Hypericin Ameliorates Depression-like Behaviors via Neurotrophin Signaling Pathway Mediating m6A Epitranscriptome Modification.

Hypericin, one of the major antidepressant constituents of St. John's wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process.

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556.

Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.

Effect of milnacipran on brain­derived neurotrophic factor and oxidative stress biomarkers in patients of major depressive disorder.

Emerging hypotheses in the pathophysiology of major depressive disorder (MDD) suggest important role of neurotrophic factors and oxidative stress. This study assessed the effect of milnacipran (a dual serotonin­noradrenaline reuptake inhibitor) on brain­derived neurotrophic factor (BDNF) and oxidative stress biomarkers i.e., malondialdehyde (MDA), glutathione­s­ transferase (GST) and glutathione reductase (GR) in patients of MDD. Thirty patients (aged 18 to 60 years) with MDD diagnosed by DSM­IV criteria, with Hamilton Depression Rating scale (HAM­D) score ≥ 14 were included in the study. Patients were given milnacipran in the doses of 50­100 mg once daily. Patients were followed up for 12 weeks. HAM­D score at the start of treatment was 17.8±1.7 which significantly reduced to 8.9±3.1 at 12 weeks of treatment. In responders, the plasma BDNF levels increased significantly at 12 weeks post treatment. There was no significant change in the pre­ and post­treatment values of oxidative stress parameters (MDA, GST and GR) after 12 week treatment. Milnacipran is effective and well tolerated in MDD patients, and its therapeutic response is associated with an increase in plasma BDNF levels. However, milnacipran did not affect oxidative stress biomarkers.

In Vivo Neuropharmacological Effects of Neophytadiene.

Neophytadiene (NPT) is a diterpene found in the methanolic extracts of Crataeva nurvala and Blumea lacera, plants reported with anxiolytic-like activity, sedative properties, and antidepressant-like actions; however, the contribution of neophytadiene to these effects is unknown. This study determined the neuropharmacological (anxiolytic-like, antidepressant-like, anticonvulsant, and sedative) effects of neophytadiene (0.1-10 mg/kg p.o.) and determined the mechanisms of action involved in the neuropharmacological actions using inhibitors such as flumazenil and analyzing the possible interaction of neophytadiene with GABA receptors using a molecular docking study. The behavioral tests were evaluated using the light-dark box, elevated plus-maze, open field, hole-board, convulsion, tail suspension, pentobarbital-induced sleeping, and rotarod. The results showed that neophytadiene exhibited anxiolytic-like activity only to the high dose (10 mg/kg) in the elevated plus-maze and hole-board tests, and anticonvulsant actions in the 4-aminopyridine and pentylenetetrazole-induced seizures test. The anxiolytic-like and anticonvulsant effects of neophytadiene were abolished with the pre-treatment with 2 mg/kg flumazenil. In addition, neophytadiene showed low antidepressant effects (about 3-fold lower) compared to fluoxetine. On other hand, neophytadiene had no sedative or locomotor effects. In conclusion, neophytadiene exerts anxiolytic-like and anticonvulsant activities with the probable participation of the GABAergic system.

Once-Daily Subcutaneous Irisin Administration Mitigates Depression- and Anxiety-like Behavior in Young Mice.

Major depression is one of the most common psychiatric disorders worldwide, usually associated with anxiety. The multi-etiological nature of depression has increased the search for new antidepressant molecules, including irisin, for which, in a previous study, we tested its effect in young mice when administered intraperitoneally in a long-term intermittent manner. Here, we evaluated the effect of subcutaneous short-term irisin administration (100 µg/Kg/day/5 days) in male and female mice subjected to behavioral paradigms: Tail Suspension Test (TST), Forced Swim Test (FST), Elevated Plus Maze (EPM), and Y Maze (YM). Moreover, a qRT-PCR assay was performed to analyze the impact of irisin treatment on Pgc-1α/FNDC5 expression in the brain. A significant reduction in immobility time in TST and FST was observed in irisin-treated mice. Furthermore, irisin treatment significantly increased the number of entries and time spent in open arms, demonstrating its anxiolytic effect. Memory-enhancing effects were not reported in YM. Interestingly, no gender differences were observed in all behavioral tests. Overall, these results suggest that short-term subcutaneous irisin administration can exert an antidepressant and anxiolytic role, probably due to the activation of the Pgc-1α/FNDC5 system in the brain. Further investigation could lead to the identification of irisin as a new agent for the treatment of psychiatric disorders.

Xiaoyaosan ameliorates depressive-like behavior and susceptibility to glucose intolerance in rat: involvement of LepR-STAT3/PI3K pathway in hypothalamic arcuate nucleus.

BACKGROUND: Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC. METHODS: A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting. RESULTS: XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC. CONCLUSIONS: XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.

SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the most common mood disturbances worldwide. The Si-ni-san formula (SNS) is a famous classic Traditional Chinese Medicine (TCM) widely used to treat depression for thousands of years in clinics. However, the mechanism underlying the therapeutic effect of SNS in improving depression-like behaviors following chronic unpredictable mild stress (CUMS) remains unknown. AIM OF THE STUDY: This study aimed to investigate whether SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy in vitro and in vivo. STUDY DESIGN AND METHODS: In vivo, mice were exposed to CUMS for 42 days, and SNS (4.9, 9.8, 19.6 g/kg/d), fluoxetine (10 mg/kg/d), 3-methyladenine (3-MA) (30 mg/kg/d), rapamycin(1 mg/kg/d), and deferoxamine (DFO) (200 mg/kg/d) were conducted once daily during the last 3 weeks of the CUMS procedure. In vitro, a depressive model was established by culture of SH-SY5Y cells with corticosterone, followed by treatment with different concentrations of freeze-dried SNS (0.001, 0.01, 0.1 mg/mL) and rapamycin (10 nM), NCOA4-overexpression, Si-NCOA4. After the behavioral test (open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST), dendritic spines, GluR2 protein expression, iron concentration, and ferritinophagy-related protein levels (P62, FTH, NCOA4, LC3-II/LC3-I) were tested in vitro and in vivo using immunohistochemistry, golgi staining, immunofluorescence, and Western blot assays. Finally, HEK-293T cells were transfected by si-NCOA4 or GluR2-and NCOA4-overexpression plasmid and treated with corticosterone(100 µM), freeze-dried SNS(0.01 mg/mL), rapamycin(25 nM), and 3-MA(5 mM). The binding amount of GluR2, NCOA4, and LC3 was assessed by the co-immunoprecipitation (CO-IP) assay. RESULTS: 3-MA, SNS, and DFO promoted depressive-like behaviors in CUMS mice during OFT, SPT, FST and TST, improved the amount of the total, thin, mushroom spine density and enhanced GluR2 protein expression in the hippocampus. Meanwhile, treatment with SNS decreased iron concentrations and inhibited NCOA4-mediated ferritinophagy activation in vitro and in vivo. Importantly, 3-MA and SNS could prevent the binding of GluR2, NCOA4 and LC3 in corticosterone-treated HEK-293T, and rapamycin reversed this phenomenon after treatment with SNS. CONCLUSION: SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy.

Zuojinwan ameliorates CUMS-induced depressive-like behavior through inducing ubiquitination of MyD88 via SPOP/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojinwan (ZJW) is a traditional Chinese medicine compound, which is often used clinically to treat gastritis and has anti-inflammatory activity. It was found that ZJW is involved in suppressing the expression of inflammatory factors, and neuroinflammation is thought to be associated with the development of depression. AIM OF THE STUDY: In this study, we investigated whether ZJW could exert antidepressant effects by regulating MyD88 ubiquitination in depressed mice and attempted to elucidate the possible mechanisms. MATERIALS AND METHODS: Six active compounds of Zuojinwan (ZJW) were identified by HPLC. Then, the effects of ZJW on depression-like behavior in mice were investigated by constructing a chronic unpredictable mild stimulation (CUMS) mouse model. Meanwhile, the effect of ZJW on hippocampal neurons was investigated by Nissl staining. In addition, western blotting, PCR, ELISA, co-immunoprecipitation and immunostaining were used to explore whether ZJW could inhibit neuroinflammation through SPOP/MyD88/NF-κB pathway and thus produce antidepressant effects. Finally, we constructed the AAV-Sh-SPOP virus vector to silence SPOP and verify the mechanism of ZJW's antidepressant action. RESULTS: ZJW could dramatically ameliorate the depressive behavior induced by CUMS stimulation and alleviate hippocampal neuronal damage. CUMS stimulation resulted in decreased SPOP expression, impaired MyD88 ubiquitination, and activation of downstream NF-κB signaling, which could be reversed by ZJW. In addition, ZJW could significantly ameliorate the abnormal activation of microglia, and the excessive levels of pro-inflammatory factors were inhibited. By blocking the expression of SPOP, we found that ZJW exerted anti-inflammatory and antidepressant effects mainly by promoting the ubiquitination of MyD88 and inhibiting the activation of downstream inflammatory signals. CONCLUSION: In conclusion, ZJW possesses alleviating effects on depression induced by CUMS stimulation. ZJW can inhibit neuroinflammation and improve neuroinflammation-induced depression-like behaviors through SPOP/MyD88/NF-κB pathway.

Associations between indices of 24-hour heart rate variability and inflammation in individuals with major depressive disorder.

Biological cardiac risk factors, including reduced heart rate variability (HRV) and inflammation, are already prominent in patients with major depressive disorder (MDD) without existing cardiovascular disease. Although inverse relations between HRV and inflammation have been found across several populations, little work has been done concerning MDD. The present work thus intended to examine whether measures of HRV indices based on 24-h electrocardiograph recordings (24-h, daytime, nighttime) relate to levels of circulating inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in eighty antidepressant-free individuals with MDD. A sample of 40 age- and sex-matched non-clinical controls was also involved to verify biological alterations in MDD. Individuals with MDD exhibited reduced total 24-h HRV (i.e., triangular index) and reduced daytime HRV (i.e., triangular index, HF-HRV, LF-HRV, RMSSD), as well as increased levels of all inflammatory markers. Multivariate analyses adjusted for age, sex, body mass index, and smoking revealed robust inverse associations of total 24-h HRV (i.e., triangular index) and daytime HRV (i.e., Triangular index, HF-HRV, LF-HRV, RMSSD) with IL-6. An attenuated daytime HRV may relate to higher circulating levels of IL-6 in the context of MDD. These findings show that biological cardiac risk factors may act in concert in MDD.

Age as a moderating factor of treatment resistance in depression.

BACKGROUND: Treatment-resistant depression (TRD) is an important clinical challenge and may present differently between age groups. METHODS: A total of 893 depressed patients recruited within the framework of the European research consortium "Group for the Studies of Resistant Depression" were assessed by generalized linear models regarding age effects (both as numerical and factorial predictors) on treatment outcome, number of lifetime depressive episodes, hospitalization time, and duration of the current episode. Effects of age as numerical predictor on the severity of common depressive symptoms, measured with Montgomery-Åsberg Depression Rating Scale (MADRS) for two-time points, were assessed by linear mixed models, respectively, for patients showing TRD and treatment response. A corrected p threshold of 0.001 was applied. RESULTS: Overall symptom load reflected by MADRS (p < 0.0001) and lifetime hospitalization time (p < 0.0001) increased with age in TRD patients but not treatment responders. In TRD, higher age was predicting symptom severity of inner tension, reduced appetite, concentrations difficulties, and lassitude (all p ≤ 0.001). Regarding clinical significance, older TRD patients were more likely to report severe symptoms (item score > 4) for these items both before and after treatment (all p ≤ 0.001). CONCLUSIONS: In this naturalistic sample of severely ill depressed patients, antidepressant treatment protocols were equally effective in addressing TRD in old age. However, specific symptoms such as sadness, appetite, and concentration showed an age-dependent presentation, impacting residual symptoms in severely affected TRD patients and calling for a precision approach by a better integration of age profiles in treatment recommendations.

Selective aryl hydrocarbon receptor modulators can act as antidepressants in obese female mice.

BACKGROUND: Obese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice. METHODS: Obesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9-10 weeks. Subsequently, mice were subjected to unpredictable chronic mild stress (UCMS) or remained unstressed. Daily administration of vehicle or 20 mg/kg DHNA began three weeks prior or on the third week of UCMS. Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash and tape groom tests), anxiety (open-field test, light/dark test, novelty-induced hypophagia), and cognition (object location recognition, novel object recognition, Morris water maze). RESULTS: UCMS did not alter, and DHNA slightly increased, weight gain in HFD-fed females. HFD decreased sucrose preference, increased FST immobility time, but did not alter splash and tape tests' grooming time. UCMS did not have additional effects on sucrose preference. UCMS further increased FST immobility time and decreased splash and tape tests' grooming time; these effects were prevented and reversed by DHNA treatment. HFD did not affect behaviors in the cognitive tests. UCMS impaired spatial learning; this effect was not prevented nor reversed by DHNA. CONCLUSIONS: DHNA protected against UCMS-induced depression-like behaviors in HFD-fed female mice. DHNA neither improved nor worsened UCMS-induced impairment of spatial learning. Our findings indicate that DHNA has high potential to act as an antidepressant in obese females.

The role of BDNF in major depressive disorder, related clinical features, and antidepressant treatment: Insight from meta-analyses.

The brain-derived neurotrophic factor (BDNF) has received considerable attention as a potential biomarker of major depressive disorder (MDD) and antidepressant response. We conducted an overview of meta-analyses investigating the relationship of BDNF with MDD, related clinical features, and antidepressant treatment. Based on a systematic screening on main electronic databases, 11 systematic reviews with meta-analyses were included. Available evidence suggests that people with MDD have peripheral and central BDNF levels lower than non-depressed individuals. A negative correlation between blood BDNF and symptom severity emerged, while no association with suicidality was detected. Moreover, an increase in blood BDNF levels after antidepressant treatment, proportional to symptom improvement, was reported. BDNF levels seem to be increased in both treatment responders and remitters, remaining stable in non-responders. Conversely, no variations of BDNF concentrations after non-pharmacological interventions (electroconvulsive therapy, repetitive transcranial magnetic stimulation, and physical activity) were found. The findings of this overview appear consistent with the neurotrophic hypothesis of depression, suggesting that BDNF may play a role in both MDD pathophysiology and pharmacological treatment response.

Systemic treatment with GnRH agonist produces antidepressant-like effects in LPS induced depression male mouse model.

Gonadotropin-releasing hormone (GnRH) is at the head of the neuroendocrine reproductive axis. However, the non-reproductive functions of GnRH expressed in various tissues, including hippocampus, are still not known. Here, we unveil a previously unknown effect of GnRH, which mediates depression-like behaviors through the modulation of microglia function during immune challenge. Specifically, we found that either systemic treatment with GnRH agonist or over-expression of endogenous hippocampal GnRH via viral tool abolished the depression-like behavior after LPS challenges in mice. And the anti-depressant of GnRH was dependent on the hippocampal GnRHR signaling, since antagonizing GnRHR by drug treatment or by hippocampal GnRHR knockdown could block the antidepressant-effect of GnRH agonist. Interestingly, we found that the peripheral GnRH treatment prevented the microglia activation mediated inflammation in the hippocampus of mice. In light of the research findings presented here, we propose that, at least in the hippocampus, GnRH appears to act on GnRHR to regulate higher order non-reproductive functions associated with the microglia mediated neuroinflammation. These findings also provide insights into the function and cross-talk of GnRH, a known neuropeptide hormone, in neuro-immune response.

Inhibition of LRRK2 Attenuates Depression-Related Symptoms in Mice with Moderate Traumatic Brain Injury.

Moderate traumatic brain injury (mTBI) has been associated with emotional dysregulation such as loss of consciousness, post-traumatic amnesia and major depressive disorder. The gene Leucine-rich repeat kinase 2 (LRRK2) is involved in protein synthesis and degradation, apoptosis, inflammation and oxidative stress, processes that trigger mTBI. The aim of this study was to investigate the role of LRRK2 in reducing depression-related symptoms after mTBI and to determine whether inhibition of LRRK2 mediated by PF-06447475 could have antidepressant effects. Moderate traumatic brain injury was induced by controlled cortical impact (CCI) and mice were treated with PF-06447475 at doses of 1, 2.5 and 5 mg/kg once daily for 14 days. We performed histological, immunohistochemical and molecular analyses of brain tissue 24 days after mTBI. Furthermore, the tissue changes found in the hippocampus and amygdala confirmed the depression-like behavior. PF-treatment with 06447475 significantly reduced the histological damage and behavioral disturbances. Thus, this study has shown that mTBI induction promotes the development of depression-like behavioral changes. LRRK2 inhibition showed an antidepressant effect and restored the changes in the copper/glutamate/N-methyl-D-aspartic acid receptor (Cu/NMDAR) system.

Gut microbiota-based metabolites of Xiaoyao Pills (a typical Traditional Chinese medicine) ameliorate depression by inhibiting fatty acid amide hydrolase levels in brain.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicines (TCMs) are often prepared in oral dosage forms, making TCMs interact with gut microbiota after oral administration, which could affect the therapeutic effect of TCM. Xiaoyao Pills (XYPs) are a commonly used TCM in China to treat depression. The biological underpinnings, however, are still in its infancy due to its complex chemical composition. AIM OF THE STUDY: The study aims to explore XYPs' underlying antidepressant mechanism from both in vivo and in vitro. MATERIALS AND METHODS: XYPs were composed of 8 herbs, including the root of Bupleurum chinense DC., the root of Angelica sinensis (Oliv.) Diels, the root of Paeonia lactiflora Pall., the sclerotia of Poria cocos (Schw.) Wolf, the rhizome of Glycyrrhiza uralensis Fisch., the leaves of Mentha haplocalyx Briq., the rhizome of Atractylis lancea var. chinensis (Bunge) Kitam., and the rhizome of Zingiber officinale Roscoe, in a ratio of 5:5:5:5:4:1:5:5. The chronic unpredictable mild stress (CUMS) rat models were established. After that, the sucrose preference test (SPT) was carried out to evaluate if the rats were depressed. After 28 days of treatment, the forced swimming test and SPT were carried out to evaluate the antidepressant efficacy of XYPs. The feces, brain and plasma were taken out for 16SrRNA gene sequencing analysis, untargeted metabolomics and gut microbiota transformation analysis. RESULTS: The results revealed multiple pathways affected by XYPs. Among them, the hydrolysis of fatty acids amide in brain decreased most significant via XYPs treatment. Moreover, the XYPs' metabolites which mainly derived from gut microbiota (benzoic acid, liquiritigenin, glycyrrhetinic acid and saikogenin D) were found in plasma and brain of CUMS rats and could inhibit the levels of FAAH in brain, which contributed to XYPs' antidepressant effect. CONCLUSIONS: The potential antidepressant mechanism of XYPs by untargeted metabolomics combined with gut microbiota-transformation analysis was revealed, which further support the theory of gut-brain axis and provide valuable evidence of the drug discovery.

Sedative-Hypnotic Effects of Glycine max Merr. Extract and Its Active Ingredient Genistein on Electric-Shock-Induced Sleep Disturbances in Rats.

Glycine max Merr. (GM) is a functional food that provides many beneficial phytochemicals. However, scientific evidence of its antidepressive and sedative activities is scarce. The present study was designed to investigate the antidepressive and calmative effects of GM and its biologically active compound, genistein (GE), using electroencephalography (EEG) analysis in an electric foot shock (EFS)-stressed rat. The underlying neural mechanisms of their beneficial effects were determined by assessing corticotropin-releasing factor (CRF), serotonin (5-HT), and c-Fos immunoreactivity in the brain using immunohistochemical methods. In addition, the 5-HT2C receptor binding assay was performed because it is considered a major target of antidepressants and sleep aids. In the binding assay, GM displayed binding affinity to the 5-HT2C receptor (IC50 value of 14.25 ± 11.02 µg/mL). GE exhibited concentration-dependent binding affinity, resulting in the binding of GE to the 5-HT2C receptor (IC50, 77.28 ± 26.57 mg/mL). Administration of GM (400 mg/kg) increased non-rapid eye movement (NREM) sleep time. Administration of GE (30 mg/kg) decreased wake time and increased rapid eye movement (REM) and NREM sleep in EPS-stressed rats. In addition, treatment with GM and GE significantly decreased c-Fos and CRF expression in the paraventricular nucleus (PVN) and increased 5-HT levels in the dorsal raphe in the brain. Overall, these results suggest that GM and GE have antidepressant-like effects and are effective in sleep maintenance. These results will benefit researchers in developing alternatives to decrease depression and prevent sleep disorders.

Impact of St. John's wort extract Ze 117 on stress induced changes in the lipidome of PBMC.

BACKGROUND: Membrane lipids have an important function in the brain as they not only provide a physical barrier segregating the inner and outer cellular environments, but are also involved in cell signaling. It has been shown that the lipid composition effects membrane fluidity which affects lateral mobility and activity of membrane-bound receptors. METHODS: Since changes in cellular membrane properties are considered to play an important role in the development of depression, the effect of St. John's wort extract Ze 117 on plasma membrane fluidity in peripheral blood mononuclear cells (PBMC) was investigated using fluorescence anisotropy measurements. Changes in fatty acid residues in phospholipids after treatment of cortisol-stressed [1 µM] PBMCs with Ze 117 [10-50 µg/ml] were analyzed by mass spectrometry. RESULTS: Cortisol increased membrane fluidity significantly by 3%, co-treatment with Ze 117 [50 µg/ml] counteracted this by 4.6%. The increased membrane rigidity by Ze 117 in cortisol-stressed [1 µM] PBMC can be explained by a reduced average number of double bonds and shortened chain length of fatty acid residues in phospholipids, as shown by lipidomics experiments. CONCLUSION: The increase in membrane rigidity after Ze 117 treatment and therefore the ability to normalize membrane structure points to a new mechanism of antidepressant action of the extract.

The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs.

Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression. It is assumed that conventional antidepressants improve these closely related disturbances. The purpose of this review was to discuss the possibility of affecting these disturbances by targeting the melanocortin system, which includes adrenocorticotropic hormone-activated receptors and their peptide ligands (melanocortins). The melanocortin system is involved in the regulation of various processes in the brain and periphery. Melanocortins, including peripherally administered non-corticotropic agonists, regulate HPAA activity, exhibit anti-inflammatory effects, stimulate the levels of neurotrophic factors, and enhance hippocampal neurogenesis and neurotransmission. Therefore, endogenous melanocortins and their analogs are able to complexly affect the functioning of those body's systems that are closely related to depression and the effects of antidepressants, thereby demonstrating a promising antidepressant potential.

Rethinking ketamine and esketamine action: Are they antidepressants with mood-stabilizing properties?

Ketamine and esketamine, the S-enantiomer of the racemic mixture, have recently generated considerable interest as potential therapeutic agents for Treatment-Resistant Depression (TRD), a complex disorder that includes various psychopathological dimensions and distinct clinical profiles (e.g., comorbid personality disorder, bipolar spectrum, dysthymic disorder). This perspective article provides a comprehensive overview of the action of ketamine/esketamine from a dimensional point of view, taking into account the high prevalence of bipolarity in TRD and the evidence of the efficacy of these substances on mixed features, anxiety, dysphoric mood, and, generally, bipolar traits. Additionally, the article underscores the complexity of the pharmacodynamic mechanisms of action of ketamine/esketamine, which goes beyond the non-competitive antagonism of NMDA-R. The need for further research and evidence is highlighted, mainly to evaluate the efficacy of esketamine nasal spray in bipolar depression, the presence of bipolar elements as a predictor of response, and the potential role of these substances as mood stabilizers. The article implies that, in the future, ketamine/esketamine could be used with fewer limitations, not only as antidepressants for the most severe form of depression but also as valuable tools to stabilize subjects with mixed symptoms or bipolar spectrum.