and pentobarbital decreased GABA(A) receptors α-subunit expression and had no effect on the expression of β- and γ-subunits and of glutamic acid decarboxylase in the hippocampus of rats. In conclusion, the EGCG enhancement of Cl(-) influx may play an important role in pentobarbital-induced sleeping behaviors.
Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H₁ receptor occupancy (H₁RO) measured using ¹¹C-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H₁ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H₁RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H₁RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.
Insomnia is an often seen primary health care problem. Valerian might be an alternative treatment with fewer secondary effects. The aim of this study is to evaluate its effectiveness on insomnia through a meta-analysis of published literature.
Search for randomized clinical trials (RCTs) of Valerian preparations compared with a placebo on Medline, the Cochrane Library, Embase and Biosis. Outcomes: sleep-quality improvement (SQ, yes/no), sleep-quality improvement quantified through visual analogical scales (SQS) and the latency time (LT) in minutes until getting to sleep. Three meta-analyses were carried out using inverse-variance weighted random effects models. Heterogeneity was determined with the Q-statistic and was explored through a sub-groups analysis. Publication bias was evaluated using the funnel plot.
Eighteen RCTs were selected; eight had a score of 5 on Jadad's scale. The mean differences in LT between the Valerian and placebo treatment groups was 0.70 min (95% CI, -3.44 to 4.83); the standardized mean differences between the groups measured with SQS was -0.02 (95% CI, -0.35 to 0.31); treatment with Valerian showed a relative risk of SQ of 1.37 (95% CI, 1.05-1.78) compared with the placebo group. There was heterogeneity in the three meta-analyses, but it diminished in the sub groups analysis. No publication bias was detected.
The qualitative dichotomous results suggest that valerian would be effective for a subjective improvement of insomnia, although its effectiveness has not been demonstrated with quantitative or objective measurements. We recommend future investigations oriented toward improving insomnia with other more promising treatments.
Insomnia is a common complaint in the general population. Interest in the use of alternative treatments for insomnia is increasing exponentially and is fairly common in Taiwan. We undertook a survey to define the drug utilization patterns of Chinese herbal medicines (CM) for insomnia in Taiwan.
The survey was conducted over a period of 4 years, from January 2003 to December 2006. Outpatients with primary insomnia and being treated with CM were studied. Core drug-use indicators were the number of CM items per prescription, the dosing frequency and duration of CM prescriptions, the most common prescribed CM herbs and CM formulae used.
Six thousand eight hundred and sixty patients, using 37,046 CM herb items, were screened during the study period. The average CM items per prescription was 5.40. Most of prescriptions (95.23%) were prescribed for administration three times a day. The most often prescribed Chinese herbal products were Hong-Hwa (Carthamus tinctorius) and Jia-Wey-Shiau-Yau-San, which includes Angelica sinensis, Atractylodes macrocephala, Paeonia lactiflora, Bupleurum chinense, and Poria coco.
This is the first extensive survey examining the drug utilization patterns of Chinese herbal medicines in the treatment of insomnia. Although the data were generated in Taiwan, the herbs and practices identified are likely to be widely generalizable wherever Chinese herbal remedies are used for insomnia. Multiple herbs and complex formulae were commonly used. The baseline data generated should be of use in informing subsequent studies, including those aimed at a thorough evaluation of the herbs' effectiveness.
Semen Ziziphi spinosae (Suanzaoren in China) and Radix et Rhizoma Salviae miltiorrhizae (Danshen in China) are conventional herbal drugs in traditional Chinese medicine and have been used widely for the treatment of insomnia. In the present study, the sedative-hypnotic activity of the active fractions extracted from Suanzaoren and Danshen were studied using the method of pentobarbital-induced sleep in the mouse model. Qualitative analysis of the standardized extracts was carried out by HPLC-DAD. The results showed that the water extract of Suanzaoren (SWE) (400 and 800 mg/kg body wt.) and the ether extract of Danshen (DTT) (300 and 600 mg/kg body wt.) can shorten sleep latency significantly, increase sleeping time and prolong movement convalescence time induced by sodium pentobarbital (55 mg/kg body wt.) administration in mice. Furthermore, the combination of SWE and DTT showed significant synergistic effect (p<0.05) in decreasing sleep latency and increasing sleeping time, but not in prolonging the movement convalescence time, which might be helpful for energy recovery in the treatment of insomnia. The results suggest that SWE, DTT, and the combination of SWE and DTT possess significant sedative-hypnotic activity, which supports the popular use of Suanzaoren and Danshen for treatment of insomnia and provide the basis for new drug discovery. Furthermore, the results demonstrate that the combination of SWE and DTT may be preferable for the treatment of insomnia.
Bioactivity-guided fractionation of Ecklonia stolonifera was used to determine the chemical identity of bioactive constituents, with potent antioxidant activities. The structures of the phlorotannins were determined on the basis of spectroscopic analysis, including NMR and mass spectrometry analysis. The antioxidant activities of the isolated compounds were evaluated by free radical scavenging activities in both in vitro and cellular systems. The anti-inflammatory effects of the isolated compounds were evaluated by determining their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophage cells. The results indicated that phlorofucofuroeckol A, dieckol, and dioxinodehydroeckol showed potential radical scavenging activities against 2,2-diphenyl-1-picrylhydrazyl. Among them, phlorofucofuroeckol A and dieckol significantly suppressed the intracellular reactive oxygen species level assayed by 2',7'-dichlorofluorescein diacetate assay in LPS-induced RAW 264.7 cells. Phlorofucofuroeckol A significantly inhibited the LPS-induced production of NO and PGE(2) through the down-regulation of inducible nitric oxide synthase and cyclooxygenase 2 protein expressions. In conclusion, these results suggest that phlorofucofuroeckol A has a potential for functional foods with antioxidant and anti-inflammatory activities.
The effect of an aqueous extract of valerian (Valeriana officinalis L.) root on subjectively rated sleep measures was studied on 128 people. Each person received 9 samples to test (3 containing placebo, 3 containing 400 mg valerian extract and 3 containing a proprietary over-the-counter valerian preparation). The samples, identified only by a code number, and presented in random order, were taken on non-consecutive nights. Valerian produced a significant decrease in subjectively evaluated sleep latency scores and a significant improvement in sleep quality: the latter was most notable among people who considered themselves poor or irregular sleepers, smokers, and people who thought they normally had long sleep latencies. Night awakenings, dream recall and somnolence the next morning were relatively unaffected by valerian. With the proprietary valerian-containing preparation, the only change was a significant increase in reports of feeling more sleepy than normal the next morning. Thus the questionnaire, simple to use and non-invasive, provides a sensitive means for detecting the effects of mild sedatives on different aspects of sleep in man. It also allows identification within the test population of the subgroups most affected.
The dried flower heads of Matricaria recutita L. (Asteraceae) are used in folk medicine to prepare a spasmolytic and sedative tea. Our fractionation of the aqueous extract of this plant led to the detection of several fractions with significant affinity for the central benzodiazepine receptor and to the isolation and identification of 5,7,4'-trihydroxyflavone (apigenin) in one of them. Apigenin competitively inhibited the binding of flunitrazepam with a Ki of 4 microM and had no effect on muscarinic receptors, alpha 1-adrenoceptors, and on the binding of muscimol to GABAA receptors. Apigenin had a clear anxiolytic activity in mice in the elevated plusmaze without evidencing sedation or muscle relaxant effects at doses similar to those used for classical benzodiazepines and no anticonvulsant action was detected. However, a 10-fold increase in dosage produced a mild sedative effect since a 26% reduction in ambulatory locomotor activity and a 35% decrement in hole-board parameters were evident. The results reported in this paper demonstrate that apigenin is a ligand for the central benzodiazepine receptors exerting anxiolytic and slight sedative effects but not being anticonvulsant or myorelaxant.
Patients with chronic insomnia are more likely to develop affective disorders, cardiac morbidity, and other adverse health outcomes, yet many clinicians tend to trivialize the complaint of insomnia or to attribute it only to psychiatric causes.
To estimate the prevalence and longitudinal course of insomnia in patients with documented chronic medical illness and/or depression and to quantify the associations between specific chronic conditions and insomnia.
The presence of mild or severe insomnia was based on responses to a sleep questionnaire completed by 3445 patients with at least 1 of 5 physician-identified chronic conditions (hypertension, diabetes, congestive heart failure, myocardial infarction, or depression) at baseline; a subsample of 1814 patients completed follow-up questionnaires at 2 years. Using multivariate techniques, we evaluated the relationship between chronic conditions, patient-reported comorbidities, and insomnia (complaints of initiating and maintaining sleep), adjusting for sociodemographics and health habits.
Sixteen percent of study patients had severe and 34% had mild insomnia at baseline. At 2-year follow-up, 59% (95% confidence interval, 55%-63%) of patients with mild insomnia and 83% (95% confidence interval, 78%-88%) of patients with severe insomnia at baseline still had sleep problems. Odds ratios corresponding to mild and severe insomnia for key risk factors were as follows: current depressive disorder, 2.6 and 8.2; subthreshold depression, 2.2 and 3.4; congestive heart failure, 1.6 and 2.5; obstructive airway disease, 1.6 and 1.5; back problems, 1.4 and 1.5; hip impairment, 2.2 and 2.7; and prostate problems, 1.6 and 1.4. The majority of insomnia-comorbidity associations observed at baseline persisted at 2-year follow-up.
Patients with insomnia require follow-up, as the majority continue to be bothered by difficulty initiating and maintaining sleep. In addition to detecting affective disorders in patients with insomnia, clinicians should focus on medical conditions that disturb sleep, especially cardiopulmonary disease, painful musculoskeletal conditions, and prostate problems.
Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.
The increasing recognition of green tea and tea polyphenols as cancer preventives has created a need for a study of their bioavailability. For this purpose, we synthesized [3H] (-)-epigallocatechin gallate ([3H]EGCG) with a specific activity of 48.1 GBq/mmol and directly administered the solution into the stomachs of CD-1 female or male mice. Radioactivity in the digestive tract, various organs, blood, urine and feces was measured with an oxidizer at various times after administration and significant radioactivity was found in the previously reported target organs of EGCG and green tea extract (digestive tract, liver, lung, pancreas, mammary gland and skin), as well as other organs (brain, kidney, uterus and ovary and testes) in both sexes. Incorporation of radioactivity in the cells was confirmed by microautoradiography. Within 24 h, 6.6 (females) and 6.4% (males) of total administered radioactivity was excreted in the urine and 37.7 and 33.1% in feces. HPLC analysis of urine from both sexes revealed that 0.03-0.59% of administered [3H]EGCG, along with at least five metabolites, was excreted. In addition, we found that a second, equal administration to female mice after a 6 h interval enhanced tissue levels of radioactivity in blood, brain, liver, pancreas, bladder and bone 4-6 times above those after a single administration. These results suggest that frequent consumption of green tea enables the body to maintain a high level of tea polyphenols and this paper is the first pharmacological evidence of a wide distribution of [3H]EGCG in mouse organs, indicating a similar wide range of target organs for cancer prevention in humans.
Polyphenols constitute one of the most numerous and ubiquitous groups of plant metabolites and are an integral part of both human and animal diets. Ranging from simple phenolic molecules to highly polymerized compounds with molecular weights of greater than 30,000 Da, the occurrence of this complex group of substances in plant foods is extremely variable. Polyphenols traditionally have been considered antinutrients by animal nutritionists, because of the adverse effect of tannins, one type of polyphenol, on protein digestibility. However, recent interest in food phenolics has increased greatly, owing to their antioxidant capacity (free radical scavenging and metal chelating activities) and their possible beneficial implications in human health, such as in the treatment and prevention of cancer, cardiovascular disease, and other pathologies. Much of the literature refers to a single group of plant phenolics, the flavonoids. This review offers an overview of the nutritional effects of the main groups of polyphenolic compounds, including their metabolism, effects on nutrient bioavailability, and antioxidant activity, as well as a brief description of the chemistry of polyphenols and their occurrence in plant foods.
The underground organs of members of the genus Valeriana (Valerianaceae), as well as related genera such as Nardostachys, are used in the traditional medicine of many cultures as mild sedatives and tranquillizers and to aid the induction of sleep. V. officinalis is the species most commonly used in northern Europe and still retains its official pharmaco-poeial status although it is most commonly encountered as an ingredient of herbal medicines. This plant is still the subject of considerable research aimed at establishing the chemical and pharmacological basis of the activity which has been clearly shown in a number of animal and clinical studies.
The constituents of the volatile oil are very variable due to population differences in genetics and to environmental factors. The major constituents include the monoterpene bornyl acetate and the sesquiterpene valerenic acid, which is characteristic of the species, in addition to other types of sesquiterpene. Some of these have been shown to have a direct action on the amygdaloid body of the brain and valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain resulting in sedation. The non-volatile monoterpenes known as valepotriates were first isolated in 1966 and contribute to the overall activity by possessing sedative activity based on the CNS although the mode of action is not clearly known. The valepotriates themselves act as prodrugs which are transformed into homobaldrinal which has been shown to reduce the spontaneous motility of mice. More recent studies have shown that aqueous extracts of the roots contain appreciable amounts of GABA which could directly cause sedation but there is some controversy surrounding the bioavailability of this compound. Another recent finding is the presence of a lignan, hydroxypinoresinol, and its ability to bind to benzodiazepine receptors.
Valerian is a good example of both the negative and positive aspects of herbal drugs. The considerable variation in its composition and content as well as the instability of some of its constituents pose serious problems for standardization but the range of components which contribute to its overall activity suggest that it may correct a variety of underlying causes of conditions which necessitate a general sedative or tranquillizing effect.
Dried flowers of Matricaria chamomilla L. are largely used to provide sedative as well as spasmolytic effects. In the present study, we examined in particular the pharmacological property of a fraction isolated from a methanolic extract of M. chamomilla, which was identified by HPLC-MS-MS analysis as apigenin. By radioreceptor binding assays, we demonstrated the ability of the flavone to displace a specific radioligand, [(3)H]Ro 15-1788, from the central benzodiazepine binding site. Electrophysiological studies performed on cultured cerebellar granule cells showed that apigenin reduced GABA (gamma-aminobutyric acid)-activated Cl(-) currents in a dose-dependent fashion. The effect was blocked by co-application of Ro 15-1788, a specific benzodiazepine receptor antagonist. Accordingly, apigenin reduced the latency in the onset of picrotoxin-induced convulsions. Moreover, apigenin injected i.p. in rats reduced locomotor activity, but did not demonstrate anxiolytic, myorelaxant, or anticonvulsant activities. The present results seem to suggest that the inhibitory activity of apigenin on locomotor behaviour in rats cannot be ascribed to an interaction with GABA(A)-benzodiazepine receptor but to other neurotransmission systems, since it is not blocked by Ro 15-1788.
Insomnia is a common problem requiring appropriate recognition and management. Despite recent advances in the development of newer hypnotics in western medicine, a significant proportion of patients with insomnia, both locally and internationally, consume herbal hypnotics regularly. The safety and efficacy of these herbal remedies remains uncertain. In this paper, details of different herbs used in western and traditional Chinese medicine for the treatment of insomnia are reviewed. Although current data suggests the use of some herbal treatments in insomnia may be efficacious, further laboratory and clinical studies are required.
To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 3'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5'-bromo-2'-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (K(i) = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made.