Search Results (37)

Background/Objectives: Insomnia is a prevalent clinical sleep disorder, with existing hypnotic therapies limited by safety concerns. There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components of Semen Ziziphi Spinosae that exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the A_2AR remains to be elucidated. Methods: In the study, the involvement of A_2ARs in spinosin’s hypnotic effect was investigated using caffeine and further elucidated in A_2AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the A_2AR. Results: The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with A_2AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in A_2AR-KO mice. Spinosin significantly increased the activity of γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in A_2AR-KO mice. Finally, the results of molecular docking showed that spinosin had a good binding potential with the A_2AR. MD simulations further demonstrated that spinosin had strong binding stability with the A_2AR. Conclusions: Our findings strongly suggest that spinosin exerts the hypnotic effects through the A_2AR, and thus may have therapeutic potential for insomnia. Our identification of spinosin’s direct molecular target supports its translational potential as a novel natural-origin candidate for clinical insomnia drug development. Full article

Background/Objectives: Baichuan Baile (BCBL), a novel functional dietary formula, has been shown to exert antidepressant-like effects through modulation of the 5-HT system in our prior studies. Given the close neurobiological connections between depression and insomnia, along with its pharmacodynamic profile guided by TCM theory and nutritional assessments, BCBL is likely to possess beneficial effects against insomnia. However, this hypothesis and its underlying mechanisms require further validation. Methods: The chemical constituents of BCBL were analyzed by UPLC-Q-TOF-MS, and network pharmacology was applied to predict potential sleep-relevant targets and pathways. Subsequently, BCBL was evaluated for sedative-hypnotic effects using pentobarbital-induced hypnosis, locomotor activity, and polysomnography (EEG/EMG). Its therapeutic efficacy was further assessed in insomnia models induced by environmental stress, serotonin depletion, and rotarod-based sleep deprivation. The rotarod-induced chronic model was selected for mechanistic studies due to its sustained insomnia-like phenotype. Finally, key network-predicted targets were validated in this model through histopathology, Western blotting, and ELISA. Results: Pharmacological evaluation confirmed that BCBL significantly promoted sleep at both behavioral and EEG levels, confirming its sedative-hypnotic properties. BCBL mitigated environmental stress-triggered impairments in NREM sleep continuity and duration, and exerted protective effects against body weight loss and sleep disturbances in a serotonin depletion-induced insomnia model. In the rotarod sleep deprivation model, BCBL treatment increased spontaneous alternation rates and recognition indices, ameliorated hippocampal pathological alterations, and reduced hippocampal levels of HIF-1α, TNF-α, and IL-1β. Furthermore, BCBL elevated the p-GSK3β/GSK3β ratio and enhanced SIRT₁ expression in the hypothalamus. It also modulated the activity of key sleep–wake neurotransmitters/neuromodulators (serotonin, dopamine, adenosine, and glutamate) and key circadian rhythm regulators (BMAL₁, PER₂, and CLOCK) in this region. Conclusions: BCBL exhibits significant therapeutic efficacy against insomnia, indicating its potential as a dietary supplement for managing insomnia. Its mechanisms appear to involve anti-inflammatory effects, rebalancing of neurotransmitters/neuromodulators, and stabilization of circadian rhythm gene expression. Full article

The Acronicta major larva is a toxic agricultural pest that poses severe ecological management challenges. This study presents a sustainable strategy to valorize this hazardous biological waste into functional nanotherapeutics for insomnia by leveraging its unique intrinsic chemical composition. Carbon dots derived from Acronicta major larva (AM-CDs) were synthesized via one-step pyrolysis, which facilitated the natural molecular pre-assembly of N,S-codoping. Their physicochemical properties and cytotoxicity were evaluated using a series of characterizations and the CCK-8 assay. The sedative and hypnotic effects were assessed in mice with PCPA-induced insomnia through hot plate, Open Field and pentobarbital-induced sleep tests, and their potential mechanism was explored via neurotransmitter detection. The thermal process effectively eliminated intrinsic toxicity while retaining bioactivity via in situ heteroatom doping. AM-CDs exhibited favorable biocompatibility and significant sedative–hypnotic activity, reducing anxiety-related agitation without motor impairment. Mechanistically, AM-CDs effectively restored the GABA/5-HT/glutamate axis. Unlike direct central receptor binding, our findings suggest that this therapeutic effect is likely mediated through a systemic or peripheral regulatory pathway. This study demonstrates the conversion of toxic pests into safe and intrinsically bioactive nanomaterials, providing a dual solution for ecological pest management and novel neuroactive agent development, and validating the “Waste-to-Wealth” concept in biomedicine. Full article

Background/Objectives: As a non-medicinal part resource of Ziziphus jujuba, this study focuses on the total flavonoids from Ziziphus jujuba mesocarp (TFZJM), aiming to optimize the extraction process and explore its sedative and hypnotic effects. Methods: The extraction process of TFZJM was optimized by using single-factor experiments and the Box-Behnken response surface design method. The material basis of TFZJM was analyzed using Ultra-Performance Liquid Chromatography-Quadrupole-Time of Flight-Mass Spectrometry (UPLC-Q-TOF-MS). The mouse insomnia model was induced by intraperitoneal injection of PCPA, and the effects of TFZJM on this model and its potential mechanism were evaluated using multiple methods, such as sleep enhancement induced by pentobarbital sodium, HE staining of tissue sections, ELISA, RT-PCR, WB, and serum metabolomics. Results: The results showed that by optimizing the extraction conditions, a solid-liquid ratio (SLR) of 1:25 g·mL⁻¹, ethanol concentration of 60%, extraction time of 60 min, and extraction rate of 1.98% were achieved. The common chemical basis of the 10 flavonoid components was identified using UPLC-Q-TOF-MS analysis. Compared with the model group, the high-dose TFZJM (TFZJM-H) group had the most significant effect, followed by the medium-dose (TFZJM-M) and low-dose (TFZJM-L) groups. Conclusions: Metabolomic analysis revealed that TFZJM regulates pathways related to the metabolism of phenylalanine, tyrosine, cytochrome P450, and alanine. This lays the foundation for further exploration of the active substances and mechanisms of action of TFZJM in sedation and hypnosis. Full article

Although opioids are effective in treating pain, they cause serious side effects. The use of regional anesthesia, although effective in the perioperative period, may not be suitable if mobility and lack of numbness is desired. Hence, there is a clear need for novel pain therapies. Low-voltage activated (T-type) calcium channels (Ca_V3.2 isoform) could be a promising therapeutic target for the development of novel pain therapies. Indeed, our published findings suggest that novel neuroactive steroid (NAS) analogs that modulate the activity of Ca_V3.2 channels have unique anti-nociceptive properties. However, the concern with current NASs appears to be their hypnotic/sedative properties, thus potentially hindering the future development of NASs for novel pain therapies. Hence, we developed a new line of NASs that are effective blockers of neuronal Ca_V3.2 channels in pain pathways while having more favorable pharmacodynamic properties, i.e., lack of sedative/hypnotic side effects. We present two promising novel analogs of NASs—B372 ((3β,5α,17β)-3-Hydroxyandrostan-17-carbonitrile) and YX23 ((3β,5α,17β)-3-Methoxyestran-17-ol). Using an in vitro approach, we show that B372 and YX23 are effective in blocking Ca_V3.2 channels. Using an in vivo approach, we show that they are effective anti-nociceptives in wild-type but not Ca_V3.2 knock-out mice. Importantly, we show that they lack sedative/hypnotic effects. Full article

Depression, anxiety, and perceived stress are common comorbidities in patients with inflammatory bowel disease (IBD) and may negatively influence the disease course. Likewise, severe IBD may contribute to the development or worsening of psychiatric symptoms. Despite the established relevance of the gut–brain axis and frequent use of psychotropic medications in IBD patients, limited evidence exists regarding the effects of psychiatric treatments on gastrointestinal disease activity. Therefore, the aim of this systematic review is to evaluate the effectiveness of psychiatric therapies on gastrointestinal symptoms and disease activity in patients with IBD. The work was conducted in accordance with PRISMA guidelines. Searches were performed across PubMed, Web of Science, and Scopus up to July 2024. Eligible studies evaluated the effectiveness of psychiatric medications—including antidepressants, antipsychotics, anxiolytics, sedative-hypnotics, mood stabilizers, anticonvulsants, and others—on at least one gastrointestinal outcome in patients with IBD. Outcomes included changes in commonly used clinical and endoscopic scores for Crohn’s disease (CD) and ulcerative colitis (UC), number of bowel movements, stool consistency, presence of blood in stool, severity of abdominal pain, as well as in surrogate markers of disease activity following treatment. Out of 8513 initially identified articles, 22 studies involving 45,572 IBD patients met the inclusion criteria. Antidepressants, particularly bupropion, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and duloxetine, were associated with improvements in IBD activity scores, including Crohn’s Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD) for CD, Mayo score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for UC. Case reports highlighted potential benefits of pregabalin and lithium carbonate, respectively, showed by the reduction in clinical and endoscopic score of disease activity for pregabalin and improvement of UC symptoms for lithium carbonate, while topiramate showed limited efficacy. Clonidine and naltrexone determined the reductions in clinical and endoscopic score of disease activity, including CDAI and Crohn’s disease endoscopy index severity score (CDEIS) for CD and Disease Activity Index (DAI) for UC. Despite the limited data and study heterogeneity, antidepressants, naltrexone, and clonidine were associated with improvements in IBD activity. Larger, prospective studies are needed to confirm the therapeutic potential of psychiatric medications in modulating IBD activity and to guide integrated clinical management. Full article

Ziziphi Spinosae Semen saponins (ZSSS) show sedative–hypnotic activity but have very low bioavailability, potentially due to their conversion into bioactive metabolites by gut microbiota. In this study, the biotransformation of ZSSS by gut microbiota from healthy humans and patients with insomnia in vitro was analyzed. A total of 21 prototype compounds and 49 metabolites were identified using UHPLC-Q-Orbitrap-MS. Deglycosylation, deoxygenation, dehydration, and deacylation were detected in both healthy individuals and insomniacs. However, oxidation and hydrogenation were uniquely observed in insomniacs. ZSSS can enhance beneficial bacteria, such as Veillonella, Dialister, and Bacteroides. ZSSS can promote the synthesis of short-chain fatty acids (SCFAs), especially acetic acid, propionic acid, and butyric acid. Furthermore, it was found that the sedative–hypnotic activity of ZSSS was enhanced after biotransformation, as determined by a sodium pentobarbital-induced sleeping test (SPST), open-field behavior test (OFBT), and molecular docking experiment (MDE). These results collectively offer valuable insight into the mechanism of action of ZSSS. Full article

Osteoclast differentiation inhibition is a viable treatment strategy for osteoporosis because osteoclasts play a vital role in disease progression. Rhusflavone (Rhus), a biflavonoid, exhibits a sedative–hypnotic effect via the positive allosteric modulation of GABA(A) receptors. Although several biflavonoids possess activities that help prevent bone loss, the potential effects of Rhus on osteoclastogenesis have not been reported yet. In this study, we investigated the effects and underlying biological mechanisms of Rhus isolated from the dried roots of Rhus succedanea on osteoclastogenesis in primary cultured bone marrow-derived macrophages. No cytotoxicity was observed in bone marrow macrophages (BMMs) or during osteoclast differentiation. However, Rhus reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts during receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis. The results of F-actin ring formation demonstrated that Rhus suppresses the bone resorption activity of osteoclasts. Additionally, Rhus inhibits the expression of osteoclast differentiation marker proteins, specifically c-Fos and NF-ATc1. Western blot analysis revealed that Rhus primarily attenuated RANKL-mediated key signaling pathways, particularly the AKT signaling pathway. Furthermore, we found that the AKT activator and inhibitor pharmacologically abolished and enhanced the inhibitory effects of Rhus on osteoclast differentiation, respectively. Taken together, our findings provide evidence that Rhus is a promising biologically active compound that regulates osteoclast differentiation by inhibiting the AKT signaling pathway, which may contribute to future drug development. Full article

Valerian possesses a multitude of pharmacological effects, including sedative and hypnotic properties, antihypertensive effects, antibacterial activity, and liver protection. Insomnia, one of the most prevalent disorders in contemporary society, significantly impacts people’s daily lives. This study aims to explore the anti-insomnia effects of valerian volatile oil (VVO) and investigate its potential mechanism of action through chemical analysis, network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation. Through gas chromatography–mass spectrometry (GC-MS) analysis and drug-likeness screening, we identified 38 active compounds. Network pharmacology studies revealed that these 38 compounds might affect 103 targets associated with insomnia, such as monoamine oxidase B (MAOB), dopamine receptor D2 (DRD2), monoamine oxidase A (MAOA), interleukin 1β (IL1B), solute carrier family 6 member 4 (SLC6A4), prostaglandin-endoperoxide synthase 2 (PTGS2), and 5-hydroxytryptamine receptor 2A (HTR2A), which contribute to regulating the neuroactive ligand–receptor interaction, 5-hydroxytryptaminergic synapse, and calcium signaling pathways. The results of the molecular dynamics simulations indicated that bis[(6,6-dimethyl-3-bicyclo[3.1.1]hept-2-enyl)methyl] (E)-but-2-enedioate exhibited a stabilizing interaction with MAOB. The animal studies demonstrated that gavage administration of a high dose (100 mg/kg) of VVO significantly diminished autonomous activity, decreased sleep latency, and extended sleep duration in mice. Furthermore, the results of the Western blot experiment indicated that VVO interacts with MAOB, resulting in decreased expression levels of MAOB in the cerebral cortex. This study demonstrates the protective mechanism of VVO against insomnia through chemical analysis, network pharmacology, and experimental validation and extends the possible applications of VVO, which is a potential therapeutic ingredient for use in insomnia treatment. Full article

Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters with beneficial effects including sedative properties. However, despite various clinical trials, scientific evidence regarding the impact on sleep of orally ingested GABA, whether natural or synthesized through biological pathways, is not clear. GABALAGEN (GBL) is the product of fermented collagen by Lactobacillus brevis BJ20 (L. brevis BJ20) and Lactobacillus plantarum BJ21 (L. plantarum BJ21), enriched with GABA and characterized by low molecular weight. The aim of this study was to investigate the effect of GBL on sleep improvement via a receptor binding assay in a pentobarbital-induced sleep-related rat model. We utilized a pentobarbital-induced sleep-related rat model to conduct this research. The present study investigated the sedative effects of GBL through electroencephalography (EEG) analysis in the pentobarbital-induced sleep animal model. Exploration of the neural basis of these positive effects involved evaluating orexin in the brain via immunohistochemical methods and 5-HT in the serum using an enzyme-linked immunosorbent assay (ELISA). Furthermore, we conducted a binding assay for 5-HT_2C receptors, as these are considered pivotal targets in the mechanism of action for sleep aids. Diazepam (DZP) was used as a positive control to compare the efficacy of GBL. Results: In the binding assay, GBL displayed binding affinity to the 5-HT_2C receptor (IC50 value, 5.911 µg/mL). Administration of a low dose of GBL (GBL_L; 100 mg/kg) increased non-rapid eye movement sleep time and decreased wake time based on EEG data in pentobarbital-induced rats. Administration of a high dose of GBL (GBL_H; 250 mg/kg) increased non-rapid eye movement sleep time. Additionally, GBL groups significantly increased concentration of the 5-HT level in the serum. GBL_H decreased orexin expression in the lateral hypothalamus. Conclusion: Overall, the sedative effect of GBL may be linked to the activation of serotonergic systems, as indicated by the heightened affinity of the 5-HT_2C receptor binding and elevated levels of 5-HT observed in the serum. This suggests that GBL holds promise as a novel compound for inducing sleep in natural products. Full article

Pinelliae Rhizoma (PR), a highly esteemed traditional Chinese medicinal herb, is widely applied in clinical settings due to its diverse pharmacological effects, including antitussive, expectorant, antiemetic, sedative-hypnotic, and antitumor activities. Pinellia ternata exhibits morphological variation in its leaves, with types resembling peach, bamboo, and willow leaves. However, the chemical composition differences among the corresponding rhizomes of these leaf phenotypes remain unelucidated. This pioneering research employed Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) to conduct the in situ identification and spatial profiling of 35 PR metabolites in PR, comprising 12 alkaloids, 4 organic acids, 12 amino acids, 5 flavonoids, 1 sterol, and 1 anthraquinone. Our findings revealed distinct spatial distribution patterns of secondary metabolites within the rhizome tissues of varying leaf types. Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) effectively differentiated between rhizomes associated with different leaf morphologies. Furthermore, this study identified five potential differential biomarkers—methylophiopogonanone B, inosine, cytidine, adenine, and leucine/isoleucine—that elucidate the biochemical distinctions among leaf types. The precise tissue-specific localization of these secondary metabolites offers compelling insights into the specialized accumulation of bioactive compounds in medicinal plants, thereby enhancing our comprehension of PR’s therapeutic potential. Full article

With the increasing prevalence of insomnia-related diseases, the effective treatment of insomnia has become an important health research topic. Lavender (Lavandula angustifolia Mill.) essential oil (LEO) is a commonly used medicine for the treatment of insomnia and neurological disorders. However, neither the active components nor its sedative–hypnotic mechanism have been fully discovered. This study aimed to screen the main active terpenes and discover the possible mechanism of LEO through network pharmacology in the treatment of insomnia-related diseases, as well as to verify our hypothesis in insomnia mice. The results showed that, in LEO’s 15 potential active ingredients, beta-myrcene had strong sedative–hypnotic effects through the serotonergic synaptic pathway according to the network pharmacological prediction. Further, PCPA(DL-4-chlorophenylalanine)-induced insomnia mice were treated with beta-myrcene for one day or seven days. The quiet state of insomnia mice was increased effectively, and the hypnotic effect was enhanced by anaobarbital sodium by prolonging sleep duration, decreasing sleep latency, and increasing the rate of falling asleep. Beta-myrcene reduced the damage to hypothalamic neuron cells induced by PCPA and increased neurotransmitter levels of GABA, 5-HT, and Glu in the serum and hypothalamus of insomnia mice. Meanwhile, beta-myrcene exerted an improvement in insomnia by upregulating relevant genes and protein expression in the serotonergic synaptic pathway. These results support the merit of the sedative–hypnotic activity of LEO. Beta-myrcene, a terpene in LEO, may be the main source of its sedative–hypnotic properties. It may serve as a good potential compound in future clinical studies on coping with insomnia. Full article

Stanhopea tigrina Bateman ex Lindl. (Orchidaceae) is an orchid endemic to Mexico, known as “Calavera” or “calaverita”, in the Huasteca Potosina (central region of Mexico). This plant species is used for the folk treatment of mental disorders and urological kidney disorders, according to the ethnomedicinal information obtained in this study. Ethanolic extracts of leaves (HE) and pseudobulb (PE) were obtained by microwave-assisted extraction (MAE). Gas Chromatography coupled with Mass Spectrometry (GC-MS) was used to carry out the chemical characterization of HE and PE. The pharmacological effects (antioxidant, diuretic, anxiolytic, locomotor, hypnotic, and sedative) of HE and PE were evaluated. The possible mechanism of action of the anxiolytic-like activity induced by HE was assessed using inhibitors of the GABAergic, adrenergic, and serotonergic systems. The possible mechanism of the diuretic action of HE was assessed using prostaglandin inhibitory antagonists and nitric oxide synthase (NOS) blockers. HE at 50 and 100 mg/kg exerted anxiolytic-like activity without inducing hypnosis or sedation. Flumazenil, prazosin, and ketanserin inhibited the anxiolytic-like activity shown by HE, which suggests the participation of GABA, α₁-adrenergic receptors, and 5-HT₂ receptors, respectively. The diuretic effect was reversed by the non-selective NOS inhibitor L-NAME, which caused the reduction in nitric oxide (NO). These results demonstrate that the ethanolic extract of S. tigrina leaves exhibited anxiolytic-like activity and diuretic effects without inducing hypnosis or sedation. This work validates the medicinal uses of this orchid species. Full article

The modification of heterocyclic systems remains one of the most promising areas in heterocyclic chemistry. Benzodiazepines (BZDs), representing a diverse class of heterocyclic molecules, have piqued interest due to their use as anticonvulsant/anti-inflammatory/analgesic/sedative/anti-depressive/hypnotic medications, as well as anti-inflammatory/anti-HIV drugs. Phosphorus heterocycle molecules fused with rings of different sizes and bearing various heteroatoms have also been attracting much interest. Phosphoramidate class compounds with an amino group linked directly to the phosphorus atom have gained considerable attention due to their wide range of biological activity and agricultural application. To date, however, only non-condensed monocyclic 1,3,5,2-oxodiazaphosphol-2-oxides have been described.Herein, we report the synthesis of previously undescribed 4H-[1,3,5,2]oxadiazophospho[3,4-a][1,5]benzodiazepine-1-amino-1-oxides, comprising benzodiazepine and a fused five-member oxodiazophospholo cycle with four heteroatoms in the “a” position, which was made possible by phosphorylation of 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin oximes with an equimolar amount of dimethylaminophosphoric acid dichloride. The chemical structures of the compounds were confirmed by IR, ¹H, ¹³C, and ³¹P NMR spectral analysis. A series of simulations were conducted by employing the semi-empirical, tight-binding computational technique GFN2-xTB to reveal the likely pathways leading to their formation. The synthesised compounds obeyed Lipinski’s rule, implying a good bioavailability, and assessment of their projected drug-like abilities revealed that they may have a strong anti-neoplastic activity and, to a lesser extent, may act as both substrates and inducers of cytochrome P-450 (CYP) super-family enzymes. Full article

Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography–mass spectrometry (GC–MS), and its active compound dihydrosanguinarine (DHS). The anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of the AOE (0.1–50 mg/kg p.o.) and DHS (0.1–10 mg/kg p.o.) were evaluated using murine models. A possible mechanism for the neurological actions induced by the AOE or DHS was assessed using inhibitors of neurotransmission pathways and molecular docking. Effective dose 50 (ED₅₀) values were calculated by a linear regression analysis. The AOE showed anxiolytic-like activity in the cylinder exploratory test (ED₅₀ = 33 mg/kg), and antidepressant-like effects in the forced swimming test (ED₅₀ = 3 mg/kg) and the tail suspension test (ED₅₀ = 23 mg/kg), whereas DHS showed anxiolytic-like activity (ED₅₀ = 2 mg/kg) in the hole board test. The AOE (1–50 mg/kg) showed no locomotive affectations or sedation in mice. A docking study revealed the affinity of DHS for α2-adrenoreceptors and GABA_A receptors. The anxiolytic-like and anticonvulsant effects of the AOE are due to GABAergic participation, whereas the antidepressant-like effects of the AOE are due to the noradrenergic system. The noradrenergic and GABAergic systems are involved in the anxiolytic-like actions of DHS. Full article