Potential antidepressant effects of Traditional Chinese botanical drug formula Chaihu-Shugan-San and its active ingredients.

Background: Depression is a severe mental disorder that poses a significant threat to both the physical and mental wellbeing of individuals. Currently, there are various methods for treating depression, including traditional Chinese herbal formulations like Chaihu-Shugan-San (CSS), which have shown effective antidepressant effects in both clinical and animal research. Objective: This review aims to provide a comprehensive synthesis of evidence related to CSS, considering both preclinical and clinical studies, to uncover its potential multi-level, multi-pathway, and multi-target mechanisms for treating depression and identify its active ingredients. Methods: A thorough search was conducted in electronic databases, including PubMed, MEDLINE, Web of Science, Google Scholar, CNKI, and Wanfang, using keywords such as "Chaihu Shugan" and "depression" to retrieve relevant literature on CSS and its active ingredients. The review process adhered to the PRISMA guidelines. Results: This review consolidates the mechanisms underlying antidepressant effects of CSS and its active ingredients. It emphasizes its involvement in the regulation of monoaminergic neurotransmitter systems, synaptic plasticity, and the hypothalamic-pituitary-adrenal axis, among other aspects. Conclusion: CSS exerts a pivotal role in treating depression through various pathways, including the monoaminergic neurotransmitter system, the hypothalamic-pituitary-adrenal axis, synaptic plasticity, inflammation, brain-derived neurotrophic factor levels, and the brain-gut axis. This review facilitates a comprehensive understanding of the current state of CSS research, fostering an in-depth exploration of the etiological mechanisms of depression and the potential discovery of novel antidepressant drugs.

Chinese herbal medicines for the treatment of depression: a systematic review and network meta-analysis.

Objectives: Amidst rising global burden of depression and the associated challenges with conventional antidepressant therapies, there is a growing interest in exploring the efficacy and safety of alternative treatments. This study uses a Bayesian network meta-analysis to rigorously evaluate the therapeutic potential of Chinese herbal medicines in the treatment of depression, focusing on their comparative efficacy and safety against standard pharmacological interventions. Methods: Five databases (PubMed, Wanfang Data, EMBASE, CNKI, and the Cochrane Library) and grey literature were searched from inception to end of July 2023 to identify studies that assessed the efficacy and safety of Chinese herbal medicines in treating depression. The response rate, Hamilton Depression Scale (HAMD) scores, and rates of adverse events were assessed through both direct and indirect comparisons. Data extraction and risk of bias assessment were meticulously performed. Statistical analysis used Markov chain Monte Carlo methods, with effect size estimates provided as odd ratios and their 95% confidence intervals. Results: A total of 198 RCTs involving 8,923 patients were analyzed, assessing 17 Chinese herbal medicines. Surface Under the Cumulative Ranking results indicated that the top three treatments with the best response rate were possibly Guipiwan, Ease Pill, and Chaihu Jia Longgu Muli Decoction; the top three treatments on the reduction of HAMD scores were Chai Hu Shu Gan San, Xingnao Jieyu Decoction, and Xiaoyao Powder; and the top three treatments with the lowest adverse effects rates were Xiaoyao Powder, Alprazolam, and Xingnao Jieyu Decoction. Interestingly, commonly used synthetic drugs such as Fluoxetine, Escitalopram, Amitriptyline, Sertraline, Flupentixol and Melitracen, and Venlafaxine, not only appeared to be less effective than specific Chinese herbal medicines (Gan Mai Da Zao Decoction, Chaihu Jia Longgu Muli Decoction, Chai Hu Shu Gan San, Danzhi-Xiaoyao-San, and Xingnao Jieyu Decoction), but they were also related to substantially higher risk of adverse events. Conclusion: Our findings elucidate the promising therapeutic potential of Chinese herbal medicines as viable alternatives in the treatment of depression, with certain herbs demonstrating enhanced efficacy and safety profiles. The outcomes of this study advocate for the integration of these alternative modalities into contemporary depression management paradigms. However, it underscores the necessity for larger, methodologically robust trials to further validate and refine these preliminary findings. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023452109.

Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Major Depressive Disorder (MDD) emerges as a complex psychosomatic condition, notable for its considerable suicidality and mortality rates. Increasing evidence suggests the efficacy of Chinese herbal medicine in mitigating depression symptoms and offsetting the adverse effects associated with conventional Western therapeutics. Notably, clinical trials have revealed the adjunctive antidepressant potential of Kaiyu Zhishen Decoction (KZD) alongside Western medication. However, the standalone antidepressant efficacy of KZD and its underlying mechanisms merit in-depth investigation. AIM OF THE STUDY: This research aims to elucidate the impact of KZD on MDD and delineate its mechanistic pathways through integrated network pharmacological assessments and empirical in vitro and in vivo analyses. MATERIALS AND METHODS: To ascertain the optimal antidepressant dosage and mechanism of KZD, a Chronic Unpredictable Mild Stress (CUMS)-induced depression model in mice was established to evaluate depressive behaviors. High-Performance Liquid Chromatography (HPLC) and network pharmacological approaches were employed to predict KZD's antidepressant mechanisms. Subsequently, hippocampal samples were subjected to 4D-DIA proteomic sequencing and validated through Western blot, immunofluorescence, Nissl staining, and pathway antagonist applications. Additionally, cortisol-stimulated PC12 cells were utilized to simulate neuronal damage, analyzing protein and mRNA levels of MAPK-related signals and cell proliferation markers. RESULTS: The integration of network pharmacology and HPLC identified kaempferol and quercetin as KZD's principal active compounds for MDD treatment. Proteomic and network pharmacological KEGG pathway analyses indicated the MAPK signaling pathway as a critical regulatory mechanism for KZD's therapeutic effect on MDD. KZD was observed to mitigate CUMS-induced upregulation of p-ERK/ERK, CREB, and BDNF protein expressions in hippocampal cells by attenuating oxidative stress, thereby ameliorating neuronal damage and exerting antidepressant effects. The administration of PD98059 counteracted KZD's improvements in depression-like behaviors and downregulated p-ERK/ERK and BDNF protein expressions in the hippocampus. CONCLUSIONS: This investigation corroborates KZD's pivotal, dose-dependent role in antidepressant activity. Both in vivo and in vitro experiments demonstrate KZD's capacity to modulate the ERK-CREB-BDNF signaling pathway by diminishing ROS expression induced by oxidative stress, enhancing neuronal repair, and thus, manifesting antidepressant properties. Accordingly, KZD represents a promising herbal candidate for further antidepressant research.

Echinacoside ameliorates post-stroke depression by activating BDNF signaling through modulation of Nrf2 acetylation.

BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.

Assessment of Pharmacokinetic Effects of Herbal Medicines on Escitalopram.

Purpose: Herbal medicines are occasionally used in combination with conventional antidepressants to mitigate various depression-associated symptoms. However, there is limited information on herb-antidepressant interactions. In this study, we investigated the pharmacokinetic (PK) effects of four herbal medicines (Gami-soyosan, Banhasasim-tang, Ojeok-san, and Bojungikgi-tang) on escitalopram, a commonly used antidepressant. Patients and Methods: In this open-label, fixed-sequence, three-period, crossover study, 18 participants were enrolled and divided into two groups. Each group received a 10 mg oral dose of escitalopram in period 1. Participants took escitalopram once daily and their assigned herbal medicines thrice a day for 7 d in periods 2 (group 1: Gami-soyosan, group 2: Ojeok-san) and 3 (group 1: Banhasasim-tang; group 2: Bojungikgi-tang). The primary endpoints were Cmax,ss and AUCtau,ss of escitalopram. Cmax,ss and AUCtau,ss in period 1 were obtained using nonparametric superposition from single-dose data. The PK endpoints were classified according to the CYP2C19 phenotype. Results: Of 18 participants, 16 completed the study. Systemic exposure to escitalopram resulted in a minor increase in the presence of each herbal medicine. The geometric mean ratios (GMRs, combination with herbal medicines/escitalopram monotherapy) and their 90% confidence intervals (CIs) for Cmax,ss and AUCtau,ss were as follows: Gamisoyosan- 1.1454 (0.9201, 1.4258) and 1.0749 (0.8084, 1.4291), Banhasasim-tang-1.0470 (0.7779, 1.4092) and 1.0465 (0.7035, 1.5568), Ojeok-san-1.1204 (0.8744, 1.4357) and 1.1267 (0.8466, 1.4996), and Bojungikgi-tang-1.1264 (0.8594, 1.4762) and 1.1400 (0.8515, 1.5261), respectively. Furthermore, no significant differences in the GMRs of Cmax,ss and AUCtau,ss were observed across different CYP2C19 phenotypes in any of the groups. Conclusion: The co-administration of escitalopram with Gami-soyosan, Banhasasim-tang, Ojeok-san, or Bojungikgi-tang did not exert significant PK effects on escitalopram. These findings provide valuable insights into the safe use of herbal medicines along with escitalopram.

Natural Herbal Compounds Exerting an Antidepressant Effect through Hypothalamic-Pituitary-Adrenal Axis Regulation.

Depression is a common mental illness that damages the life and health of patients and causes economic burden, and HPA (hypothalamic-pituitary-adrenal) axis dysfunction is considered to be one of the important factors leading to depression. In this case, it is essential to explore possible treatment methods by using natural compounds with HPA axis regulating and antidepressant effects. However, no one has reviewed it so far. Therefore, the purpose of this review is to systematically sort out the related natural products that play an antidepressant role by regulating the function of the HPA axis. Natural products are divided into flavonoids, polyphenols, terpenoids, saponins, polysaccharides and so on according to their chemical structures, which play a variety of biological activities such as regulating the HPA axis, anti-inflammation and neuroprotection. These effects may provide a useful reference for the potential treatment of depression so as to develop new antidepressants.

Gamma-Aminobutyric Acid in Rice Bran Extract Exerts Antistress Effects in Mouse Models with Depressive-Like Behaviors.

Various neurotransmitters are involved in regulating stress systems. In this study, we investigated the effects of gamma-aminobutyric acid-rich rice bran extract (GRBe) in mice stressed by forced swimming and tail suspension tests. Four weeks of oral administration of GRBe (500-2000 mg/kg) reduced the levels of dopamine and corticosterone in the blood and brain while increasing serotonin levels. GRBe was involved not only in stress but also in regulating sleep and obesity-related genes. Modern society experiences diverse and tense lives because of urbanization and informatization, which cause excessive stress due to complicated interpersonal relationships, heavy work burden, and fatigue from the organized society. High levels of stress cause psychological instability and disrupt the balance in the autonomic nervous system, which maintains the body's equilibrium, resulting in cardiovascular and cerebrovascular diseases, hormonal imbalances, and sleep disorders. Therefore, our results suggest that GRBe is a useful substance that can relieve tension by ultimately influencing a depressive-like state by lowering the levels of neuronal substances, hormones, and cytokines involved in stress and sleep disorders.

Depression risk in users of different doses of levonorgestrel intrauterine systems: a nationwide prospective cohort study.

Background: Use of the high-dose levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with increased risk of incident depression. Evidence is lacking on the influence of use of two recently marketed low-dose LNG-IUS on risk of depression. This study aims to examine associations between use of different doses of LNG-IUS and risk of depression. Methods: We conducted a nationwide prospective cohort study involving all first-time users of an LNG-IUS among all Danish nulliparous women aged 15-34 years with no medical history of depression, major psychiatric diseases, endometriosis, heavy menstrual bleeding, polyp, myoma, dysmenorrhoea, iron supplement use, abortion, and infertility treatment. Findings: A total of 46,565 first-time users of LNG-IUS were followed for 80,516 person-years with 1,531 incident initiations of antidepressant use observed during follow-up. Use of the high-dose LNG-IUS containing 52 mg levonorgestrel was initiated by 9,902 (21%) women, while 20,665 (44%), and 15,998 (34%) initiated use of the low-dose LNG-IUS containing 19·5 mg and 13·5 mg levonorgestrel, respectively.The age-, calendar-time-, and education-standardised incidence rates of first-time depression per 1,000 person-years at full LNG-IUS duration were 30.8 (95% CI 23·6-39·5) for the 52 mg LNG-IUS, 19·8 (95% CI 16·1; 24·0) for the 19·5 mg LNG-IUS, and 17·7 (95% CI 14·4-21·5) for the 13·5 mg LNG-IUS-. Compared to the high-dose 52 mg LNG-IUS, the adjusted number of avoided depressions per 1,000 person-years were 11·0 (95% CI 7·1-14·9) for the 19·5 mg LNG-IUS and 13·1 (95% CI 9·6-16·6) for the 13·5 mg LNG-IUS. The corresponding adjusted rate ratios were 0·77 (95% CI 0·68; 0·88) and 0·85 (95% CI 0·75-0·96). The reduced risk of depression with low-dose LNG-IUS compared to high-dose LNG-IUS was observable throughout duration of use. Interpretation: Use of low-dose LNG-IUS containing 19·5 mg and 13·5 mg levonorgestrel, respectively, were associated with a reduced risk of incident depression compared to use of the high-dose 52 mg LNG-IUS. The study suggests that low-dose LNG-IUS should be preferred over the high-dose LNG-IUS for contraceptive purpose. Funding: Sygeforsikringen "Danmark" grant: 2021-0128.

Unraveling the potential of Morinda officinalis oligosaccharides as an adjuvant of escitalopram in depression treatment and exploring the underlying mechanisms.

ETHNOPHAMACOLOGICAL RELEVANCE: Morinda officinalis oligosaccharides (MOs) is a mixture of oligosaccharides extracted from the roots of Morinda officinalis (MO). It is approved by Chinese Food and Drug Administration (CFDA) for depression treatment. MOs could improve the antidepressant efficacy of escitalopram in clinic. AIM OF THE STUDY: We aim to explore the antidepressant activity and potential mechanism of the combination usage of MOs and escitalopram on animal model of depression. MATERIALS AND METHODS: Depressive animal model was induced by chronic mild stress (CMS). Behavioral tests were conducted to evaluate the antidepressant efficacy of MOs and escitalopram. Serum neurotransmitter levels were detected by High-performance liquid chromatography (HPLC). Quantitative real-time PCR and Western blotting were applied to assay the hippocampus neurotrophic factors' mRNA and protein levels. Peripheral cytokines levels were measured through Enzyme-Linked Immunosorbent Assay (ELISA). Micorglia polization phenotype was assayed by immunofluorescence and flow cytometry. RESULTS: MOs and escitalopram obviously attenuated depression-like behaviors of CMS mice. Importantly, MOs plus escitalopram exhibited better antidepressant activity on CMS mice than monotherapy. At the same time, MOs combined escitalopram treatment significantly increased hippocampus neurotransmitters and neurotrophic factor levels, stimulated hippocampus neurogenesis and relieved central nervous system (CNS) microglia over-activation of CMS mice. The combination therapy had greater effect on neuroprotection and inflammation attenuation of CMS mice than monotherapy. CONCLUSION: Our results indicates MOs combined escitalopram might produce antidepressant activity through protecting neuron activity, relieving inflammation and modulating microglia polarization process.

Phytomedicine Fructus Aurantii-derived two absorbed compounds unlock antidepressant and prokinetic multi-functions via modulating 5-HT3/GHSR.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Aurantii (FA), a well-known phytomedicine, has been employed to evoke antidepressant and prokinetic multi-functions. Therein, systematically identifying bioactive components and the referred mechanism is essential for FA. AIM OF THE STUDY: This study was planned to answer "2 W" (What and Why), such as which components and pathways contribute to FA's multi-functions. We aimed to identify bioactive compounds as the key for opening the lock of FA's multi-functions, and the molecule mechanisms are their naturally matched lock cylinder. MATERIALS AND METHODS: The phytochemical content of FA extract was determined, and the compounds were identified in rats pretreated with FA using liquid chromatography with mass spectrometry (LC-MS). The contribution strategy was used to assess bioactive compounds' efficacy (doses = their content in FA) in model rats with the mechanism. The changes in functional brain regions were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD). RESULT: Eight phytochemicals' content was detected, and merely six components were identified in rats in vivo. Meranzin hydrate + hesperidin (MH), as the primary contributor of FA, exerted antidepressant and prokinetic effects (improvement of indexes for immobility time, gastric emptying, intestinal transit, CRH, ghrelin, ACTH, DA, NA, 5-HT, CORT, and 5-HT3) by regulating 5-HT3/Growth hormone secretagogue receptor (GHSR) pathway. These results were validated by 5-HT2A, 5-HT3, and GHSR receptor antagonists combined with molecule docking. MH restored the excessive BOLD activation of the left accumbens nucleus, left corpus callosum and hypothalamus preoptic region. CONCLUSION: Absorbed MH accounts for FA's anti-depressant and prokinetic efficacy in acutely-stressed rats, primarily via 5-HT3/GHSR shared regulation.

(2-Cyclohexyl-1-methylpropyl) cyclohexane isolated from garlic extract exhibits antidepressant-like activity: extraction, docking, drug-like properties, molecular dynamics simulations and MM/GBSA studies.

Depressive disorders are among most common psychiatric diseases and second most common form of psychiatric illness globally. Commonly available chemical drugs used for treatment of nervous system disorders exert undesirable effects. Therefore, there is a growing need towards exploring novel antidepressants of herbal origin. Earlier, the antidepressant effect of methanolic extract of garlic has been shown. In this study, the ethanolic extract of garlic was prepared and chemically analysed using Gas Chromatography - Mass Spectrometry (GC-MS) screening. A total of 35 compounds were found to be present, which might act as antidepressant. Using computational analyses, these compounds were screened as potential inhibitors (selective serotonin reuptake inhibitor (SSRI)) against serotonin transporter (SERT)/leucine receptor (LEUT). In silico docking studies and other physicochemical, bioactivity and ADMET studies resulted in the selection of compound 1 ((2-Cyclohexyl-1-methylpropyl) cyclohexane) as potential SSRI (binding energy -8.1 kcal/mol) compared to known reference SSRI fluoxetine (binding energy -8.0 kcal/mol). Analysis of conformational stability, residue flexibility, compactness, binding interactions, solvent accessible surface area (SASA), dynamic correlation, and binding free energy predicted from molecular mechanics (MD) with generalised Born and surface area solvation (MM/GBSA) studies revealed formation of a more stable SSRI like complex with compound 1 having strong inhibitory interaction compared to known SSRI fluoxetine/reference complex. Thus, compound 1 may act as an active SSRI leading to discovery of potential antidepressant drug.Communicated by Ramaswamy H. Sarma.

Exploring the prevalence of antidepressant medication discontinuation among pregnant veterans.

US female veterans have higher rates of mental health (MH) disorders compared to US civilian females and, consequently, are at risk for poor MH outcomes during pregnancy. This study evaluated the MH burden and identified the prevalence of antidepressant prescription and discontinuation among pregnant veterans (PGVets). The electronic health records (EHR) of PGVets using the US Veterans Administration's (VA) maternity care benefits over a two-year period were retrospectively reviewed. Inclusion criteria for this study were a current MH diagnosis of depression, anxiety, or posttraumatic stress disorder (PTSD) at the onset of pregnancy (n=351). Outcomes examined included antidepressant use prior to pregnancy, the use and discontinuation of antidepressants during pregnancy, and risk factors for discontinuation. PGVets had a high MH burden, as indicated by multiple comorbid diagnoses of unipolar depression, anxiety, and PTSD in 67% of the sample. At the onset of pregnancy, 163 (46%) were treated with an antidepressant. Only 56 (34%) continued using antidepressants through the pregnancy. Self-discontinuation (34%) and VA provider discontinuation (31%) of antidepressants were found. Among PGVets with documented past suicidal behaviors, 90% discontinued their active antidepressants. PGVets with indicators for more severe MH diagnoses were most likely to discontinue. The MH burden of PGVets and high rates of antidepressant discontinuation have implications for engaging this population in a higher level of perinatal monitoring and intervention. The findings suggest that VA providers and veterans would benefit from risks and benefits education regarding antidepressant use during pregnancy as well as the provision of alternative therapies.

Cellular neurobiology of hyperforin.

Hyperforin is a phloroglucinol derivative isolated from the medicinal plant Hypericum perforatum (St John's wort, SJW). This lipophilic biomolecule displays antibacterial, pro-apoptotic, antiproliferative, and anti-inflammatory activities. In addition, in vitro and in vivo data showed that hyperforin is a promising molecule with potential applications in neurology and psychiatry. For instance, hyperforin possesses antidepressant properties, impairs the uptake of neurotransmitters, and stimulates the brain derived neurotrophic factor (BDNF)/TrkB neurotrophic signaling pathway, the adult hippocampal neurogenesis, and the brain homeostasis of zinc. In fact, hyperforin is a multi-target biomolecule with a complex neuropharmacological profile. However, one prominent pharmacological feature of hyperforin is its ability to influence the homeostasis of cations such as Ca2+ , Na+ , Zn2+ , and H+ . So far, the pathophysiological relevance of these actions is currently unknown. The main objective of the present work is to provide an overview of the cellular neurobiology of hyperforin, with a special focus on its effects on neuronal membranes and the movement of cations.

Inhaled Litsea glaucescens K. (Lauraceae) leaves' essential oil has anxiolytic and antidepressant-like activity in mice by BDNF pathway activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Litsea glaucescens K. (Lauraceae) is a small tree from the Mexican and Central American temperate forests, named as "Laurel". Its aromatic leaves are ordinarily consumed as condiments, but also are important in Mexican Traditional Medicine, and among the most important non wood forest products in this area. The leaves are currently used in a decoction for the relief of sadness by the Mazahua ethnic group. Interestingly, "Laurel" has a long history. It was named as "Ehecapahtli" (wind medicine) in pre-Columbian times and applied to heal maladies correlated to the Central Nervous System, among them depression, according to botanical texts written in the American Continent almost five centuries ago. AIM OF THE STUDY: Depression is the first cause of incapacity in the world, and society demands alternative treatments, including aromatherapy. We have previously demonstrated the antidepressant-like activity of L. glaucescens leaves' essential oil (LEO), as well as their monoterpenes linalool, and beta-pinene by intraperitoneal route in a mice behavioral model. Here we now examined if LEO and linalool exhibit this property and anxiolytic activity when administered to mice by inhalation. We also investigated if these effects occur by BDNF pathway activation in the brain. MATERIALS AND METHODS: The LEO was prepared by distillation with water steam and analyzed by gas chromatography-mass spectrometry (GC-MS). The monoterpenes linalool, eucalyptol and ß-pinene were identified and quantified. Antidepressant type properties were determined with the Forced Swim Test (FST) on mice previously exposed to LEO or linalool in an inhalation chamber. The spontaneous locomotor activity and the sedative effect were assessed with the Open Field Test (OFT), and the Exploratory Cylinder (EC), respectively. The anxiolytic properties were investigated with the Elevated Plus Maze Apparatus (EPM) and the Hole Board Test (HBT). All experiments were video documented. The mice were subjected to euthanasia, and the brain hippocampus and prefrontal cortex were dissected. RESULTS: The L. glaucescens essential oil (LEO) contains 31 compounds according to GC/MS, including eucalyptol, linalool and beta-pinene. The LEO has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene, as indicated by OFT and EC tests. The LEO and imipramine have antidepressant like activity in mice as revealed by the FST; however, linalool and ketamine treatments didn't modify the time of immobility. The BDNF was increased in FST in mice treated with LEO in both areas of the brain as revealed by Western blot; but did not decrease the level of corticosterone in plasma. The OFT indicated that LEO and imipramine didn't reduce the spontaneous motor activity, while linalool and ketamine caused a significant decrease. CONCLUSION: Here we report by the first time that L. glaucescens leaves essential oil has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene. This oil also maintains its antidepressant-like activity by this administration way, similarly to the previously determined intraperitoneally. Since inhalation is a common administration route for humans, our results suggest L. glaucescens essential oil deserve future investigation due to its potential application in aromatherapy.

Structural elucidation of a non-starch polysaccharides from Lilii Bulbus and its protective effects against corticosterone-induced neurotoxicity in PC12 cells.

Lilii Bulbus is a folk medicine for both culinary and medicinal purpose. In traditional medicine theory, Lilii Bulbus is usually used as an complementary therapy for nourishing the heart and lung, clearing heat in the treatment of mental instability and depression. In this study, NLPS-1a (Mw = 2610 Da, DP = 16), a water-soluble non-starch Lilii Bulbus polysaccharides, was isolated and purified. Structural analysis showed that NLPS-1a mainly contained Man and Glc with a molar ratio of 11.137 and 9.427. The glycosidic linkages of NLPS-1a were 1,3-Manp (59.93%), 1,2-Glcp (37.93%), T-Glcp (1.21%) and T-Manp (0.93%), indicating the highly-linear structures. In addition, NLPS-1a could significantly repair the injury of PC12 cells induced by corticosterone (CORT), reduce Lactate dehydrogenase (LDH) leakage and decrease the cell apoptosis in a dose-dependent manner. Above all, the results indicated that NLPS-1a had protective effects against CORT-induced neurotoxicity in PC12 cells, and might be a natural antidepressant, which enriched the study of the metabolic mechanism between herbal polysaccharides and antidepressant.

Assessment of the anxiolytic, antidepressant, and antioxidant potential of Parquetina nigrescens (Afzel.) Bullock in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The recent growing concerns about the multisystemic nature of mental health conditions in the global population are facilitating a new paradigm involving alternative natural, nutritional, and complementary therapies. Herbal remedies despite accounts in literature of their ethnobotanical as alternative remedies for diverse ailments, remain underexplored for psychiatric disorders like anxiety, depression, and insomnia. AIM OF THE STUDY: Hence, the anxiolytic, antidepressant, and antioxidant properties of a hydro-ethanolic leaf extract of Parquetina nigrescens (PN) in male Wistar rats were investigated. MATERIALS AND METHODS: The sedative effect was evaluated using the Diazepam sleeping time test while anxiety was induced with a single intraperitoneal injection of 20 mg/kg pentylenetetrazol (PTZ). This was after pre-treatment with 100, 150, and 250 mg/kg of PN or the standard drugs (1 mg/kg diazepam and 30 mg/kg imipramine) for 14 consecutive days. Behavioral tests (Open Field test, Elevated Plus-Maze test, and Forced Swim test) were performed on days 1 and 14, to evaluate the antidepressant and anxiolytic activities of PN. Oxidative stress and neurochemical markers were determined in the brain homogenates of the animals. RESULTS: The duration of sleep was significantly (p < 0.001) increased in the PN-administered group compared to the control. The behavioral models showed that PN exhibited antidepressant and anxiolytic properties in PTZ-induced animals. Significant reductions were observed in GSH level and SOD activity while MDA, nitrite, and GPx levels were significantly increased in PTZ-induced rats. However, treatment with PN significantly improved brain antioxidant status by ameliorating the PTZ-induced oxidative stress. Dopamine, cortisol, and acetylcholine esterase activity levels were significantly (p < 0.05) elevated while serotonin and brain-derived neurotrophic factors were reduced in PTZ-induced rats compared with the control. CONCLUSION: The PN demonstrated neurotransmitter modulatory ability by ameliorating the PTZ-induced neurochemical dysfunction. Findings from this study showed that PN exhibited sedative, antidepressant, and anxiolytic activities in rats.

Public Interest in Psilocybin and Psychedelic Therapy in the Context of the COVID-19 Pandemic: Google Trends Analysis.

BACKGROUND: Psychedelic substances have demonstrated promise in the treatment of depression, anxiety, and substance use disorders. Significant media coverage has been dedicated to psychedelic medicine, but it is unclear whether the public associates psilocybin with its potential therapeutic benefits. The COVID-19 pandemic led to an increase in depression, anxiety, and substance abuse in the general population. OBJECTIVE: This study attempts to link increases in interest in these disorders with increases in interest in psilocybin using Google Trends. METHODS: Weekly interest-over-time Google Trends data for 4 years, from the week of March 11, 2018, to the week of March 6, 2022, were obtained for the following terms: "psilocybin," "psychedelic therapy," "cannabis," "cocaine," "antidepressant," "depression," "anxiety," and "addiction." Important psilocybin-related news and the declaration of the pandemic were noted. Trends data for each of the queried terms were plotted, and multiple regression analysis was performed to determine the slope of the prepandemic and postpandemic data with 95% CIs. Nonparametric Tau-U analysis was performed correcting for baseline trends. Results from this test were used to make inferences about the pre- and postpandemic trends and inferences about the change in overall level of searches between the 2 groups. RESULTS: Tau values for prepandemic data were significant for stable trends, all ranging -0.4 to 0.4. Tau values for postpandemic data showed positive trends for "psilocybin," "psychedelic therapy," and "antidepressant." All other trends remained stable in the range of -0.4 to 0.4. When comparing Tau values for pre- and postpandemic data, overall increases in relative search volume (RSV) were seen for "psilocybin," "psychedelic therapy," and "anxiety," and overall decreases in RSV were seen for "depression," "addiction," and "cocaine." Overall RSVs for "cannabis" and "antidepressant" remained stable as Tau values ranged between -0.4 and 0.4. In the immediate aftermath of the declaration of the pandemic, drop-offs in interest were seen for all terms except for "anxiety" and "cannabis." After the initial shock of a global pandemic, "psilocybin" and "psychedelic therapy" groups demonstrated increases in interest trends and overall RSV. CONCLUSIONS: These data suggest that overall interest in "psilocybin" and "psychedelic therapy" increased at higher rates and to higher levels after than before the declaration of the pandemic. This is consistent with our hypothesis that interest increased for these treatments after the pandemic as incidence of depression, anxiety, and addiction increased. However, there may be other drivers of interest for these topics, since interest in antidepressants-the typical pharmacologic treatments for depression and anxiety-followed the expected pattern of drop-off and accelerated interest back to prepandemic levels. Interest in "psilocybin" and "psychedelic therapy" may have also been partially driven by popular culture hype and novelty, explaining why interest increased at a higher rate post pandemic and continued to grow, surpassing prior interest.

[Gender differences in antidepressant effect of raw Rehmanniae Radix].

For the first time, this study evaluated the gender differences and mechanisms of the antidepressant effects of raw Rehmanniae Radix(RRR) based on the classic depression model with traditional Chinese medicine syndrome of Yin deficiency and internal heat. The depression model with Yin deficiency and internal heat was established by the widely recognized and applied method of thyroxine induction of the classic depression model with Yin deficiency and internal heat(chronic unpredictable mild stress). Male and female mice were simultaneously treated with RRR. The study analyzed indicators of nourishing Yin and clearing heat, conventional antidepressant efficacy test indicators, and important biomolecules reflecting the pathogenesis and prevention and treatment mechanisms of depression, and conducted a correlation analysis of antidepressant efficacy, Yin-nourishing and heat-clearing efficacy, and biological mechanism in different genders, thereby comprehensively assessing the antidepressant effects of RRR on depression of Yin deficiency and internal heat, as well as its gender differences and mechanisms. RRR exhibited antidepressant effects in both male and female mouse models, and its antidepressant efficacy showed gender differences, with a superior effect observed in females. Moreover, the effects of RRR on enhancing or improving hippocampal neuronal pathology, nucleus-positive areas, postsynaptic dense area protein 95, and synaptophysin protein expression were more significant in females than in males. In addition, RRR significantly reversed the abnormal upregulation of nuclear factor(NF)-κB/cyclooxygenase 2(COX2)/NOD-like receptor thermal protein domain associated protein 3(NLRP3) pathway proteins in the hippocampus of both male and female mouse models. The antidepressant effects of RRR were more pronounced in depression female mice with Yin deficiency and internal heat syndrome, possibly due to the improvement of neuronal damage and enhancement of neuroplasticity. The antidepressant mechanisms of RRR for depression with Yin deficiency and internal heat syndrome may be associated with the downregulation of the NF-κB/COX2/NLRP3 pathway to reduce neuronal damage and enhance neuroplasticity.

Adult hippocampal neurogenesis: pharmacological mechanisms of antidepressant active ingredients in traditional Chinese medicine.

Depression is characterized by prominent indicators and manifestations, such as anhedonia, which refers to the inability to experience pleasure, and persistent feelings of hopelessness. In clinical practice, the primary treatment approach involves the utilization of selective serotonin reuptake inhibitors (SSRIs) and related pharmacological interventions. Nevertheless, it is crucial to recognize that these agents are associated with significant adverse effects. Traditional Chinese medicine (TCM) adopts a multifaceted approach, targeting diverse components, multiple targets, and various channels of action. TCM has potential antidepressant effects. Anomalies in adult hippocampal neurogenesis (AHN) constitute a pivotal factor in the pathology of depression, with the regulation of AHN emerging as a potential key measure to intervene in the pathogenesis and progression of this condition. This comprehensive review presented an overview of the pharmacological mechanisms underlying the antidepressant effects of active ingredients found in TCM. Through examination of recent studies, we explored how these ingredients modulated AHN. Furthermore, we critically assessed the current limitations of research in this domain and proposed novel strategies for preclinical investigation and clinical applications in the treatment of depression in future.

Antidepressant pharmacological mechanisms: focusing on the regulation of autophagy.

The core symptoms of depression are anhedonia and persistent hopelessness. Selective serotonin reuptake inhibitors (SSRIs) and their related medications are commonly used for clinical treatment, despite their significant adverse effects. Traditional Chinese medicine with its multiple targets, channels, and compounds, exhibit immense potential in treating depression. Autophagy, a vital process in depression pathology, has emerged as a promising target for intervention. This review summarized the pharmacological mechanisms of antidepressants by regulating autophagy. We presented insights from recent studies, discussed current research limitations, and proposed new strategies for basic research and their clinical application in depression.