Efficacy of patient education and duloxetine, alone and in combination, for patients with multisystem functional somatic disorder: Study protocol for the EDULOX trial.

BACKGROUND: Multisystem functional somatic disorder is characterized by specific patterns of persistent physical symptoms with a complex biopsychosocial etiology. The disorder can lead to disability and personal suffering. Current treatment options require specialized settings, therefore patients often wait a long time to receive specific treatment. Patient education is considered important in most treatment programs, but has only been investigated sparsely as a stand-alone treatment. Pharmacological treatment is limited to tricyclic antidepressants in low doses with no antidepressant properties. Duloxetine has been found effective in single organ functional disorders. As a treatment for multisystem functional somatic disorder, duloxetine could reduce symptoms and treat comorbid anxiety and depression. It may furthermore enhance the effect of patient education through a hypothesized effect on cognitive functioning. The purpose of the EDULOX trial is to study psycho-EDUcation and duLOXetine alone and in combination. METHODS: This is a nested study design. The parent trial "EDULOX1" (n = 424) will compare a patient education program with enhanced usual care in an open-labelled, randomized controlled trial. In addition to this, eligible participants will furthermore receive either duloxetine or active placebo in the nested, double-blinded, randomized controlled trial, "EDULOX2" (n = 212). Patient and clinician reported outcomes will be collected through questionnaires. CONCLUSION: The EDULOX trial may establish evidence for treatments applicable for the majority of patients with multisystem functional somatic disorder. If effective, duloxetine would be a more tolerable pharmacological treatment option that can target comorbid depression and anxiety, and potentially boost the effect of patient education. Trial registration number The study is registered at www. CLINICALTRIALS: gov (NCT06232473) and the internal list of research projects at the Region of Central Denmark (Case number 1-16-02-305-23). Approval from the Danish Medical Research Ethics Committees (Case number: 2212291) and the Danish Medicines Agency was obtained under EudraCT Number: 2022-002780-30 and Sponsor's Protocol Code Number: 9515.

An acute dose-ranging evaluation of the antidepressant properties of Sceletium tortuosum (Zembrin®) versus escitalopram in the Flinders Sensitive Line rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. AIM OF THE STUDY: To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. MATERIALS AND METHODS: The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. RESULTS: Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. CONCLUSIONS: Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST, as assessed in FSL rats. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.

New Insights into Depressive Disorder with Respect to Low-Grade Inflammation and Fish Oil Intake.

Unipolar depression has been recognized as one of the major diseases by the World Health Organization in the 21st century. The etiology of depression is complicated and includes genetic factors, stress, aging, and special physical status (pregnancy, metabolic syndrome, and trauma). Numerous animal and human studies have demonstrated that n-3 polyunsaturated fatty acids (n-3 PUFAs) are highly correlated to cognition and depression. These nutritional antidepressants, including EPA and DHA, have a range of neurobiological activities contributing to their potential antidepressant effects. Our preclinical and clinical studies have indicated that n-3 PUFA supplementation in addition to standard antidepressant medications may provide synergistic neuroprotective and antioxidant/inflammatory effects. To translate our preliminary findings into clinical application, this paper reviews the existing evidence on the antidepressant effects of n-3 PUFAs and the potential underlying mechanisms, which include modulation of chronic lowgrade inflammation and the corresponding changes in peripheral blood immune biomarkers.

Clinical efficacy of Danzhi Xiaoyao Powder in the treatment of post-stroke depression: A protocol for randomized, double-blind clinical study.

BACKGROUND: Depression is a common complication after stroke and is closely related to the poor prognosis of stroke. Antidepressants are the priority drug in the treatment of post-stroke depression (PSD), but there are dependence and adverse reactions. Danzhi Xiaoyao Powder has a good effect on depression without obvious adverse reactions. At present, there is a lack of rigorous randomized controlled trials to evaluate the clinical efficacy of Danzhi Xiaoyao Powder in the treatment of PSD. METHODS: This is a prospective, randomized, double-blind, parallel controlled trial to explore the efficacy and safety of Danzhi Xiaoyao Powder in the treatment of PSD. The participants were randomly divided into treatment group and control group. The treatment group used Danzhi Xiaoyao Powder combined with escitalopram oxalate, and the control group used Danzhi Xiaoyao Powder simulant combined with citalopram oxalate. The two groups were both treated for 8 weeks and followed up for 3 months. Observational index includes: Total response rate, Hamilton depression scale, Barthel index, national institutes of health stroke scale, the modified Edinburgh-Scandinavian stroke scale, Incidence of adverse reactions. Finally, SPASS 22.0 software was used for statistical analysis of the data. DISCUSSION: This study will evaluate the clinical efficacy of Danzhi Xiaoyao Powder in the treatment of PSD. The results of this study will provide reliable evidence for the clinical use of Xiaoyao Powder in the treatment of PSD. TRIAL REGISTRATION: Open Science Framework Registration number: DOI 10.17605/OSF.IO/5V926.

Antidepressant and anxiolytic compounds isolated from Salvia elegans interact with serotonergic drugs.

Salvia elegans belongs to a genus plants with biological activities in central nervous system. In this work, the purpose was to evaluate the anxiolytic and antidepressant effects of fractions and compounds isolated from S. elegans and its interaction with serotoninergic drugs by using behavioral tests in mice. Fractions from aerial parts of S. elegans were obtained by column chromatography, SeF1, SeF2, SeF3, and SeF4. Each of them was administered to 25 mg/k in ICR mice subject to forced swimming test (FST), or elevated plus maze test (EPM), or open field test (OFT). The most active fractions were chemically separated until compounds, which were analyzed as anxiolytic or antidepressant and the coadministration of these treatments with 5-HT1A and 5-HT2 drugs was measured in the different biological tests. All fractions were anxiolytic and antidepressant, oleanolic acid (OA) was found in SeF2, and from SeF3, a mixture of terpenes was found; a GC-MS analysis confirmed the presence of two main compounds: rosifoliol and agaraspirol (TM, mixture of terpenes). TM (doses-response curve, 0.01, 0.1, 0.5, 1.0, and 2.0 mg/kg) and OA (5 mg/kg) were also evaluated demonstrating an antidepressant and anxiolytic effect, respectively. The combination of TM (0.5 mg/kg) with 8-OH (selective 5-HT1A receptor agonist) induced an increment of antidepressant activity, while with the antagonist WAY-100635, the effect diminished. But with DOI (5-HT1c/5-HT2 receptor agonist), there was no change, and with KET (5-HT2 receptor antagonist), the activity was increased. When OA is co-administered with 8-OH or with DOI, the anxiolytic activity of this terpene, diminished; but with the combination with antagonists, the effect of OA shows no change. TM and OA were antidepressant and anxiolytic, respectively, on mice exposed to different tests, and these are able to interact with serotoninergic drugs.

Morinda officinalis oligosaccharides alleviate depressive-like behaviors in post-stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation.

AIMS: Morinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive-like behaviors in post-stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation. METHODS: Behavioral tests were performed to evaluate the effect of MOOs on depressive-like behaviors in PSD rats. The effects of MOOs on the expression of IL-18, IL-1ß, and nucleotide-binding domain leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence and Western blot analysis. Adeno-associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence. RESULTS: MOOs can alleviate depressive-like behaviors in PSD rats. PSD rats showed increased expression of IL-18, IL-1ß, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive-like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive-like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL-18, IL-1ß, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF-κB p65 signaling pathway. CONCLUSION: Overall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.

Antidepressant effects of total iridoids of Valeriana jatamansi via the intestinal flora-blood-brain barrier pathway.

CONTEXT: Valeriana jatamansi Jones [syn. V. wallichii DC, (Valerianaceae)] (VJJ) is used to treat depression. OBJECTIVE: To explore the effects of total iridoids of VJJ extract (TIV) on chronic unpredictable mild stress (CUMS) in mice. MATERIALS AND METHODS: VJJ roots and rhizomes were extracted with 70% ethanol. CUMS rats were treated daily with fluoxetine (2.6 mg/kg, i.g.) or TIV (5.7, 11.4, and 22.8 mg/kg, i.g.) for 14 days. Male Kun Ming mice on normal chow and 0.5% CMC-Na solution were used as a control. Behavioural tests included the tail suspension (TST) and sucrose preference tests (SPT). Evans blue staining was used to evaluate blood-brain barrier (BBB) permeability. Western blotting was used to measure zonula occludens-1 (ZO-1) and occludin expression. 16S rRNA sequencing was used to analyse intestinal flora abundance. Tax4Fun was used to predict KEGG metabolic pathways. RESULTS: TIV treatment reduced TST time (117.35 ± 8.23 or 108.95 ± 6.76 vs. 144.45 ± 10.30 s), increased SPT (55.83 ± 7.24 or 53.12 ± 13.85 vs. 38.98 ± 5.43%), increased the abundance of phylum Firmicutes (86.99 ± 0.03 vs. 60.88 ± 0.19%) and genus Lactobacillus (75.20 ± 0.19 vs. 62.10 ± 0.13%), reduced the abundance of phylum Bacteroidetes (6.69 ± 0.06 or 11.50 ± 0.09 vs. 25.07 ± 0.20%). TIV increased carbohydrate metabolism (14.50 ± 3.00 × 10-3 or 14.60 ± 2.00 × 10-3 or 14.90 ± 2.00 × 10-3 vs.13.80 ± 4.00 × 10-3%), replication and repair functions (5.60 ± 1.00 × 10-3 or 5.60 ± 1.00 × 10-3 vs. 5.10 ± 4.00 × 10-3%), reduced the frequency of infectious disease (1.60 ± 2.00 × 10-4 or 1.90 ± 5.00 × 10-4 or 1.80 ± 3.00 × 10-4 vs. 2.20 ± 7.00 × 10-3%), BBB permeability (0.77 ± 0.30 vs. 1.81 ± 0.33 µg/g), and up-regulated the expression of ZO-1 (1.42-fold, 1.60-fold, 1.71-fold) and occludin (1.79-fold, 2.20-fold). CONCLUSIONS: TIV may modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect.

Sublingual AKBA Exerts Antidepressant Effects in the Aß-Treated Mouse Model.

The 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) is the most active compound of Boswellia serrata proposed for treating neurodegenerative disorders, including Alzheimer's disease (AD), characterized in its early phase by alteration in mood. Accordingly, we have previously demonstrated that an intracerebroventricular injection of soluble amyloid beta 1-42 (Aß) peptide evokes a depressive-like phenotype in rats. We tested the protective effects of AKBA in the mouse model of an Aß-induced depressive-like phenotype. We evaluated the depressive-like behavior by using the tail suspension test (TST) and the splash test (ST). Behavioral analyses were accompanied by neurochemical quantifications, such as glutamate (GLU), kynurenine (KYN) and monoamines, and by biochemical measurements, such as glial fibrillary acid protein (GFAP), CD11b and nuclear factor kappa B (NF-kB), in mice prefrontal cortex (PFC) and hippocampus (HIPP). AKBA prevented the depressive-like behaviors induced by Aß administration, since we recorded a reduction in latency to initiate self-care and total time spent to perform self-care in the ST and reduced time of immobility in the TST. Likewise, the increase in GLU and KYN levels in PFC and HIPP induced by the peptide injection were reverted by AKBA administration, as well as the displayed increase in levels of GFAP and NF-kB in both PFC and HIPP, but not in CD11b. Therefore, AKBA might represent a food supplement suitable as an adjuvant for therapy of depression in early-stage AD.

Approach to the Patient with Chronic Pruritus.

Chronic pruritus (itch lasting ≥6 weeks) is a bothersome chief complaint that may present in a broad variety of diseases. Most itch-causing diagnoses fit into 1 of 5 categories (inflammatory, secondary to systemic disease, neuropathic, chronic pruritus of undetermined origin, and psychogenic itch) and this broad differential can be narrowed using key findings in the history and physical. In this article, we discuss which key findings are most pertinent for narrowing this differential and guiding further workup and treatment, as well as how to treat many itchy conditions.

Saffron Extract-Induced Improvement of Depressive-Like Behavior in Mice Is Associated with Modulation of Monoaminergic Neurotransmission.

Depressive disorders represent a major public health concern and display a continuously rising prevalence. Importantly, a large proportion of patients develops aversive side effects and/or does not respond properly to conventional antidepressants. These issues highlight the need to identify further therapeutic strategies, including nutritional approaches using natural plant extracts with known beneficial impacts on health. In that context, growing evidence suggests that saffron could be a particularly promising candidate. This preclinical study aimed therefore to test its antidepressant-like properties in mice and to decipher the underlying mechanisms by focusing on monoaminergic neurotransmission, due to its strong implication in mood disorders. For this purpose, the behavioral and neurobiochemical impact of a saffron extract, Safr'Inside™ (6.5 mg/kg per os) was measured in naïve mice. Saffron extract reduced depressive-like behavior in the forced swim test. This behavioral improvement was associated with neurobiological modifications, particularly changes in serotonergic and dopaminergic neurotransmission, suggesting that Safr'Inside™ may share common targets with conventional pharmacological antidepressants. This study provides useful information on the therapeutic relevance of nutritional interventions with saffron extracts to improve management of mood disorders.

Formulation of Medicated Chewing Gum Containing Sceletium tortuosum and Process Optimization Utilizing the SeDeM Diagram Expert System.

Sceletium tortuosum is one of the most promising medicinal plant species for treating anxiety and depression. Traditionally, aerial parts are chewed (masticatory herbal medicine) providing fast relief and rendering the masticatory route for delivery, ideal. This study intended formulating novel medicated chewing gum containing S. tortuosum to alleviate depression and anxiety. S. tortuosum extract was formulated into directly compressed medicated chewing gum (MCG) containing different Health-in-Gum® (HIG) bases through process optimization with the SeDeM Diagram Expert System. Physical properties of MCGs were characterized, and specialized drug release studies performed. According to the manufacturer, only HIG-03 was specifically developed for direct compression; however, the SeDeM System was successfully applied to all HIG-bases investigated. HIG-01 and HIG-04 are also considered useful in direct compression as no considerable differences in these MCG formulations' physical properties were recognized. Inclusion of a lubricant, however, is deemed essential, and MCG comprising HIG-01, most suited for direct compression. Dissolution experiments found only two alkaloids used as markers, mesembrine and mesembrenone, were released in quantifiable concentrations regardless formulation constituents. Novel directly compressed MCG-containing S. tortuosum extract was successfully formulated by which the biologically active phytochemicals of S. tortuosum can be scientifically delivered through the traditionally applied mastication method.

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor.

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.

Natural volatile oils derived from herbal medicines: A promising therapy way for treating depressive disorder.

Depression is a common global mental disorder that seriously harms human physical and mental health. With the development of society, the increase of pressure and the role of various other factors make the incidence of depression increase year by year. However, there is a lack of drugs that have a fast onset, significant effects, and few side effects. Some volatile oils from traditional natural herbal medicines are usually used to relieve depression and calm emotions, such as Lavender essential oil and Acorus tatarinowii essential oil. It was reported that these volatile oils, are easy to enter the brain through the blood-brain barrier and have good antidepressant effects with little toxicity and side effects. In this review, we summarized the classification of depression, and listed the history of using volatile oils to fight depression in some countries. Importantly, we summarized the anti-depressant natural volatile oils and their monomers from herbal medicine, discussed the anti-depressive mechanisms of the volatile oils from natural medicine. The volatile oils of natural medicine and antidepressant drugs were compared and analyzed, and the application of volatile oils was explained from the clinical use and administration routes. This review would be helpful for the development of potential anti-depressant medicine and provide new alternative treatments for depressive disorders.

Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis.

The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the antidepressant fluoxetine (FLX) with two natural polyphenolic compounds viz., kaempferol (KMP) and/or epigallocatechin-gallate (EGCG). The obtained results revealed that single FLX pre-treatment possess a significant apoptotic effect by increasing the activity of serum and colon tissue caspase 3. It also attenuated the DMH driven increase in, colon tissue MDA, NO, PCNA and COX-2 expression as well as serum and colon tissue ß-catenin, with a decrease in the multiplicity of ACF and number of MPLs. The combination of FLX with either KMP or EGCG improved the antioxidant, anti-inflammatory and antiproliferating activities but with higher apoptotic activity in case of KMP. Eventually, histopathological assessment of colon tissues exposed that while sole pre-treatment can improve DMH-induced hyperplasia with only moderate inflammatory infiltration, tissues from the combined pre-treatment regimens groups exhibited almost a normal colonic architecture with slight submucosal edema. The study proved that single FLX administration prior to DMH exerts a chemopreventive effect and that the investigated combined pre-treatment regimens demonstrated more potent chemopreventive and antiproliferative actions.

Anti-depressant like effects of quercetin 4'-O-glucoside from Allium cepa via regulation of brain oxidative stress and monoamine levels in mice subjected to unpredictable chronic mild stress.

Objectives: Depression is a common neuropsychiatric disorder. The available pharmacotherapy is ineffective for a substantial proportion of patients and has numerous side effects. Therefore, finding safer drugs for the management of depression is of paramount importance. The present study was aimed to identify the compound responsible for anti-depressant like effects of Allium cepa outer scale extract (ACE) and to elucidate its mechanism of action. Methods:The anti-depressant compound from ACE was separated using bioactivity guided fractionation. Furthermore, mouse model of unpredictable chronic mild stress (UCMS) induced depressive behaviour was employed to investigate the anti-depressant like activity and potential mechanism of bioactive compound using behavioural tests (forced swim test (FST), sucrose preference test (SPT), open field test (OFT)) as well as by assessing brain oxidative stress, monoamine oxidase A and serotonin levels. Results:ACE and its ethylacetate fraction (EF) showed marked anti-depressant like effects in mice in the FST model. Chromatographic and spectroscopic studies of EF lead to the isolation of quercetin and quercetin 4'-O-glucoside (QG). Of these, QG (20 mg/kg) treated animals showed activity similar to that shown by fluoxetine in mice using FST. Thus, QG was tested for anti-depressant like activity against UCMS induced depressive behaviour in mice. Treatment of UCMS- exposed mice with QG (20 mg/kg) improved UCMS induced behaviour anomalies and restored brain biochemical parameters (oxidative stress, MAO-A activity and serotonin levels). Discussion:QG is responsible for anti-depressant like effects of ACE possibly via prevention of brain oxidative stress and restoring serotonin levels by inhibiting MAO-A activity.

Water extract of Armillaria mellea (Vahl) P. Kumm. Alleviates the depression-like behaviors in acute- and chronic mild stress-induced rodent models via anti-inflammatory action.

ETHNOPHARMACOLOGY RELEVANCE: Armillaria mellea (Vahl) P. Kumm. (AM) is an edible mushroom that has been reported as treatment for several neurological disorders, such as dizziness and epilepsy in Asia. Importantly, AM shares a symbiotic relationship with Gastrodia elata Blume (GE), a medicinal herb with antidepressant-like properties. Researchers believe that AM may possess pharmacological properties similar to GE due to their symbiosis, however, few studies have investigated the pharmacological effect of AM. AIM OF THE STUDY: The aim of this study was to explore the potential of AM as an antidepressant in forced-swimming test (FST) and unpredictable chronic mild stress (UCMS) rodent models and investigate its possible underlying mechanism. MATERIALS AND METHODS: Rats were orally administrated with 250, 500, and 1000 mg/kg body weight (bw) water extract of AM (WAM) for 28 and 35 consecutive days prior to the FST and UCMS protocols, respectively. The cerebral serotonin (5-HT) and the metabolites in the frontal cortex of rats were measured. The brain was dissected and the blood was collected to investigate the levels of inflammatory-related signaling pathway. RESULTS: All doses of WAM reduced the immobility time in the FST without disturbing autonomic locomotion. All doses of WAM prevented stress-induced abnormal behaviors in the UCMS model, including decreased sucrose preference and hypoactivity. 500 and 1000 mg/kg bw WAM attenuated the stress-induced increases in IL-1ß and TNF-α in the serum and cerebrum. 1000 mg/kg bw WAM alleviated brain inflammation by reducing the protein expression of ionized calcium binding adaptor molecule 1. CONCLUSION: WAM exhibited acute and chronic antidepressant-like effects, and may result from the anti-inflammatory actions. Therefore, the development of AM as a dietary therapy or adjuvant for depression treatment should be considered.

Meranzin hydrate elicits antidepressant effects and restores reward circuitry.

The burden of depression is enormous, and numerous studies have found that major depressive disorder (MDD) induces cardiovascular disorders (CVD) and functional dyspepsia (FD). Excitingly, meranzin hydrate (MH), an absorbed bioactive compound of Aurantii Fructus Immaturus, reverses psychosocial stress-induced mood disorders, gastrointestinal dysfunction and cardiac disease. Pharmacological methods have repeatedly failed in antidepressant development over the past few decades, but repairing aberrant neural circuits might be a reasonable strategy. This article aimed to explore antidepressant-like effects and potential mechanisms of MH in a rat model of unpredictable chronic mild stress (UCMS). Utilizing blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), we sought to find reliable neurocircuits or a dominant brain region revealing the multiple effects of MH. The results show that compared with UCMS rats, MH (10 mg/kg/day for 1 week i.g.)-treated rats exhibited decreased depression-like behaviour; increased expression of brain-derived neurotrophic factor (BDNF) in the hippocampal dentate gyrus; and normalized levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and acylated ghrelin (AG). Additionally, the UCMS-induced rise in BOLD activation in the reward system was attenuated after MH treatment. A literature search shown that nucleus accumbens (NAc) and hypothalamus of the reward system might reveal multiple effects of MH on MDD-FD-CVD comorbidity. Further research will focus on the role of these two brain regions in treating depression associated with comorbidities.

Radix Polygalae extract exerts antidepressant effects in behavioral despair mice and chronic restraint stress-induced rats probably by promoting autophagy and inhibiting neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Polygalae (RP) has been traditionally used for the treatment of various psychiatric disorders in East Asia. AIM OF THE STUDY: Depression is a severe mental disease with high prevalence in people, and neurobiology changes of depression are not fully clarified yet. The present study aimed to investigate the antidepressant effect and underlying mechanism of RP in behavioral despair mice and chronic restraint stress (CRS)-induced rats. MATERIALS AND METHODS: ICR mice were treated with various doses of RP (0.13-1.0 g/kg) for 14 days and then subjected to forced swimming test (FST). Wistar rats were exposed to 6-hour restraint stress daily for 28 days, and RP (0.5 and 1 g/kg) was administered by gavage 1 h prior to CRS procedure. Subsequently, behavioral tests were performed and brains were collected for biochemical analysis. RESULTS: RP reduced immobility time of mice in FST and reversed abnormal behaviors of rats induced by CRS in sucrose preference test, novelty-suppressed feeding test, open field test and FST. Moreover, RP could enhance the expression of LC3-II and beclin1 and decrease the level of p62 both in cortex of mice and prefrontal cortex (PFC) of rats, and regulate the dysfunction of AMPK-mTOR pathway in PFC of CRS rats. Activated microglia, impaired astrocyte, elevated protein expression of NLRP3, ASC and caspase-1, and increased mRNA levels of proinflammatory cytokines were observed in PFC of CRS rats, all of which were corrected by RP treatment. CONCLUSION: RP exerted remarkable antidepressant activity in behavioral despair mice and CRS-induced rats, probably by promoting autophagy and inhibiting neuroinflammation.

Calea zacatechichi Schltdl. (Compositae) produces anxiolytic- and antidepressant-like effects, and increases the hippocampal activity during REM sleep in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.

Xanthotoxin affects depression-related behavior and neurotransmitters content in a sex-dependent manner in mice.

The present study aimed to evaluate xanthotoxin's influence on male and female Swiss mice's depression-like behaviors and investigate the potential mechanism of this effect. Naturally derived furanocoumarin (the Apiaceae family), xanthotoxin, administered acutely (12.5 mg/kg), diminished the immobility level in the forced swim test only in males. The immobility level was lower in females than males, which may be associated with a higher serotonin level in the female prefrontal cortex. A dose-dependent increase of serotonin and noradrenaline was reported in the reverse-phase ion-pair liquid chromatography in the female prefrontal cortex but not in the hippocampus. We suggest that xanthotoxin may exert antidepressant properties and affect males and females differently. The increasing level of serotonin in the male and female prefrontal cortex may underlie this effect.