Sleep-enhancing Effects Research Articles

Metabolomic Analysis Reveals the Linkage between Sleep-Enhancing Effects and Metabolite Biomarkers and Pathways of Different Casein Hydrolysates in Chronic Unpredictable Mild Stressed Mice.

Casein hydrolysates have been proven to exert varying sleep-enhancing and anxiolytic effects due to their distinct release of potential peptides. However, their underlying sleep-enhancing mechanisms at the metabolic level remain unclear. This study aims to investigate the potential sleep-enhancing mechanism of casein hydrolysates through an integrated approach of untargeted and targeted metabolomics in CUMS-induced anxiety mice for the first time. The results showed seven potential biomarkers were identified and screened using orthogonal partial least-squares discriminant analysis, random forest model, and pathway analysis, including ornithine, l-proline, l-prolinamide, inhibitory neurotransmitters gamma-aminobutyric acid, 5-HIAA, fumaric acid, and 4-oxoglutaramate. Moreover, casein hydrolysates exerted sleep-enhancing effects through multiple metabolic pathways, mainly including the GABAergic system, tryptophan metabolism, and cAMP response signaling pathway, which was validated by targeted metabolomics and vital protein expressions. It was interesting that casein hydrolysates with diverse representative peptide compositions exhibited varying activity, which could be attributed to distinct alterations in metabolites via different pathways.

Sleep-enhancing effect of Hongcheon-hop (Humulus lupulus L.) extract containing xanthohumol and humulone through GABAA receptor

Ethnopharmacological relevanceThe bitter resins in hops (Humulus lupulus) modulate GABA receptors, leading to central nervous system suppression, which induces sedative effects and enhances sleep. Aim of the studyThis study intends to explore the sleep-enhancing properties of Hongcheon-hop extract, a hop native to Korea, by analyzing sleep structure and its mechanisms through EEG. Materials and methodsA pentobarbital-induced sleep model was used, along with EEG analysis to study sleep architecture. The receptor binding of Hongcheon-hop extract was analyzed using GABA receptor antagonists. ResultsThe extract contained 7.44 mg/g of xanthohumol, 133.04 mg/g of α-acids including 13.74 mg/g of humulone and 84.52 mg/g of β-acids. Administration of the extracts resulted in a dose-dependent enhancement of sleep duration. Both low (100 mg/kg) and high doses (200 mg/kg) of the extract increased non-rapid eye movement (NREM) sleep by enhancing δ wave sleep, which represents deep sleep. The extract exerted its sleep-promoting effects by binding to the γ-aminobutyric acid (GABA) binding site on GABAA receptor. In an insomnia model, low dose of the extract was more effective than the same dose of GABA in enhancing sleep. Administration of the extract for 3 weeks increased the expression and protein levels of 5-HT1A receptors in addition to GABAA receptor, and also increased the content of GABA in the brain. A mixture of xanthohumol (1.49 mg) and humulone (2.75 mg) within Hongcheon-hop extract (200 mg) exhibited a sleep-enhancing effect comparable to that of the extract. ConclusionThese findings suggest that Hongcheon-hop extract, which contains xanthohumol and humulone, improves sleep quality by increasing NREM sleep through the enhancement of δ-wave sleep via GABAA receptors. Hongcheon-hop shows potential as a natural therapeutic agent for treating insomnia and enhancing sleep.

Extracts of Prunella vulgaris Enhanced Pentobarbital-Induced Sleeping Behavior in Mice Potentially via Adenosine A2A Receptor Activity.

The increasing prevalence of sleep dysregulation cases has prompted the search for effective and safe sleep-enhancing agents. Numerous medications used in the treatment of sleep disorders function by enhancing γ-aminobutyric acid neurotransmitter activity. Unfortunately, these substances may induce significant adverse effects in chronic users, such as dependence and motor behavior impairments. Consequently, there is a growing interest in exploring therapeutic sleep-enhancing agents derived from natural sources, with the anticipation of causing less severe side effects. Prunella vulgaris (PV), a perennial plant indigenous to South Korea, exhibits various pharmacological effects, likely attributed to its chemical composition. Rosmarinic acid, one of its components, has previously demonstrated sleep-potentiating properties, suggesting the potential for PV to exhibit similar pharmacological effects. This study aims to investigate the potential effects of repeated administration of PV extract on the sleep behavior, brainwave activity, sleep-wake cycle, and physiological behavior of mice. Findings indicate that PV extracts exhibit sleep-enhancing effects in mice, characterized by prolonged sleep duration and a reduced onset time of pentobarbital-induced sleep. However, PV extracts only reduced alpha wave powers, with minor alterations in wakefulness and rapid-eye-movement sleep duration. In contrast to diazepam, PV extracts lack adverse effects on locomotor activity, motor coordination, or anxiety in mice. Receptor-binding assay and caffeine treatment support the potential involvement of adenosine A2A receptors in the effects of PV, suggesting distinct mechanisms of action compared to diazepam, despite both exhibiting sleep-altering effects. Overall, our results suggest that PV holds promise as a potential source of sleep-aiding agents.

Flavonoids from Polygoni Multiflori Caulis alleviates p-chlorophenylalanine-induced sleep disorders in mice

Polygoni Multiflori Caulis (PMC) has been traditionally served as a functional medicine due to its various biological activities, but a lack of researches focused on the sleep-enhancing effects of flavonoids from PMC. In this study, the total flavonoids (PMCF) were isolated from PMC. In vitro antioxidant experiments suggested that PMCF exhibited remarkable antioxidant capacity, as evidenced by its scavenging activity on several radicals and reducing power. Subsequently, PMCF was given to insomnia mice via intragastric administration. In behavior test, PMCF exhibited sleep-enhancing effect through suppressing depression, shortening the sleep latency time while prolonging the duration sleep time in insomnia mice. To clarified the mechanism, the neurotransmitter receptors, cytokines and hormone in brain were investigated. PMCF exhibited significant sleep promoting effect by up-regulating the expression levels of hormone-related genes, and producing stimulation on the immune system by increasing interleukin-1β mRNA expression. In addition, PMCF-mediated sleep promotion accompanied the recovery of 5-hydroxytryptamine 1 A (5-HT1A), γ-aminobutyric acid A receptor α2 (GABAARα2) and GABAA receptor α3 (GABAARα3) mRNA expression, which was more effective in the hypothalamus. Collectively, all these data implied that PMCF might produce beneficial activities in relieving sleep disturbances via the antioxidant pathway, as well as the immune, serotonergic and GABAergic systems.

Bifidobacterium adolescentis SBT2786 Improves Sleep Quality in Japanese Adults with Relatively High Levels of Stress: A Randomized, Double-Blind, Placebo-Controlled Study.

Sleep disorders associated with lifestyle changes and unhealthy habits are major public health concerns. Our previous study showed that Bifidobacterium adolescentis SBT2786 has a potent sleep-promoting effect on fruit flies. Fruit flies share many similarities with mammals, making them suitable model organisms for studying sleep. Thus, in the present study, we conducted a randomized, double-blind, placebo-controlled clinical trial to test whether SBT2786 has sleep-enhancing effects in humans. In this study, 61 participants in the SBT2786 group and 65 participants in the placebo group were analyzed. The results showed that SBT2786 increased sleep time; however, it predominantly increased light sleep and did not improve subjective sleep quality. Interestingly, mood improvement was observed. A subgroup analysis was conducted on participants with high stress levels, and results showed that these participants experienced an increase in sleep duration and an improvement in sleepiness upon waking up and reported feeling well-rested during the day. We concluded that SBT2786 may improve sleep quality, particularly in individuals experiencing high levels of stress, and that SBT2786 can be used as a dietary supplement to improve sleep and mood.

Impact of a Novel Valerian Extract on Sleep Quality, Relaxation, and GABA/Serotonin Receptor Activity in a Murine Model.

Insomnia is a major global health issue, highlighting the need for treatments that are both effective and safe. Valerian extract, a traditional remedy for sleep problems, offers potential therapeutic options. This research examined the potential sleep-enhancing effects of VA (Valerian Pdr%2) in mice. The study evaluated sleep quality by comparing the impact of the VA extract against melatonin on brain activity, using electrocorticography (ECoG) to assess changes in brain waves. For this purpose, the study utilized two experimental models on BALB/c mice to explore the effects of caffeine-induced insomnia and pentobarbital-induced sleep. In the first model, 25 mice were assigned to five groups to test the effects of caffeine (caffeine, 7.5 mg/kg i.p) alone, caffeine with melatonin (2 mg/kg), or caffeine with different doses of valerian extract (100 or 300 mg/kg) given orally on brain activity, assessed via electrocorticography (ECoG) and further analyses on the receptor proteins and neurotransmitters. In the second model, a different set of 25 mice were divided into five groups to examine the impact of pentobarbital (42 mg/kg) alone, with melatonin, or with the valerian extract on sleep induction, observing the effects 45 min after administration. The study found that ECoG frequencies were lower in groups treated with melatonin and two doses of valerian extract (100 and 300 mg/kg), with 300 mg/kg showing the most significant effect in reducing frequencies compared to the caffeine control group, indicating enhanced sleep quality (p < 0.05). This was supported by increased levels of serotonin, melatonin, and dopamine and higher levels of certain brain receptors in the melatonin and valerian extract groups (p < 0.05). Modulatory efficacy for the apoptotic markers in the brain was also noted (p < 0.05). Additionally, melatonin and both doses of VA increased sleep duration and reduced sleep onset time compared to the pentobarbital control, which was particularly notable with high doses. In conclusion, the findings suggest that high doses (300 mg/kg) of valerian extract enhance both the quantity and quality of sleep through the GABAergic pathway and effectively increase sleep duration while reducing the time to fall asleep in a pentobarbital-induced sleep model in mice.

Heukharang (Lactuca sativa L.) extracts enhanced the sleep behavior of mice: potential involvement of adenosine A1 and A2A receptors.

A significant proportion of the world's population suffers from insomnia, a disorder characterized by complications in initiating and maintaining sleep. Many medications used to treat insomnia target the γ-aminobutyric acid (GABA) neurotransmitter system. However, these substances, such as benzodiazepines, induce significant adverse consequences, including dependence and memory impairment, after prolonged use. Thus, current studies are aimed at developing therapeutic hypnotics derived from natural sources that may cause less severe side effects. Heukharang is a variety of lettuce from Korea that was discovered to contain sleep-promoting compounds. Therefore, we investigated the potential effects of sub-chronic administration of Heukharang extract (FSD-LS) on sleep behavior (pentobarbital-induced sleeping test), brain wave activity and sleep architecture (electroencephalography), and physiological behavior (open-field test and rota-rod) in mice, along with radioligand binding assays (GABAA, adenosine A1 and A2A receptors). We found that FSD-LS prolonged the total sleep duration and reduced the onset time of sleep, and enhanced delta wave power and non-rapid eye movement (NREM) sleep duration, all indicating persistent sleep-enhancing effects. FSD-LS lacked adverse effects on the spontaneous locomotor activity and motor coordination of mice, unlike diazepam. Pharmacological blocking using caffeine and bicuculline supported the possible involvement of adenosine receptors in the sleep-promoting effects of FSD-LS, with partial contribution from GABA receptor activity. Overall, our study recommends FSD-LS as a potential source for the development of sleep-aiding therapeutics.

Potential Mechanisms of Casein Hexapeptide YPVEPF on Stress-Induced Anxiety and Insomnia Mice and Its Molecular Effects and Key Active Structure.

The hexapeptide YPVEPF with strong sleep-enhancing effects could be detected in rat brain after a single oral administration as we previously proved. In this study, the mechanism and molecular effects of YPVEPF in the targeted stress-induced anxiety mice were first investigated, and its key active structure was further explored. The results showed that YPVEPF could significantly prolong sleep duration and improve the anxiety indexes, including prolonging the time spent in the open arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing effects by significantly increasing the level of the GABA/Glu ratio, 5-HT, and dopamine in brain and serum and regulating the anabolism of multiple targets, but the effects could be blocked by bicuculline and WAY100135. Moreover, the molecular simulation results showed that YPVEPF could stably bind to the vital GABAA and 5-HT1A receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-, and the electrostatic and van der Waals energy played dominant roles in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing and anxiolytic effects by regulating the GABA-Glu metabolic pathway and serotoninergic system depending on distinctive self-folding structures with Tyr and two Pro repeats.

Sedative and hypnotic effects of Polygala tenuifolia willd. saponins on insomnia mice and their targets

Ethnopharmacological relevancePolygala tenuifolia Willd. has been widely used in the treatment of cancer, forgetfulness, depression and other diseases. Aim of reviewThe purpose of this study was to investigate the sleep-enhancing effect and mechanism of P. tenuifolia saponins (PTS). Materials and methodsThe total saponin (YZ-I) and purified saponin (YZ-II) fractions were extracted and ICR mice model of insomnia was established by p-chlorophenylalanine (PCPA) induction to observe anxiety and depression behaviors. Effects of YZ-I and YZ-II on the levels of neurotransmitters, hormones, and inflammation cytokines were detected by ELISA, RT-qPCR and western blotting. ResultsThe results showed that YZ-I and YZ-II reduced the immobility time of mice and prolonged the sleep time of mice and significantly increased the concentrations of 5-HT, NE, PGD2, IL-1β and TNF-α. YZ-I and YZ-II regulated GABAARα2, GABAARα3, GAD65/67, 5-HT1A and 5-HT2A, while regulated the levels of inflammatory cytokines such as DPR, PGD2, iNOS and TNF-α to exert sedative and hypnotic effects. ConclusionPTS are mainly achieved sedative and hypnotic effects by altering serotonergic, GABAergic and immune systems, but the effects and mechanisms of action of YZ-I were different from YZ-II.

Combined Effects of Ziziphus jujuba, Dimocarpus longan, and Lactuca sativa on Sleep-Related Behaviors through GABAergic Signaling.

We aimed to analyze the increase in the sleep-promoting effects based on the mixed ratio of botanical extracts, Ziziphus jujuba seeds, Dimocarpus longan fruits, and Lactuca sativa leaves, using animal models. Behavioral analyses, including an analysis of the total sleep time of Drosophila melanogaster, were conducted to select the optimal mixed ratio of the three botanical extracts. The effects were verified in a caffeine-induced sleepless model, specific neurotransmitter receptor antagonists, and ICR mice. In D. melanogaster exposed to 2.0% of each extract, group behavior was significantly reduced, and the mixed extracts of Z. jujuba, D. longan, and L. sativa (4:1:1 and 1:4:1) significantly increased the total sleep time with individual fruit flies. In the caffeine-induced insomnia model, mixed extracts (4:1:1 and 1:4:1) led to the highest increase in total sleep time. An analysis of locomotor ability revealed a significant reduction in the mobility percentage in the mixed extract groups (0:0:1, 1:0:1, 1:1:1, 4:1:1, and 1:4:1). The administration of Z. jujuba extract and mixed extracts (4:1:1) significantly increased the expression of GABAA-R, whereas the administration of the mixed extracts (4:1:1) and (1:4:1) significantly increased the expression of GABAB-R1 and GABAB-R2, respectively. D. longan extract and the mixed ratio (1:4:1) reduced the subjective nighttime movement and increased the total sleep time in the presence of flumazenil. An analysis of ICR mice indicated that the administration of mixed extracts (4:1:1) significantly increased sleep duration in a dose-dependent manner. These results indicated that the mixed ratio of Z. jujuba, D. longan, and L. sativa extracts, particularly the mixed ratio of 4:1:1, may have sleep-enhancing effects in fruit flies and mice. The study also identified changes in gene expression related to GABA receptors, indicating the potential mechanism for the observed sleep-promoting effects.

Sleep-Enhancing Effect of Water Extract from Jujube (Zizyphus jujuba Mill.) Seeds Fermented by Lactobacillus brevis L32.

Although Ziziphus jujuba Mill (jujube) is used in folk medicine for hypnotic sedative, anxiolytic, and many other purposes, to date, only a few studies have revealed its sleep-promoting effects and related mechanisms. Currently, drugs used for the treatment of sleep disorders have various side effects, so it is essential to develop safe natural materials. Therefore, we evaluated the sleep-enhancing activity and mechanism of action of an aqueous extract of jujube seeds (ZW) fermented with Lactobacillus brevis L-32 in rodent models. The starch contained in ZW was removed by enzymatic degradation and fermented with L. brevis to obtain a fermented product (ZW-FM) with a high γ-aminobutyric acid (GABA) content. To evaluate the sleep-promoting effect of ZW-FM, pentobarbital-induced sleep tests were performed on ICR mice, and electroencephalography analysis was undertaken in Sprague Dawley rats. Additionally, the awakening relief effects of ZW-FM were confirmed in a caffeine-induced insomnia model. Finally, the mechanism of sleep enhancement by ZW-FM was analyzed using GABA receptor type A (GABAA) antagonists. The ZW-FM-treated groups (100 and 150 mg/kg) showed increased sleep time, especially the δ-wave time during non-rapid eye movement (NREM) sleep. In addition, the 150 mg/kg ZW-FM treatment group showed decreased sleep latency and increased sleep time in the insomnia model. In particular, NREM sleep time was increased and REM sleep time, which was increased by caffeine treatment, was decreased by ZW-FM treatment. ZW-FM-induced sleep increase was inhibited by the GABAA receptor antagonists picrotoxin, bicuculline, and flumazenil, confirming that the increase was the result of a GABAergic mechanism. These results strongly suggest that the increased GABA in water extract from jujube seeds fermented by L. brevis acts as a sleep-promoting compound and that the sleep-promoting activity is related to GABAA receptor binding.

0225 Effect of thermoneutral temperature exposure in the APP/PS1 knock-in mouse model of Alzheimer’s disease

Abstract Introduction There is growing evidence that disordered sleep in Alzheimer’s disease (AD) may accelerate neuropathology, thus promoting a vicious cycle. In a previous study, we found that improving sleep through thermoneutral ambient temperature exposure may slow disease progression in 3xTg-AD mice. However, the confounding effects of temperature on metabolism in addition to sleep remained an open question. Methods To test whether the effect of thermoneutral warming on amyloid pathology is mediated by sleep changes rather than other non-specific physiologic effects of temperature, we conducted a new study on APP/PS1 knock-in (KI) mice. First, 6-m.o. male APP/PS1-KI mice were instrumented for EEG/EMG sleep analysis. After a week-long baseline recording, we split the mice into 4 separate groups: 1. SE (n=8), which were exposed to 30°C thermoneutral ambient temperature during the 12-hour light period; 2. SE-SD (n=9), which received sleep disruption through mild intermittent cage vibration alongside thermoneutral temperature exposure; 3. SD (n=8), which received sleep disruption at room temperature (22°C); and 4. CTRL (n=8), which were undisturbed and at room temperature. This design aims to decouple the sleep-enhancing effect of thermoneutral exposure from other non-specific effects. After four weeks of treatment, the animals were euthanized and the brains dissected to assay Aβ levels by ELISA. Vigilance states, i.e., Wake, REM, NREM, and slow wave sleep (SWS) within NREM – were scored in 4-second epochs from the EEG/EMG recordings and sleep metrics computed. Results Initial analysis of sleep revealed some SE-induced increases in SWS similar to our findings in 3xTg-AD mice. Sleep disruption reduces SWS even when thermoneutral warming occurs. Biochemical assays are in progress to reveal the treatment effects on Aβ levels in the brain. Conclusion Sleep disruption through vibration seems to be an effective way to negate the sleep-specific effect of thermoneutral temperature exposure. Incorporation of the biochemical assay data will help uncover the correlation between SWS and AD progression. Support (if any) R01AG068215

Stability, Bioavailability, and Structure-Activity Relationship of Casein-Derived Peptide YPVEPF with a Sleep-Enhancing Effect.

YPVEPF (Tyr-Pro-Val-Glu-Pro-Phe) is an outstanding sleep-enhancing peptide derived from casein. This study aimed to evaluate the bioavailability of YPVEPF in vitro and in vivo and to explore its structure-activity relationship through a sleep test and cheminformatics. Our results showed that YPVEPF was unstable against gastrointestinal enzymes and almost totally degraded to YPVEP in vitro. However, the pharmaco-kinetics results in vivo showed that the Cmax of YPVEPF was 10.38 ± 4.01 ng/mL at 5 min, and YPVEPF could be detected in the stomach, intestine, and brain at 12.89 ± 0.55, 10.26 ± 0.23, and 2.47 ± 0.55 ng/g, respectively. The main metabolites including YPVEP, YP, PVEPF, and PVEP were identified. We first explored whether the fragment YPVEP also had a strong sleep-enhancing effect, and the sleep-enhancing effects of PVEPF and PVEP (lacking a Tyr residue) significantly decreased compared with those of YPVEPF and YPVEP. Moreover, molecular docking and quantum calculations revealed that the N-terminus Tyr played a dominant role in YPVEPF and YPVEP. They had distinctive self-folding structures and varying electron-withdrawing properties of the groups at the N terminus, allowing different binding modes and electron/proton transfer.

Application of 4-Diethylaminobenzoic Acid &lt;i&gt;N&lt;/i&gt;-Succinimidyl Ester and Its Deuterated Isotopologue as Derivatization Reagents to Quantitative Analysis of γ-Aminobutyric Acid in Serum by LC/ESI-MS/MS

γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter having anti-anxiety, stress-reducing and sleep-enhancing effects. The blood GABA concentration has the potential to become a diagnostic index for depression and schizophrenia. In this study, we developed a method for the quantification of GABA in human serum by liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) combined with derivatization using a pair of reagents, 4-diethylaminobenzoic acid N-succinimidyl ester (DEABAS) and its deuterated isotopologue (dDEABAS). The deproteinized serum samples were derivatized with DEABAS, to which the dDEABAS-derivatized standard GABA of known amount was then added. The DEABAS-derivatization enhanced not only the ESI-MS/MS sensitivity but also the LC retention, which enabled the separation of GABA from the interfering isomers. Satisfactory assay precision and accuracy were also acquired by adding dDEABAS-derivatized GABA, which served as the internal standard and worked well for correcting the matrix effect and instrument drift. The developed method had satisfactory applicability to the real sample analysis because it was successfully used to quantify the serum GABA of the healthy subjects.

Dietary Gamma-Aminobutyric Acid (GABA) Induces Satiation by Enhancing the Postprandial Activation of Vagal Afferent Nerves.

Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates brain function through stress-reducing and sleep-enhancing effects. However, its underlying mechanisms remain poorly understood, as it is reportedly unable to cross the blood–brain barrier. Here, we explored whether a single peroral administration of GABA affects feeding behavior as an evaluation of brain function and the involvement of vagal afferent nerves. Peroral GABA at 20 and 200 mg/kg immediately before refeeding suppressed short-term food intake without aversive behaviors in mice. However, GABA administration 30 min before refeeding demonstrated no effects. A rise in circulating GABA concentrations by the peroral administration of 200 mg/kg GABA was similar to that by the intraperitoneal injection of 20 mg/kg GABA, which did not alter feeding. The feeding suppression by peroral GABA was blunted by the denervation of vagal afferents. Unexpectedly, peroral GABA alone did not alter vagal afferent activities histologically. The coadministration of a liquid diet and GABA potentiated the postprandial activation of vagal afferents, thereby enhancing postprandial satiation. In conclusion, dietary GABA activates vagal afferents in collaboration with meals or meal-evoked factors and regulates brain function including feeding behavior.

Methanol leaf extract of Paullinia pinnata exerts sleep-enhancing and anticonvulsant effects via a mechanism involving the GABAergic pathway

PurposeLeaf extracts of Paullinia pinnata L. (Sapindaceae) are used in ethnomedicine for the treatment of central nervous system-related diseases such as insomnia and epilepsy. We determined the bioactive constituents, sleep-enhancing and anti-convulsant potentials, and possible mechanisms of action of P. pinnata methanol leaf extract (PPME). MethodsGas Chromatography-Mass spectrometry (GC-MS) was used to identify the bioactive compounds in PPME. Adult Swiss albino mice were used. Oral LD50 was estimated before administering PPME at oral doses of 100, 200, and 400 mg/kg to test for sleep-enhancing and anticonvulsant properties. To evaluate the possible mechanisms involved, mice were pretreated for five days with isoniazid (NIH) a GABA synthesis inhibitor before re-evaluation of sleep-enhancing property. The activities of glutamic acid decarboxylase (GAD), superoxide dismutase (SOD), catalase (CAT), and the level of malondialdehyde (MAD) in the brain of mice were also evaluated after a 7-day treatment with the extract. ResultsTwenty-five phytochemical compounds were identified from GC-MS analysis with fatty acid esters of lauric and fumaric acids being the most abundant. The oral LD50 of PPME was estimated to be greater than 5000 mg/kg. Doses of PPME significantly (p < 0.001) reduced sleep latency and increased the duration of sleep of phenobarbital-treated mice. Except for 100 mg/kg, the doses also significantly protected mice against maximum electroshock (p < 0.001) and pentylenetetrazole (p < 0.05) but not strychnine-induced convulsions. Pretreatment with isoniazid (INH) almost completely reversed the sleep-enhancing effects of PPME. The activities of GAD, SOD, and CAT, and level of MDA in brains of the mice were significantly (p < 0.001) increased by doses of PPME administered for five days. ConclusionThe extract possesses sleep-enhancing and anticonvulsant properties which depend on increased level of GABA in the brain. Its antioxidant action may be neuroprotective against free radicals-induced damage.

Curcuminoids, a major turmeric component, have a sleep-enhancing effect by targeting the histamine H1 receptor.

Turmeric (Curcuma longa) had been considered as a universal panacea in functional foods and traditional medicines. In recent, the sedative-hypnotic effect of turmeric extract (TE) was reported. However, sleep-promoting compounds in TE have been not yet demonstrated. Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the major constituents of turmeric being responsible for its various biological activities. Therefore, they can be first assumed to be sedative-hypnotic compounds of TE. In the present study, we aimed to investigate the effects and underlying mechanisms of curcuminoids and each constituent on the sleep-wake cycle of mice. Molecular docking studies, histamine H1 receptor (H1R) binding assays, and H1R knockout animal studies were used to investigate the molecular mechanisms underlying the sleep-promoting effects. Curcuminoids and their constituents reduced sleep latency and increased sleep duration in the pentobarbital-induced sleep test in mice. In addition, curcuminoids significantly increased the duration of NREMS and reduced sleep latency without altering the REMS and delta activity. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin were predicted to interact with H1R in the molecular model. In the binding affinity assay, we found that curcuminoids, as well as their constituents, significantly bind to H1R with the Ki value of 1.49 μg mL-1. Furthermore, sleep latency was reduced and NREMS frequency was increased following curcuminoid administration in wild-type mice but not in H1R knockout mice. Therefore, we conclude that curcuminoids reduce sleep latency and enhance the quantity of NREMS by acting as modulators of H1R, indicating their usefulness in treating insomnia.

Linarin, a Glycosylated Flavonoid, with Potential Therapeutic Attributes: A Comprehensive Review.

Many flavonoids, as eminent phenolic compounds, have been commercialized and consumed as dietary supplements due to their incredible human health benefits. In the present study, a bioactive flavone glycoside linarin (LN) was designated to comprehensively overview its phytochemical and biological properties. LN has been characterized abundantly in the Cirsium, Micromeria, and Buddleja species belonging to Asteraceae, Lamiaceae, and Scrophulariaceae families, respectively. Biological assessments exhibited promising activities of LN, particularly, the remedial effects on central nervous system (CNS) disorders, whereas the remarkable sleep enhancing and sedative effects as well as AChE (acetylcholinesterase) inhibitory activity were highlighted. Of note, LN has indicated promising anti osteoblast proliferation and differentiation, thus a bone formation effect. Further biological and pharmacological assessments of LN and its optimized semi-synthetic derivatives, specifically its therapeutic characteristics on osteoarthritis and osteoporosis, might lead to uncovering potential drug candidates.

Identification and Screening of Potential Bioactive Peptides with Sleep-Enhancing Effects in Bovine Milk Casein Hydrolysate.

Casein tryptic hydrolysate (CTH) has been proven to possess stress-relieving and sleep-enhancing effects, but only one decapeptide YLGYLEQLLR (α-CZP) in CTH was reported to exhibit affinity for the benzodiazepine site of a GABAA receptor (GABAAR). This study aimed to compare the sleep-enhancing effects between CTH and α-CZP and to explore novel sleep-enhancing peptides. Our results showed that CTH significantly prolonged sleep duration in mice, which was almost 2-fold longer than that of α-CZP. The α-CZP in CTH was degraded more slowly than the synthetic α-CZP; meanwhile, CTH could release other potential sleep-enhancing peptides during gastrointestinal digestion. Additionally, two peptides YPVEPF and YFYPEL with strong sleep-enhancing activity were explored by virtual screening. Especially, YPVEPF could significantly prolong the sleep duration from 559.00 ± 272.24 to 2501.63 ± 1021.21 s and increase the sleep rate from 58.33 to 83.33% in mice. Moreover, YPVEPF and YFYPEL could bind with the Ser-205 and Phe-77 residues of GABAAR via hydrogen bonds and lipid contacts. They were largely released after digestion with 11.19 ± 0.15 and 1.78 ± 0.01 g/kg, respectively.

An investigation into an evening intake of a saffron extract (affron®) on sleep quality, cortisol, and melatonin concentrations in adults with poor sleep: a randomised, double-blind, placebo-controlled, multi-dose study

Objective/backgroundTo validate and extend on previous positive findings of the sleep-enhancing effects of saffron supplementation in adults with unsatisfactory sleep. Patients/methodsIn this 28-day, 3-arm, parallel-group, double-blind, randomised controlled trial, 120 adults with unsatisfactory sleep received either a placebo, 14 mg, or 28 mg of a standardised saffron extract (affron®), 1 h before bed. Outcome measures included the Pittsburgh Sleep Diary (with sleep quality ratings as the primary outcome measure), Insomnia Symptom Questionnaire (ISQ), Profile of Mood States, Restorative Sleep Questionnaire, the Functional Outcomes of Sleep Questionnaire, and evening salivary melatonin and cortisol concentrations. ResultsCompared to the placebo, saffron supplementation was associated with greater improvements in sleep quality ratings (primary outcome measure), mood ratings after awakening, the ISQ total score, and ISQ-insomnia classifications. However, there were no significant differences between the saffron and placebo groups in other questionnaire and sleep diary outcome measures. Sleep improvements were similar for the two administered saffron doses. Compared to the placebo, saffron supplementation was associated with increases in evening melatonin concentrations but did not affect evening cortisol. Saffron supplementation was well-tolerated with no reported significant adverse effects. ConclusionsThese results provide further validation of the sleep-enhancing effects of 28-days of saffron supplementation in adults with unsatisfactory sleep. Further research is required to examine the efficacy and safety of saffron supplementation using objective sleep measures, over a longer duration, in people presenting with a diagnosed insomnia disorder and other psychogenic and demographic characteristics, and into its potential sleep-enhancing mechanisms of action.