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Natural Products for Sleep Aids


Many effective pharmacological treatments of insomnia focus on different aspects of pathophysiologic processes. GABA, for example, is released from specific inhibitory neuron terminals and then binds with its receptors. This enhances chloride influx and facilitates GABAA-ergic transmission (Olsen 1981; Ticku & Maksay 1983). This effect is supported in part by barbiturates and benzodiazepines due to their agonistic effects upon the GABAA receptors. Their binding to the receptors increases the affinity for the GABA-binding sites. There are four types of GABA.A Each receptor subunit contains a different membrane. The critical step in GABA biosynthesis, is also the decarboxylation glutamate by glutamic Acid Decarboxylase (GAD), and it exists in two isoforms: GAD.65 GAD67. The GAD level65 GAD67 GABA is believed to have increased regulation of this substanceA-ergic interneurons. GABA is a complex substance.A It has been shown that receptors play an important role when barbiturate-induced sleep is modulated by interaction with GABA.A-ergic systems (Doghramji 2006). GABA-benzodiazepine receptor agonists, which are usually effective in the treatment insomnia, can promote sleep by increasing the widespread function GABA. This suggests that it is possible to develop new compounds for specific molecular targets, with sleep-related effects. Non-GABA compounds are also possible.A-chloride channel receptor complex agonist like melatonin receptor agonist, 5-HT1A For the treatment of insomnia, receptor agonists, receptor antagonists, orexin receptoragonists, adenosine agonists, and adenosine agonists have all been proposed (Dujardin). et al., 2018). Benzodiazepines remain the most popular and widely prescribed hypnotic medication. However, they are being replaced in recent years by non-benzodiazepine hypnotic drug, so-called “z drugs” (eszopiclone zolpidem, zaleplon). These non-benzodiazepine medications have been controversial due to concerns about side effects. et al., 2017).

Consideration has been given to the possible role of 5-HT in sleep disorders. Ursin gives a great overview of the current concept of the role serotonin (5 HT) plays in sleep and its sleep-promoting effects (Ursin 2002). It has been analyzed how specific receptor subtypes play a role in sleep-wake regulation. Gronli described the effects of drugs on 5-HT1A and 5-HT1B These receptors have an affinity at the pre and post-synaptic, as well as later, inhibitory auto-receptors for serotonin neurons (Gronli). et al., 2007).

Particularly, 5-HT1A/1BThe brain regulates serotonin transmission by playing a critical role. Recent research also suggests a role of the 5-HT1B Receptor in anxiety, depression, and sleep. 5-HT1B An antagonists decrease the time it takes for anxiolytic behavior to begin and they play a role with stress regulation similar to diazepam. et al., 2004). Some antagonists to serotonin might increase non-rapid eyes movement (NREM), but this is not a conclusive finding. These findings support 5-HT’s role in complex ways.1A, 5-HT1B 5-HT7 receptors in REM control (Leiser et al., 2015).

For the treatment of insomnia, non-benzodiazepine antihypnotics like diphenhydramine or doxylamine can be used. Antihistamines have sedative effects by targeting histamine receptors in the arousal system. Recent developments in the development and use of antagonists of the orexin receptors have allowed for better treatment of insomnia. Orexin systems target on the promotion of arousal of brainstem/hypothalamic arousal centers (Mieda, 2017). Other molecular targets, such as melatonin or adenosine, have been suggested to treat insomnia (Di Bella). et al., 2017).

As possible treatments for insomnia, there are a variety of compounds being examined with new approaches. Korea FDA is currently reviewing applications for new sleep-promoting herbs. There have been clinical indications for insomnia that are related to problems of sleep onset, maintenance, or middle-of-the night awakenings. There are many other options for treating insomnia. These include an off-label basis, over-the counter sleep aids and a variety of unregulated substances that are marketed to improve sleep. Appropriate hypnotics are substances that prevent continuous awakenings, reduce latency for sleep initiation, and increase sleep duration.

Key physiological measurements indicators of sleep include electroencephalography (EEG) of brain waves, electrooculography (EOG) of eye movements, electromyography (EMG) of skeletal muscle activity. This simultaneous collection is known as polysomnography and can be done in a specialized laboratory for sleep research (Rundell & Jones, 1990). Simplified electrocardiography (ECG), which measures cardiac activity, and actigraphy to measure motor movements is also used by sleep researchers (Jafari & Mohsenin 2010, 2010). This has prompted the search for other approaches, such as the use of phythotherapeutic agent. After surgery, agent treatment was performed on animals for behavioral experiments ().

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EEG measurement in rats 1. After the transmitter body was inserted on the backs of male rats, the rats were sutured to measure EEG changes. 2. After puncturing the skull, the electrode is inserted. The dental cement is used to fix it. 3. EEG recording is made after one week of healing from surgery. 4. Based on the EEG record that is sent to the computer, the sleep architecture can be analyzed.





Many medicinal plants have anxiolytic and sedative properties. This led to the search for phythotherapeutic compounds, which have been used in animal behavioral experiments (). This context provides a wealth of information about medicinal plants that have sedative or hypnotic qualities. We will now describe the natural products that we have studied in our laboratory. These include magnolia (Magnolia officinalis, Magnoliaceae), Semen zizyphi spinosae (Zizyphus jujube Mill. var. Spinosa Rhamnaceae), sinomenine (Sinomenium acutum Menispermaceae), decursinol (Angelica gigasUnbelliferae), rosemaryPerilla frutescens, Lamiaceae), Euphoria longan (Spindaceae), GinsengPanax Ginseng, Araliacae), EGCG (Epigallocatechin-3-O-gallate, Camellia sinensis), Chrysanthemum morifolium (Asteraceae), Apigenin (Circium japonicum, Asteraceae), and others that have sedative effects (

MagnoliaM. obovate, M. officinalisMagnoliaceae (or Magnoliaceae) has been used traditionally to treat thrombotic strokes, anxiety, depression, and other neuronal conditions in the oriental countries for a long period of time (Watanabe). et al., 1983; Hirano, 1991; Lo et al., 1994). Isolated biophenolic compounds like magnolol and honokiol from M. obovate/ and M. officinalis They have been shown to be both anxiolytic (Maruyama) and a muscle relaxant (Maruyama). et al., 1998; Seo et alHan, 2007. et al., 2010).

From a previous experiment, it was reported that obovatol has anxiolytic-like effects in animal models, and enhanced pentobarbital-induced sleep suggesting that these effects are involved in GABA/benzodiazepine receptor complex (Seo et al., 2007 et al., 2009b). Research has also shown that magnolol, honokiol, and essigoniol are the main active components of M. officinalis They are positive allosteric modators of GABAA receptors. They have also been shown to increase GABA densityA Alpha subunit-containing receptors are a common mechanism for diazepam (a benzodiazepine often used to treat insomnia). et al., 2008, 2009b; Lee et al., 2010).

These effects all increase GABA activity which promotes relaxation and decreases anxiety. Magnolol enhanced the amount of REM (and NREM) sleep via the GABA.A receptors (Chen et al., 2012). Magnolia bark is used to treat anxiety and depression in humans. It also helps with stress reduction, anxiety, and sleep facilitation. These results could indicate its potential to be a natural sleep aid agent.

Semen zizyphi Spinosae (Rhamnaceae) – The dried seed of Zizyphus jujube Mill var. spinosaIn oriental countries,, has been used to tranquilize, anxiolytic, and anticonvulsant. It has also been prescribed for anxiety and insomnia (Park et al., 2004). 2004.A-ergic transmission et al., 2008). Sanjoinine A and cyclopeptide fraction from Semen zizyphi spinosae exert hypnotic effect and/or enhances pentobarbital-induced sleeping behaviors (Ma et alHan et al., 2009). Sanjoinine

A in combination with muscimol showed synergistic effects on pentobarbital-induced sleeping and increased Cl Infusion works in the same way as pentobarbital. Similar effects were also seen with Sanjoinine A and muscimolin potentiating Cl Influx inducing the effects low dose pentobarbital. This suggested that sanjoinineA might be able to act on GABAA Cl receptors channel opening, and modulate pentobarbital-induced pharmacological properties like a GABAA receptor agonist (Ma et al., 2007). Furthermore, the cyclopeptide-alkaloid fraction of semen zizyphi spinosae increased pentobarbital-induced sleeping behaviors, through activation of GABA receptor Cl Channels (Ma et al., 2008). It has been suggested that it may be high-affinity for 5-HT1A and 5-HT2 Receptors in in vivo Analysis (Yi) et al., 2007).

Sinomenine is an alkaloid that’s derived from Sinomenium acutumIt is the chief ingredient in which it has been reported that it has a range of pharmacological properties, including anxiolytic (Rao et al., 2017). From a recent experiment, sinomenine enhanced pentobarbital-induced sleeping behaviors, and modulate sleep architecture via GABAARodents have a higher level of NREM sleep due to their -ergic system.

GABA is the most abundantA The hypnotic/sedative effects of GABA are related to the receptor subunit compositions a1,b2 and g2.A Receptors (Rudolph & Mohler 2006). Studies in the past have shown that the a1 subunit is associated with sedation (Rudolph & Feiger 1999; McKernan 2006). et al., 2000). Low anxiety was associated with subunits of a2/3. et al., 2000; Crestani et al., 2001). The a5 subunit was linked to spatial and temporal memory (Collinson et al., 2002; Crestani et al., 2002). These subunits of GABA were non-selectively activated by SinomenineA receptors. Major subunits of GABA were identified during our experiment.A Sinomenine, with the exception of the a3 or a5 subunits, overexpressed receptor

Decursinol is one major component of Angelica gigas The traditional folk medicine of the East, Umbelliferea, has been around for many years. This herb is traditionally used to treat psychosomatic diseases such as anxiety, depression, excess stress and insomnia. The essential oil components of this herb have been shown to be effective in treating psychosomatic diseases such as excess stress, anxiety, depression and insomnia.

Angelica gigas In rodent tests, anxiolytic-like reactions were observed (Chen). et al., 2004). Similarly, Japanese Angelica root extract reversed stress-induced loss of sleep in pentobarbital-induced sleeping in mice through the inhibition of the central noradrenergic or the activation of GABAA receptors (Matsumoto et al., 1998). 1998.65/67) and GABAA receptors subtypes. On the other hand, decurcinol potentiates pentobarbital-induced sleeping behaviors through the activation of GABAA-ergic systems. All of these indicate that decurcinol can be a useful agent in the treatment insomnia (Woo). et al., 2017).

Rosemary (fromPerilla frutescens, Lamiaceae() has been used in folk remedies for sedation in the East. Multiple studies have so far shown that Perilla frutescens Takeda has sedative effects et alJohnston,. et al., 2006). Rosemary contains many phytochemicals including rosmarinic and camphor acids, caffeic acids, betulinic, ursolic, betulinic, carnosic, carnosic, and carnosol (Vallverdu Queralt). et al., 2014). Rosmarinic acid, which belongs to the phenolic substances is a component of Perilla frutescens (Igarashi & Miyazaki (2013); Raskovic et al., 2014). The GABA-ergic system has been affected by many of the phenolic compounds that come from plants (Johnston). et al., 2006). Rosmarinic acid also inhibited GABA transaminase, (GABA-T). In vitro (Awad et al., 2009), and increased GAD protein expression65/67 GABA and other substancesA receptors subunits except b1 subunit. Rosmarinic acid augmented pentobarbital-induced sleeping behaviors through GABAA-ergic transmission. Rosmarinic acid could be a useful agent in the treatment of insomnia (Kwon). et al., 2017).

Euphoria longan (Or Dimocarpus longanSpindaceae, also known as Spindaceae), is commonly eaten as dried Euphoria longana fruit. The pulp, seed, and peel of the fruit were used to identify phytochemicals like gallic acid, Elastic acid, and Corilagin (ellagitanin). In Asia, the pulp from the dried fruit and the fresh Longanae Arillus has been used to treat anxiety and insomnia. Longane Arillus extract was found to be anxiolytic (Okuyama). et al., 1999). From our experiment, methanol extract of Longane Arillus was proven to prolong sleeping time and reduced pentobarbital-induced sleep onset in rodents through GABAA-ergic Systems (Ma et al., 2009b). Longane Arillus Methanol Extract regulated sleep architectures in restraint-stressed rats (Ma). et al., 2009b).

Ginseng (Panax GinsengAraliaceae), may have a part to do with maintaining sleep and wakefulness and alter EEG spectrums of the sleep-wake stage in mice. et al., 2008; 2009a, 2009.b; Yang et al., 2011b). Panax quinquefolium American ginseng (or American ginseng) has been reported to have sleep-modulating properties. Saponin fraction Panax Ginseng Extract prolonged the duration of hexobarbital-induced sleeping in mice (Takagi et al., 1972). Red ginseng extract also increased total sleep time (Ma) and NREM sleep. et alYang,. et al., 2011a). Majono-sides, R2, a major Saponin Panax vietnamensis

Pentobarbital’s hypnotic activity, which had been reduced by psychological stress (Nguyen), was restored. et al., 1993). Ginsenoside Rg3 standarzied Ginseng extract showed antistress effects, and improved sleeping in restraint stress animals (Kim et al., 2010). Evidence suggests that GABA regulation is necessary.AGinseng’s sedative effects are primarily focused on -ergic transmission (Kimura et al., 1994; Cha et alPark,. et al., 2005). It has been proven that ginseng can improve sleep quality in humans (Han). et al., 2013). GABA increased NREM sleep in Korea red GinsengA-ergic system (Lee) et al., 2012).

EGCG (Epigallocatechin-3-O-gallate) is a major component of green tea (Camellia sinensisIt is also known as EGCG (egg white chocolate), which is very popular in the world. Green tea has both caffeine and EGCG. Both are stimulant caffeine and EGCG, which can be sedative. From our experiment, it was interesting that only EGCG from green tea augmented pentobarbital-induced sleeping time through Cl channel activation (Park et al., 2011). This could suggest that EGCG counteracts the caffeine-induced stimulant effects like hyperactivity, arousal, and anxiogenic effects. (Park et al., 2010). GABA could also be used to treat anxiety and enhance sleep with EGCG.A-ergic Systems (Bae) et alCampbell, 2002 et alVignes,. et al., 2006; Haque et al., 2008; Park et al., 2011).

Chrysanthemum morifolium (Asteraceae). The flower Chrysanthemum morifolium It is a traditional medicinal herb used in tea preparation in the East. Chrysanthemumsp Flavonoids, phenols and cinnamic acid are all contained in this dry flower. The dried flower of Chrysanthemum morifolium In Korea, the traditional treatment for insomnia has been to use tea and pillows. Ethanol extract Chrysanthemum morifolium augments pentobarbital-induced sleeping behaviors through activation of Cl channels (Kim et al., 2011).

Apigenin (from Circium japonicumAsteraceae (also known as Asteraceae), is a natural product that belongs to flavonoids, which are the aglycones of many naturally occurring glycosides. Apigenin is a weakligand for central-benzodiazepine receptors. In vitro It has anxiolytic effects and a slight sedative effect in an animal model (Viola et al., 1995). Apigenin exhibits second-order positive modulatory activity at GABAA Receptors (Campbell) et al., 2004. Rosi et al., 2004). It was reported that enhancement of pentobarbital-induced sleep by apigenin is mediated by GABAA Receptors via Cl channel complex activation (Kim et al., 2012).

Others. Some natural products such as Polygalae Radix (3,4,5-trimethoxycinnamic acid), Gastrodiae Rhizoma (4-hydroxybenzaldehyde), Poria cocos (pachymic acid), Rhychophilline (Uncariae Ramulus et Uncus) and Perilla Herba were examined to determine if they improve sleep (Lee et al., 2013 Choi et al., 2014 Shah et al., 2014; Choi et al., 2015 Shah et alKwon,., 2015. et al., 2017). From the behavioral and molecular data, those natural products augmented pentobarbital-induced sleep, and modulated sleep architectures of EEG spectra in rodents. GABA seems to play a role in the increase in sleep.A-benzodiazepine receptors Cl channel complex.

Cordycepin (Cordyceps militaris/sinensisNREM sleep was markedly affected by theta wave power density. Cordycepin over-expressed the AR subtypes A1, A2A, and A2B and are now showing non-specific AR activation. et al.



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