Sclareol antagonizes the sedative effect of diazepam in thiopental sodium-induced sleeping animals: In vivo and in silico studies.

BACKGROUND: Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis. METHODS: The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs [diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg] were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds RESULTS: SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABAA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABAA receptor subunits A2 and A5. CONCLUSIONS: Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.

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.

Effects of propofol on sleep architecture and sleep-wake systems in rats.

Previous studies have shown that the synchronization of electroencephalogram (EEG) signals is found during propofol-induced general anesthesia, which is similar to that of slow-wave sleep (SWS). However, a complete understanding is lacking in terms of the characteristics of EEG changes in rats after propofol administration and whether propofol acts through natural sleep circuits. Here, we examined the characteristics of EEG patterns induced by intraperitoneal injection of propofol in rats. We found that high (10 mg/kg) and medium (5 mg/kg) doses of propofol induced a cortical EEG of low-frequency, high-amplitude activity with rare electromyographic activity and markedly shortened sleep latency. The high dose of propofol increased deep slow-wave sleep (SWS2) to 4 h, as well as the number of large SWS2 bouts (>480 s), their mean duration and the peak of the power density curve in the delta range of 0.75-3.25 Hz. After the medium dose of propofol, the total number of wakefulness, light slow-wave sleep (SWS1) and SWS2 episodes increased, whereas the mean duration of wakefulness decreased. The high dose of propofol significantly increased c-fos expression in the ventrolateral preoptic nucleus (VLPO) sleep center and decreased the number of c-fos-immunoreactive neurons in wake-related systems including the tuberomammillary nucleus (TMN), perifornical nucleus (PeF), lateral hypothalamic nucleus (LH), ventrolateral periaqueductal gray (vPAG) and supramammillary region (SuM). These results indicated that the high dose of propofol produced high-quality sleep by increasing SWS2, whereas the medium dose produced fragmented and low-quality sleep by disrupting the continuity of wakefulness. Furthermore, sleep-promoting effects of propofol are correlated with activation of the VLPO cluster and inhibition of the TMN, PeF, LH, vPAG and SuM.

A Novel Potent Sleep-Promoting Effect of Turmeric: Turmeric Increases Non-Rapid Eye Movement Sleep in Mice Via Histamine H1Receptor Blockade.

SCOPE: Turmeric has a broad spectrum of biological properties; however, the sleep-promoting effects of turmeric have not yet been reported. Thus, this study aims to investigate the effect of turmeric on sleep and the molecular mechanism underlying this effect. METHODS AND RESULTS: Pentobarbital-induce sleep test and sleep-wake profile assessment using recorded electroencephalography are used to evaluate the hypnotic effects of the turmeric extract (TE) compared to diazepam on sleep in mice. Additionally, the molecular mechanism of TE's sleep effect is investigated using ex vivo electrophysiological recordings from brain slices in histamine H1 receptor (H1 R) knockout mice. Oral administration of TE and diazepam significantly reduce sleep latency and increase non-rapid eye movement sleep (NREMS) duration without delta activity in mice. Like doxepin, TE inhibits the H1 R agonist (2-pyridylethylamine dihydrochloride)-induced increase in action potentials in the hypothalamic neurons. In animal tests using neurotransmitter agonists or antagonists, TE effect mimick H1 R antagonistic effect of doxepin. Additionally, both reduce sleep latency and increase NREMS in wild-type mice, although these effects are not observed in H1 R knockout mice. CONCLUSION: TE has a sleep-promoting effect owing to reduction in sleep latency and enhancement of NREMS via H1 R blockade; therefore, it could be useful in insomnia.

Efficacy of Triprolidine in the Treatment of Temporary Sleep Disturbance.

Triprolidine, a first-generation antihistamine for allergic rhinitis, has a shorter half-life and fewer persistent effects relative to other antihistamines and may be useful in the treatment of temporary sleep disturbance. Patients aged ≥18 years old were randomized 1:1:1 to receive either triprolidine 2.5 mg (n = 65), triprolidine 5 mg (n = 66), or placebo (n = 67) on 3 consecutive nights. Sleep disturbance index was monitored via wrist actimeter. Subjective measures were assessed via diary card. Triprolidine 2.5 mg had a significantly lower sleep disturbance index versus placebo on night 1 (P = .02); however, when adjusted for outliers, sleep disturbance index did not significantly differ between either dose of triprolidine versus placebo on night 1. Adjusted sleep disturbance index was significantly lower with triprolidine 2.5 and 5 mg versus placebo on night 3 (P = .0017 and P = .011, respectively) and for the mean of all 3 nights (P = .01 and P = .015, respectively). Sleep latency was significantly improved for triprolidine 2.5 mg versus placebo on nights 2 and 3 and for the mean of all 3 nights and for triprolidine 5 mg versus placebo for the mean of all 3 nights. Subjective measures showed those on both doses of triprolidine felt more refreshed on awakening versus placebo for the mean of all 3 nights, with no increase in daytime sleepiness. The frequency of adverse events was similar across groups. The optimum dose of triprolidine for treatment of temporary sleep disturbance was 2.5 mg. There were improvements in both objective and subjective measures of sleep quality versus placebo, with no safety concerns raised.

Anticonvulsant effects of the aqueous and methanol extracts from the stem bark of Psychotria camptopus Verdc. (Rubiacaea) in rats.

ETHNOPHARMACOLOGY RELEVANCE: The decoction from the stem bark of Psychotria camptopus (Rubiaceae) is used in the Cameroonian pharmacopoeia to treat neurological pathologies including epilepsy. AIM: The present work was undertaken to study the anticonvulsant properties of the aqueous (AE) and methanol (ME) extracts from the stem bark of P. camptopus in acute models of epileptic seizures in Wistar rats. METHOD: AE and ME were obtained by decoction and maceration of the stem bark powder in water and methanol, respectively. They were tested orally at the doses of 40, 80 and 120 mg/kg, on the latency of onset and duration of epileptic seizures induced by pentylene tetrazole (PTZ, 70 mg/kg, i.p.). The kinetic effect of both extracts at 120 mg/kg was evaluated. Their effects on diazepam (50 mg/kg) induced sleep and strychnine (STR, 2.5 mg/kg, i.p.) induced seizures were determined. ME was further tested on picrotoxin (PIC, 7.5 mg/kg, i.p.) and thiosemicarbazide (TSC, 50 mg/kg, i.p.) induced seizure models. The phytochemical composition of ME was assessed using LC-MS method, as well as its acute toxicity. RESULTS: AE and ME significantly (p < 0.001) reduced the duration of seizures in both PTZ and STR models. Their maximal effect was observed at 1 h after administration, though their effect at 120 mg/kg was maintained (p < 0.05) up to 24 h post-treatment. Both extracts significantly (p < 0.01) reduced sleep duration. ME significantly (p < 0.001) increased the latency of rat death on PIC-induced convulsions. In TSC rats, ME significantly (p < 0.001) delayed the latency to the first convulsion, and decreased the duration and frequency of convulsions. ME showed no acute toxicity while its phytochemical screening revealed the presence of two flavonoids (Rutin and Butin), two triterpenoid saponins (Psycotrianoside B and Bauerenone) and four alkaloids (10-Hydroxy-antirhine, 10-hydroxy-iso-deppeaninol, Emetine and Hodkinsine). In conclusion, AE and ME from the stem bark of P. camptopus have comparable anticonvulsant properties. The effect of ME is likely due to the presence of flavonoids and alkaloid and the activation of GABA pathway. These results further justify and support the use of P. camptopus in traditional medicine for the treatment of epilepsy.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Nelumbo nucifera promotes non-rapid eye movement sleep by regulating GABAergic receptors in rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Nelumbo nucifera are used in folk medicine for anti-depressant, anti-convulsant, neuroprotective, and many other purposes. AIM OF THE STUDY: The present work evaluated the sleep potentiating effects of water extract from lotus seed in rat, and the neuropharmacological mechanisms underlying these effects. MATERIALS AND METHODS: Pentobarbital-induced sleep test and electroencephalogram (EEG) analysis were applied to investigate sleep latency, duration, total sleeping time and sleep quality of Lotus extract. In addition, real-time PCR and HPLC analysis were applied to analyze the signaling pathway. RESULTS: We found that the amounts of the possible active compounds GABA (2.33 mg/g) and L-tryptophan (2.00 mg/g) were higher than quinidine (0.55 mg/g) and neferine (0.16 mg/g) in lotus seed extract. High dose (160 mg/kg) administration of lotus extract led to a tendency towards decreased sleep latency time and an increase in sleep duration time compared to the control group in a pentobarbital-induced sleep model (p < 0.05). After high dose administration, total sleep and NREM were significantly increased compared to control, while wake time and REM were significantly decreased. Lotus extract-treated rats showed significantly reduced wake time and increased sleep time in a caffeine-induced model of arousal. The transcription level of GABAA receptor, GABAB receptor, and serotonin receptor tended to increase with dose, and lotus extract showed a strong dose-dependent binding capacity to the GABAA receptor. CONCLUSION: The above results strongly suggest that GABA contained in lotus seed extract acts as a sleep potentiating compound, and that sleep-potentiating activity involves GABAA receptor binding.

Effects of Tangerine Essential Oil on Brain Waves, Moods, and Sleep Onset Latency.

Tangerine (Citrus tangerina) is one of the most important crops of Thailand with a total harvest that exceeds 100,000 tons. Citrus essential oils are widely used as aromatherapy and medicinal agents. The effect of tangerine essential oil on human brain waves and sleep activity has not been reported. In the present study, we therefore evaluated these effects of tangerine essential oil by measurement of electroencephalography (EEG) activity with 32 channel platforms according to the international 10-20 system in 10 male and 10 female subjects. Then the sleep onset latency was studied to further confirm the effect on sleep activity. The results revealed that different concentrations, subthreshold to suprathreshold, of tangerine oil gave different brain responses. Undiluted tangerine oil inhalation reduced slow and fast alpha wave powers and elevated low and mid beta wave powers. The subthreshold and threshold dilution showed the opposite effect to the brain compared with suprathreshold concentration. Inhalation of threshold concentration showed effectively decreased alpha and beta wave powers and increased theta wave power, which emphasize its sedative effect. The reduction of sleep onset latency was confirmed with the implementation of the observed sedative effect of tangerine oil.

Is time elapsed between cannabis use and sleep start time associated with sleep continuity? An experience sampling method.

BACKGROUND: A substantial proportion of people using cannabis report using it to improve sleep. Yet, little research exists on the associations between the timing of cannabis use and sleep. This study examines the time elapsed between cannabis use and sleep start time and its association with two of the main indicators of sleep continuity: (1) sleep onset latency (SOL) and (2) number of awakenings (NOA) throughout the night. METHODS: Each morning, for 7 consecutive days, daily cannabis users (n = 54) reported on the timing of previous night's cannabis use and sleep indicators on their smartphones. Mixed effects models examined the relations of within- and between-subjects' time elapsed between previous night cannabis use and sleep start time, with (1) SOL and (2) NOA. RESULTS: Within subjects, shorter time elapsed between cannabis use and sleep start time was associated with shorter SOL (ß = 0.519, p = 0.010), but not NOA (ß = -0.030, p = 0.535). Furthermore, between individuals, the time gap between the previous night cannabis use and sleep start time was not associated with SOL or NOA (p > 0.05). CONCLUSIONS: It is possible that cannabis use proximal to bedtime is associated with shorted sleep onset latency but not nighttime awakenings. Cannabis users should be informed about both the potential sleep aid effects of cannabis and its limitations. Pending further evidence of the effects of cannabis on sleep, cannabis users experiencing sleep problems should be provided with evidence-based alternatives to improve sleep, e.g., pharmacological and behavioral treatments.