Although drugs such as barbiturates and benzodiazepines are often used for the treatment of insomnia, they are associated with various side effects such as habituations, tolerance and addiction. Alternatively, natural products with minimal unwanted effects have been preferred for the treatment of acute and/or mild insomnia, with additional benefits of overall health-promotion. Basic and clinical researches on the mechanisms of action of natural products have been carried out so far in insomnia treatments. Recent studies have been focusing on diverse chemical components available in natural products, with an interest of developing drugs that can improve sleep duration and quality. In the last 15 years, our co-workers have been actively looking for candidate substances from natural products that can relieve insomnia. This review is, therefore, intended to bring pharmacological data regarding to the effects of natural products on sleep duration and quality, mainly through the activation of GABAA receptors. It is imperative that phytochemicals will provide useful information during electroencephalography (EEG) analysis and serve as an alternative medications for insomnia patients who are reluctant to use conventional drugs.
Most people often or chronically experience insomnia characterized by difficulty in falling asleep, overnight loss of sleep, trouble to resume sleep, waking up too early, unable to refreshed after sleep and loss of working time due to tiredness and faintness (National Sleep Foundation, USA). Sleep is vital to maintain mood, memory, cognitive function by restoring the majority of human body systems through endocrine and immune functions. Therefore, sleep is one of the most instinctive and essential physiological demand for normal life such as maintaining health and mental stability. Meanwhile, humans may suffer from various sleep disorders, including insomnia, hypersomnia, narcolepsy, and sleep apnea (Jacobson
On the other hand, insomnia has been associated with psychiatric conditions, unhealthy sleep habits, specific excitatory substances, and/or certain biological factors. Moreover, medical conditions with comorbidities may aggravate these insomnia related abnormalities (Starks
So far, studies have been focusing on various molecules leading into insomnia. Many of these molecules involved in sleep-wake regulation are produced by specific brain regions with widespread projections. Research findings have been largely interpreted within the context of hyperarousal hypothesis. For instance, insomnia patients with GABA in the occipital cortex has been reported to be consistent with the hyperarousal model of insomnia. In addition, emotional and cognitive systems lead to suppression of sleep-promoting regions such as the ventrolateral preoptic area (VLPO) (Wang and Liu, 2016; Bourcier
Rats were anesthetized with pentobarbital (50 mg/kg, i.p.) and the transmitter was implanted for recording EEG via telemetry as described earlier (Sanford
For telemetric recording of signals from cortical EEG, the gain of transmitters was set at −0.5/+0.5 volts per units ×2 with raw signals ranging from 0.5 to 0.0 Hz and these signals were processed by Data Sciences analog converter and routed to an analog-to-digital (AD) converter (Eagle PC30, Data Sciences International). The AD converter digitized the EEG and activity signals; subsequently data were transferred to a computer and graphically displayed. An on-line fast Fourier transformation (FFT) analyzed EEG data and generated power density values from 0.0 to 20.0 Hz at a resolution of 0.5 Hz. The FFT data were further averaged between 0 to 20 Hz at 10-s intervals. The sleep data and FFT results were saved to the hard disk every 10 s for additional off-line analysis. Movements of the animal in relation to the telemetry receiver generated transistor-transistor logic pulses that were collected and counted as a measure of activity. The signal of EEG was measured for 6 hours between 11:00 am and 5:00 pm. Each group has 5–6 rats (Hu
Time elapsed in wakefulness, NREM sleep or REM sleep was determined from digitized data within 10 s using the animal sleep analysis software Sleep-Sign 2.1 (Kissei Comtec, Matsumoto, Japan). Briefly, the software identifies wakefulness as a high-frequency with low-amplitude of EEG whereas in NREM sleep, it showed spindles interspersed with slow waves compared with REM sleep characterized by δ-waves (0.75 to 4.0 Hz) and θ-wave activity (5.0 to 9.0 Hz) with peak value at 7.5 Hz.
Several efficacious pharmacological treatments for insomnia target to various aspects of identified pathophysiologic processes. For instance, GABA is released from the terminal of specific inhibitory neurons and then it binds to its receptors, thereby enhancing chloride influx and facilitates GABAA-ergic transmission (Olsen, 1981; Ticku and Maksay, 1983). This effect is supported by benzodiazepines and barbiturates by their agonistic effects on the GABAA receptors. Thus, their binding to the allosteric site of the receptors enhances the affinity of the GABA-binding site. However, four different types of GABAA receptor subunits have been described, each of which encloses different membranes. Likewise, the critical step in GABA biosynthesis is the decarboxylation of glutamate by glutamic acid decarboxylase (GAD), which exists in two different isoforms, GAD65 and GAD67. The level of GAD65 and GAD67 is reported to be up-regulated in the GABAA-ergic interneurons. With this intricate nature, GABAA receptors have been known to play an important role in the modulation of barbiturate-induced sleeping through interaction with GABAA-ergic systems (Doghramji, 2006). GABA-benzodiazepine receptor agonists which are generally effective in the treatment of insomnia can promote sleep by enhancing the widespread function of GABA. This suggest that new compounds can be developed for specific molecular targets with known sleep-related actions. Apart from this, non-GABAA-chloride channel receptor complex agonist such as melatonin (MT) receptor agonist, 5-HT1A receptor agonist, orexin receptor agonist, adenosine receptor agonist and histamine receptor antagonist have been suggested for the treatment of insomnia (Dujardin
The possible role of serotonin (5-HT) in human sleep disorders has been considered. Ursin provides an excellent overview of the evolving concept of the role of serotonin (5-HT) in sleep, supporting the sleep-promoting effects (Ursin, 2002). The role of specific receptor subtypes in sleep-wake regulation has been focused. Gronli reported the effect of certain drugs affecting 5-HT1A and 5-HT1B receptors, which have affinity at the pre- and post-synaptic receptors, later including inhibitory auto-receptors on serotonin neurons, themselves (Grønli
Non-benzodiazepine hypnotics such as diphenhydramine and doxylamine have been used for the treatment of insomnia. The sedative effect of antihistamines is mainly achieved by targeting the histamine receptors in arousal systems. More recently, there has been progress in the development of orexin receptor antagonists for the treatment of insomnia. Orexin systems target on the promotion of arousal of brainstem/hypothalamic arousal centers (Mieda, 2017). In addition to this, other molecular targets such as melatonin and adenosine have been suggested for the treatment of insomnia (Di Bella
Various compounds, with novel approaches are being evaluated currently as possible insomnia treatments. Currently, Korea FDA is reviewing new applications for innovative sleep-promoting herbs. Clinical indications have been developed for insomnia associated with problem of sleep onset, sleep maintenance, and middle-of-the-night awakenings. Alternative approaches to treating insomnia have included an off-label basis for insomnia, over-the-counter sleep aids, and assorted unregulated substances marketed to enhance sleep. Substances regarded as appropriate hypnotics are those which prevent continuous awakenings, shorten the period of latency for sleep initiation and increase sleep duration, besides displaying low toxicity.
Key physiological measurements indicators of sleep include electroencephalography (EEG) of brain waves, electrooculography (EOG) of eye movements, electromyography (EMG) of skeletal muscle activity. Simultaneous collection of these measurements is called polysomnography, and can be performed in a specialized sleep laboratory (Rundell and Jones, 1990). Sleep researchers also use simplified electrocardiography (ECG) for cardiac activity and actigraphy for motor movements (Jafari and Mohsenin, 2010). This has promoted the search for alternative approaches such as the employment of phythotherapeutic agents. Animal behavioral experiments were done after surgery and agent treatment (Fig. 1).
A number of medicinal plants are traditionally endowed with anxiolytic or sedative properties. This has motivated the searching of phythotherapeutic agents, which has been used in animal behavioral experiments performed by surgery (Fig. 1). In this context, there is a lot of information in medicinal plants possessing sedative and hypnotic properties. Here, we describe some natural products studied in our laboratory. These are magnolia (
Semen zizyphi spinosae (Rhamnaceae, the dried seed of
Sinomenine, an alkaloid derived from
The most abundant GABAA receptor subunit compositions, α1, β2 and γ2, are related to the hypnotic/sedative effect of GABAA receptors (Rudolph and Möhler, 2006). Previous studies have shown that α1 subunit was associated with sedation (Rudolph and Feiger, 1999; McKernan
Decursinol is one of the major components of
EGCG (Epigallocatechin-3-O-gallate) is a major component of green tea (
Others. Some natural products such as Polygalae Radix (3,4,5-trimethoxycinnamic acid), Gastrodiae Rhizoma (4-hydroxybenzaldehyde),
However, cordycepin (
Up to date, over the counter sleep aiding agents have been introduced. St. John’s wort (
All authors declare no conflict of interest.
This research was supported by the National Research Foundation (NRF) grant funded by the Korea government, Ministry of Science, ICT & Future Planning (MRC 2010-0029355).