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Background/Objectives: Argemone platyceras Link & Otto, an endemic plant of Mexico, is widely distributed in the central area of the country, mainly in the states of Tlaxcala, Puebla, and the State of Mexico. Ethnobotanical studies in different communities of these states have demonstrated that it is primarily used to treat diabetes and mental illnesses, such as "los nervios" (nerves) and "el ansia" (anxiety); these terms are used in traditional medicine, but it is accepted that they refer to anxiety disorders. This study aimed to validate the traditional use of aerial parts of A. platyceras Link & Otto in treating these illnesses. Methods: a standardized acidic method to obtain alkaloids was used to obtain an extract (AlkExt), which was tested in adult male Swiss Webster mice in the tail suspension (TST) and forced swimming (FST) tests. Results: AlkExt was analyzed using mass spectrometry techniques (DI-ESI and UHPLC-MS) to detect 2,3′,4,5′-Tetramethoxystilbene (m/z 301.14, 3%), scoulerine (m/z 328.16, 19.8%), tetrahydro-columbamine (m/z 342.17, 28.8%), 8-(hydroxymethyl)-2,10-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-1,11-diol (m/z 358.17, 22.8%), and glaucine (m/z 356.19, 11.1%); these were assayed in a single oral administration of AlkExt, which caused robust anxiolytic- and antidepressant-like effects without affecting the spontaneous ambulatory activity of the mice. Conclusions: The easy and standardized AlkExt analyzed in pharmaceuticals assays in this study strongly suggest its therapeutic potential to treat the comorbidity of anxiety and depression disorders and support further investigations in people with these diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients. Methods In this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months. Results 23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts. Conclusions Introducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality.

Background: Chronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients. Methods: In this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months. Results: 23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts. Conclusions: Introducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality. [ABSTRACT FROM AUTHOR]

Blueberries (Vaccinium corymbosum L.) are cultivated worldwide and are among the best dietary sources of bioactive compounds with beneficial health effects. This study aimed to investigate the components of Peruvian blueberry using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC–ESI–QTOF–MS/MS), identifying 11 compounds. Furthermore, we assessed in vitro the antioxidant activity and in vivo the antidepressant effect using a rat model and protective effect on lipid peroxidation (in the serum, brain, liver, and stomach). We also conducted molecular docking simulations with proteins involved in oxidative stress and depression for the identified compounds. Antioxidant activity was assessed by measuring total phenolic and flavonoid contents, as well as using 1,1-diphenyl-2-picrylhydrazin (DPPH), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+), and ferric-reducing antioxidant power (FRAP) assays. Peruvian blueberries demonstrated higher antioxidant activity than Vaccinium corymbosum fruits from Chile, Brazil, the United States, Turkey, Portugal, and China. The results showed that oral administration of Peruvian blueberries (10 and 20 mg/kg) for 28 days significantly (p < 0.001) increased swimming and reduced immobility in the forced swimming test (FST). Additionally, at doses of 40 and 80 mg/kg, oxidative stress was reduced in vivo (p < 0.001) by decreasing lipid peroxidation in brain, liver, stomach, and serum. Molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed. In the molecular docking studies, quercitrin and 3,5-di-O-caffeoylquinic acid showed the best docking scores for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase, and xanthine oxidase; while 3,5-dicaffeoylquinic acid methyl ester and caffeoyl coumaroylquinic acid had the best docking scores for monoamine oxidase and serotonin receptor 5-HT2. In summary, our results suggest that the antidepressant and protective effects against lipid peroxidation might be related to the antioxidant activity of Peruvian Vaccinium corymbosum L. [ABSTRACT FROM AUTHOR]

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression. [ABSTRACT FROM AUTHOR]

Background: Depression is a serious mental illness that has a significant impact on suicidal thoughts. It is ranked as the fourth most significant mental disability globally. Current research is concentrating on increasing the effectiveness of conventional treatments due to highly undesirable effects. Natural goods, herbal plants, and phytochemicals offer a wide range of study opportunities for antidepressant treatments. Objective: The present study aim at the review of various photoPharmacological effects of medicinal plants for the treatment of depression in a traditional approach Methods: The methodology includes a thorough search of every electronic source to gather all information on herbal plants, pharmacological effects, and antidepressant mechanisms of phytochemicals from the year 2000 to 2023. Results: Different plant metabolites were shown to have powerful antidepressant effects, including polyphenols (phenolic acids, flavonoids, lignans, and coumarins), alkaloids, terpenes and terpenoids, saponins and sapogenins. Major group of phytochemicals crucial in evaluating antidepressant effectiveness includes piperine, diterpene alkaloids, berberine, hyperforin, riparin derivatives, ginsenosides, and -carboline alkaloids. A great inhibitor of monoamine oxidase enzymes, an elevation in brain 5-HT and BDNF (BrainDerived Nicotinic Factor) levels and modulatory effects on the hypothalamuspituitary-adrenal axis were all demonstrated by piperine. Numerous studies have demonstrated berberine's serotonergic, noradrenergic, and dopaminergic effects, demonstrating the importance of phytochemicals from various sources in the treatment of depression. Conclusion: All of the medicinal plants listed in this study's thorough review indicated the ability to cure depression using various traditional methods and a variety of processes. In order to discover potential natural, semi-synthetic, or synthetic antidepressants with fewer side effects, the structure-activity relationship of extremely effective antidepressant phytochemicals was evaluated. For verification of natural antidepressant effectiveness and fulfilment of their safety profile, more clinical investigations are also required. [ABSTRACT FROM AUTHOR]

Chronic pain is a prevalent and persistent ailment that affects individuals worldwide. Conventional medications employed in the treatment of chronic pain typically demonstrate limited analgesic effectiveness and frequently give rise to debilitating side effects, such as tolerance and addiction, thereby diminishing patient compliance with medication. Consequently, there is an urgent need for the development of efficacious novel analgesics and innovative methodologies to address chronic pain. Recently, a growing body of evidence has suggested that multireceptor ligands targeting opioid receptors (ORs) are favorable for improving analgesic efficacy, decreasing the risk of adverse effects, and occasionally yielding additional advantages. In this study, the intrathecal injection of a recently developed peptide (VYWEMEDKN) at nanomolar concentrations decreased pain sensitivity in naïve mice and effectively reduced pain-related behaviors in nociceptive pain model mice with minimal opioid-related side effects. Importantly, the compound exerted significant rapid-acting antidepressant effects in both the forced swim test and tail suspension test. It is possible that the rapid antihyperalgesic and antidepressant effects of the peptide are mediated through the OR pathway. Overall, this peptide could both effectively provide pain relief and alleviate depression with fewer side effects, suggesting that it is a potential agent for chronic pain and depression comorbidities from the perspective of pharmaceutical development.

Lin Sheng,1– 4,&ast; Yumeng Wei,1,3,&ast; Chao Pi,1,3,&ast; Ju Cheng,3,4 Zhilian Su,1– 4 Yuanyuan Wang,1,5 Tao Chen,1– 4 Jie Wen,1– 4 Yuxun Wei,1– 4 Jingwen Ma,1– 4 Jia Tang,1– 4 Huiyang Liu,1– 4 Zerong Liu,6,7 Hongping Shen,8 Ying Zuo,9 Wenwu Zheng,10 Ling Zhao2– 4 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Key Laboratory of Medical Electrophysiology, Ministry of Education, Development Planning Department of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 6Central Nervous System Drug Key Laboratory of Sichuan Province, Sichuan Credit Pharmaceutical CO., Ltd. Luxian County, Luzhou City, People’s Republic of China; 7Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, People’s Republic of China; 8Clinical Trial Center, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 9Department of Comprehensive Medicine, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 10Department of cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenwu Zheng, Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3165311, Email zhengwenwu888@163.com Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling@swmu.edu.cnPurpose: The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect.Methods: The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted.Results: The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC(0-t) of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the Cmax was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration.Conclusion: TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.Keywords: turmeric extract, curcuminoids, nanoemulsion, stability, antidepressant effect, 5-hydroxytryptamine

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Blueberries (Vaccinium corymbosum L.) are cultivated worldwide and are among the best dietary sources of bioactive compounds with beneficial health effects. This study aimed to investigate the components of Peruvian blueberry using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC–ESI–QTOF–MS/MS), identifying 11 compounds. Furthermore, we assessed in vitro the antioxidant activity and in vivo the antidepressant effect using a rat model and protective effect on lipid peroxidation (in the serum, brain, liver, and stomach). We also conducted molecular docking simulations with proteins involved in oxidative stress and depression for the identified compounds. Antioxidant activity was assessed by measuring total phenolic and flavonoid contents, as well as using 1,1-diphenyl-2-picrylhydrazin (DPPH), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+), and ferric-reducing antioxidant power (FRAP) assays. Peruvian blueberries demonstrated higher antioxidant activity than Vaccinium corymbosum fruits from Chile, Brazil, the United States, Turkey, Portugal, and China. The results showed that oral administration of Peruvian blueberries (10 and 20 mg/kg) for 28 days significantly (p < 0.001) increased swimming and reduced immobility in the forced swimming test (FST). Additionally, at doses of 40 and 80 mg/kg, oxidative stress was reduced in vivo (p < 0.001) by decreasing lipid peroxidation in brain, liver, stomach, and serum. Molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed. In the molecular docking studies, quercitrin and 3,5-di-O-caffeoylquinic acid showed the best docking scores for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase, and xanthine oxidase; while 3,5-dicaffeoylquinic acid methyl ester and caffeoyl coumaroylquinic acid had the best docking scores for monoamine oxidase and serotonin receptor 5-HT2. In summary, our results suggest that the antidepressant and protective effects against lipid peroxidation might be related to the antioxidant activity of Peruvian Vaccinium corymbosum L.

Sleep loss robustly disrupts mood and emotion regulation in healthy individuals but can have a transient antidepressant effect in a subset of patients with depression. The neural mechanisms underlying this paradoxical effect remain unclear. Previous studies suggest that the amygdala and dorsal nexus (DN) play key roles in depressive mood regulation. Here, we used functional MRI to examine associations between amygdala- and DN-related resting-state connectivity alterations and mood changes after one night of total sleep deprivation (TSD) in both healthy adults and patients with major depressive disorder using strictly controlled in-laboratory studies. Behavioral data showed that TSD increased negative mood in healthy participants but reduced depressive symptoms in 43% of patients. Imaging data showed that TSD enhanced both amygdala- and DN-related connectivity in healthy participants. Moreover, enhanced amygdala connectivity to the anterior cingulate cortex (ACC) after TSD associated with better mood in healthy participants and antidepressant effects in depressed patients. These findings support the key role of the amygdala-cingulate circuit in mood regulation in both healthy and depressed populations and suggest that rapid antidepressant treatment may target the enhancement of amygdala-ACC connectivity. [ABSTRACT FROM AUTHOR]

We investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, on a depression-like phenotype in mice exposed to chronic unpredictable stress (CUS). Learning and memory were also assessed using the Morris water maze (MWM) test. Liraglutide (0.3 mg/kg/day for 21 days) was administered to mice with or without exposure to CUS. After 21 days of CUS, the forced swim test (FST) was performed to assess its antidepressant effect. To evaluate cognitive function, liraglutide was administered to mice under stress-free conditions for 21 days, and then the MWM test was performed on 6 consecutive days. Chronic liraglutide treatment reduced FST immobility in mice with and without CUS. In the probe trial of the Morris water maze test, the search error rate was reduced and the time spent and path length in the target quadrant and the number of platform crossings were increased. Additional animal model experiments and molecular level studies are needed to support the results obtained in this study. Liraglutide appears to exert antidepressant effects and could improve cognitive function. Based on these results, GLP-1 agonists could have potential as novel antidepressants. • Liraglutide has an antidepressant-like effect. • Liraglutide may improve cognitive function. • GLP-1 agonists could be a target for the development of novel antidepressants. [ABSTRACT FROM AUTHOR]

Chaihushugan san (CSS), a classic formula for soothing the liver and relieving depression, has been identified to produce rapid antidepressant-like effects in female mice. However, the gender predominance and underlying mechanisms of CSS's antidepressant remain unclear. In this study, we focused on unraveling the gender predominance of CSS in antidepressant and the specific neuronal mechanisms that mediate this predominance. Tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT) were used to evaluate depressive phenotypes or antidepressant-like effects of CSS in female and male chronic unpredictable mild stress (CUMS) mice model. RNA-sequencing was used to screen specific target for CSS antidepressant gender dominance. RT-PCR and elisa were used to detect the expressions of specific molecule, hormones, and inflammatory factors in the hippocampus. hippocampal viral overactivation and pharmacological blockade were used to detect the correlation between CSS antidepressant gender dominance and related targets. In the present study, both female and male mice displayed depressive phenotypes including significant increasing immobility time in TST and reducing sucrose preference ratio in SPT after exposing CUMS for 3 weeks. However, acute administration of CSS (2, 4 g/kg) improved the depressive phenotypes only in female mice or not male mice at 2 h later. Moreover, the expressions of TC2N were increased only in female mice after exposing CUMS for 3 weeks, which were also reversed by CSS after a single administration 2 h later, but no alterations in male mice. The hippocampal expressions of estrogen receptor β (Erβ), pro-inflammatory factors (IL-1β and TNF-α) and anti-inflammatory factors (IL-10, TGF-β and IL-1Rα) were all abnormal in female CUMS mice model, which were all normalized by CSS. Furthermore, overactivation of hippocampal TC2N by AAV-TC2N+/+ blocked the antidepressant-like effects of CSS and the up-regulation of hippocampal Erβ in female mice. However, inhibition of Erβ blunted the antidepressant-like effects of CSS and CSS's suppression of pro-inflammatory factors (IL-1β and TNF-α), which had no any effect on hippocampal TC2N and anti-inflammatory factors (IL-10 and TGF-β). The study revealed that CSS had antidepressant superiority in female mice depending on inhibiting hippocampal TC2N and then activating Erβ, further inhibiting the release of pro-inflammatory factors to produce antidepressant effects, which provided a basis for the guidance of CSS in clinical application, new ideas and targets for the development of drugs for depression with gender differences. [Display omitted] • Chaihushugan san (CSS) had a stronger depressive effect in female mice. • Abnormal TC2N was only present in the hippocampus of female depressive model mice. • CSS was able to inhibit hippocampal TC2N and further activate Erβ. • CSS was able to activate hippocampal Erβ to inhibit pro-inflammatory factors. [ABSTRACT FROM AUTHOR]

Yu Li,1,&ast; Mei-Ling Wang,1,&ast; Bo Zhang,1 Xiao-Xu Fan,1 Qin Tang,1 Xue Yu,2 Li-Na Li,2 Ang-Ran Fan,2 Hong-Sheng Chang,1 Lan-Zhen Zhang1 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China; 2School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lan-Zhen Zhang; Hong-Sheng Chang, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Northeast Corner of the Intersection of Sunshine South Street and Baiyang East Road, Fangshan District, Beijing, 102488, People’s Republic of China, Tel +86 10 5391 2122, Email zhanglanzhen01@126.com; chs1971@sina.comBackground: There is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study.Objective: This study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd.Methods: In this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors.Results: Our data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2.Conclusion: Our results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.Keywords: ginsenoside Rd, antidepressant effect, HIF-1α-VEGF signaling pathway, VEGFR-2, synaptic plasticity-related regulators, molecular docking

Major depressive disorder (MDD) is a leading cause of disability worldwide. A comprehensive understanding of the molecular mechanisms of this disorder is critical for the therapy of MDD. In this study, it is observed that deubiquitinase Mysm1 is induced in the brain tissues from patients with major depression and from mice with depressive behaviors. The genetic silencing of astrocytic Mysm1 induced an antidepressant‐like effect and alleviated the osteoporosis of depressive mice. Furthermore, it is found that Mysm1 knockdown led to increased ATP production and the activation of p53 and AMP‐activated protein kinase (AMPK). Pifithrin α (PFT α) and Compound C, antagonists of p53 and AMPK, respectively, repressed ATP production and reversed the antidepressant effect of Mysm1 knockdown. Moreover, the pharmacological inhibition of astrocytic Mysm1 by aspirin relieved depressive‐like behaviors in mice. The study reveals, for the first time, the important function of Mysm1 in the brain, highlighting astrocytic Mysm1 as a potential risk factor for depression and as a valuable target for drug discovery to treat depression. [ABSTRACT FROM AUTHOR]

Objectives: Suicidality is a serious public health problem and is closely associated with the severity of depression. In this work, we examined the effects of accelerated intermittent theta burst stimulation (iTBS) on suicidal status, risk factors for suicide, and severity of depressive symptoms in subjects with major depressive disorder (MDD). Methods: We present data from a quadruple‐blind (patient, care provider, investigator, rater) sham‐controlled crossover randomized clinical trial. During a 6‐week observation period, each participant underwent 2 weeks of stimulation ‐ each week with 20 sessions of active or sham iTBS. A suicide score was created using a composite of individual items from Montgomery–Åsberg Depression Scale (MADRS), Hamilton Depression Scale, and Beck Depression Inventory. The severity of depression was determined by MADRS total scores. In addition, we used demographic and Columbia Suicidality Rating Scale information to assess suicide risk. Results: Among 81 participants, we observed a significant reduction in suicidality and this change was positively correlated with a change in depressive symptoms. A significant difference between active and sham iTBS provided evidence for antidepressant effects. Higher changes in levels of anxiety and impulsiviness also correlated with larger changes in suicidality. Conclusions: As neither suicide nor other serious adverse events were evidenced, this intervention was a safe and viable procedure to reduce suicidality and severity of depressive symptoms. Moreover, we identified more pronounced anti‐suicidal effects in those with higher risk profiles. Unlike MADRS, composite suicidal scores did not provide evidence of an effect between stimulation conditions in this crossover design study. Even so, based on our promising results, parallel and larger studies could contribute to a better characterization of the anti‐suicidal placebo effect and the benefit of using iTBS against suicidal symptoms. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the antidepressant effect of Jujuboside A (JuA) on corticosterone (CORT)-induced depression in mice and explore the underlying mechanisms. The mice models were submitted to CORT and treated with JuA (10 and 30 mg/kg) for three weeks. Experiments were also performed on mice with brain-derived neurotrophic factor knockdown (BDNF (±)) as control subjects. Behavioral tests, including the open field test (OFT), tail suspension test (TST), forced swimming test (FST) and Morris water maze (MWM), were then performed to evaluate the antidepressant effect of JuA. The expression levels of BDNF, tyrosine kinase receptor B (TrkB), and cyclic AMP response element binding protein (CREB) in the hippocampi of mice were examined by immunohistochemistry (IHC) and Western blot. The effect of JuA on the viability of mouse hippocampal cells (HT22) was also assessed by CCK-8 assay. JuA significantly decreased the OFT and TST immobility time of the mice, the total distance travelled and the time spent in the central area also effectively increased in the OFT. In the MWM, the escape latencies of the mice decreased remarkably, while the number of times the mice crossed the platform and the target quadrant increased significantly after treatment with JuA. In addition, the BDNF, TrkB, and CREB expression levels were significantly increased in the hippocampi of the mice treated with JuA. Furthermore, JuA clearly attenuated CORT-induced cell injury, as evidenced by the increased viability of the HT22 cells. These findings demonstrated that JuA may exhibit potential antidepressant effect in mice by increasing protein expression levels of BDNF, TrkB, CREB, and improving the viability of the hippocampal cells. [Display omitted] • JuA showed significant antidepressant activity in CORT-induced mice models. • The levels of BDNF, TrkB, CREB were obviously increased in mice treated with JuA. • JuA remarkably attenuated CORT-induced cell injury in HT22 cells. • BDNF (±) mice were used in the experiments as controls. [ABSTRACT FROM AUTHOR]

Alarin is a pleiotropic peptide involved in a multitude of putative biological activities, notably, it has a regulatory effect on depression-like behaviors. Although further elucidating research is needed, animal-based cumulative evidence has shown the antidepressant-like effects of alarin. In light of its regulatory role in depression, alarin could be used as a promising antidepressant in future treatment for depression. Nevertheless, the available information is still insufficient and the therapeutic relevance of alarin in depression is still of concern. Moreover, a plethora of studies have reported that the actions of alarin, including antidepressant activities, are mediated by a separate yet unidentified receptor, highlighting the need for more extensive research. This review focuses on the current understanding of the regulatory effects and future therapeutic relevance of alarin on depression, and the arguments on its receptors.

• IV ketamine and IN esketamine were effective and tolerable for MDD-TRD management. • IV ketamine and IN esketamine had comparable treatment outcomes. • No association found between patient age or sex and treatment response. Intravenous (IV) ketamine and intranasal (IN) esketamine are novel therapies to manage treatment resistant depression within major depressive disorder (MDD-TRD). This is a multi-site observational study aiming to assess the real-world effectiveness and tolerability of these novel therapies in the management of MDD-TRD. 53 patients were referred to receive IV ketamine (n = 26, 69.23 % female, 52.81 ± 14.33 years old) or IN esketamine (n = 27, 51.85 % female, 43.93 ± 13.57 years old). Treatment effectiveness was assessed using the Montgomery and Åsberg Depression Rating Scale (MADRS) for depression severity and item 10 of the MADRS for suicidal ideation (SI). Tolerability was assessed by systematically tracking side effects and depersonalization using the 6-item Clinician administered dissociative symptom scale (CADSS-6). The data was analyzed using descriptive statistics, risk ratio and effect size. Both IV ketamine and IN esketamine significantly reduced depressive symptoms and suicidal ideation by treatment endpoint. Patients receiving IN esketamine, and patients receiving IV ketamine had a similar risk of developing side effects. All side effects reported were mild and transient. These results suggested that both IV ketamine and IN esketamine are effective in the management of depressive symptoms and were well tolerated. Therefore, the results of this study could serve to inform clinical practice. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that the pathogenesis of depression is closely linked to impairments in neuronal synaptic plasticity. Honokiol, a biologically active substance extracted from Magnolia Officinalis, has been proven to exert significant antidepressant effects. However, the specific mechanism of action remains unclear. In this study, PC12 cells and chronic unpredictable mild stress (CUMS) model rats were used to explore the antidepressant effects and potential mechanisms of honokiol in vitro and in rats. In vitro experiment, a cell viability detection kit was used to screen the concentration and time of honokiol administration. PC12 cells were administered with hypoxia-inducible factor-1a (HIF-1a) blocker, 2-methoxyestradiol (2-ME), and vascular endothelial growth factor receptor 2 (VEGFR-2) blocker, SU5416, to detect the expression of HIF-1a, VEGF, synaptic protein 1 (SYN 1), and postsynaptic density protein 95 (PSD 95) by western blotting. In effect, we investigated whether the synaptic plasticity action of honokiol was dependent on the HIF-1a-VEGF pathway. In vivo, behavioral tests were used to evaluate the reproducibility of the CUMS depression model and depression-like behaviors. Molecular biology techniques were used to examine mRNA and protein expression of the HIF-1a-VEGF signaling pathway and synaptic plasticity-related regulators. Additionally, molecular docking techniques were used to study the interaction between honokiol and target proteins, and predict their binding patterns and affinities. Experimental results showed that honokiol significantly reversed CUMSinduced depression-like behaviors. Mechanically, honokiol exerted a significant antidepressant effect by enhancing synaptic plasticity. At the molecular level, honokiol can activate the HIF-1a-VEGF signaling pathway in vitro and in vivo, as well as promote the protein expression levels of SYN 1 and PSD 95. Taken together, the results do not only provide an experimental basis for honokiol in the clinical treatment of depression but also suggest that the HIF-1a-VEGF pathway may be a potential target for the treatment of depression. [ABSTRACT FROM AUTHOR]

Cognitive reappraisal (CR) is one of the core treatment components of cognitive behavioral therapy (CBT) and is the gold standard treatment for major depressive disorders. Accumulating evidence indicates that cognitive reappraisal could function as a protective factor of cognitive vulnerability to depression. However, the neural mechanism by which CR training reduces cognitive vulnerability to depression is unclear. There is ample evidence that the prefrontal–amygdala circuit is involved in CR. This study proposes a novel cognitive bias model of CR training which hypothesizes that CR training may improve the generation ability of CR with altered prefrontal–amygdala functional activation/connectivity, thus reducing negative cognitive bias (negative attention bias, negative memory bias, negative interpretation bias, and/or negative rumination bias) and alleviating depressive symptoms. This study aims to (1) explore whether there is abnormal CR strategy generation ability in individuals who are cognitively vulnerable to depression; (2) test the hypothesis that CR training alleviates depressive symptoms through the mediators of cognitive bias (interpretation bias and/or rumination bias); (3) explore the neural mechanism by which CR training may enhance the ability of CR strategy generation; and (4) examine the short- and long-term effects of CR training on the reduction in depressive symptoms in individuals who are cognitively vulnerable to depression following intervention and 6 months later. The study is promising, providing theoretical and practical evidence for the early intervention of depression-vulnerable individuals. [ABSTRACT FROM AUTHOR]

The present study describes the synthesis of a novel type of harmine derivatives, containing substituent at the C-8 position and their physicochemical characterization by FTIR, NMR, and elemental analysis. Computer simulation of the interaction of harmine and its derivatives (Z)-8-(1-hydrazonoethyl)-7-methoxy-1-methyl-9H-pyrido[3,4-b]indole and 8-{(Z)-1-[(Z)-1-(2-fluorophenyl)hydrazono]ethyl}-7-methoxy-1-methyl-9H-pyrido[3,4-b]indole with biological targets dopamine D2 receptor and enzymes monoamine oxidase A and B is discussed. Harmine alkaloid derivatives were studied for antidepressant and analgesic activity. It was found that 8-{(Z)-1-[(Z)-(2-fluorophenyl) hydrazono]ethyl}-7-methoxy-1-methyl-9H-pyrido[3,4-b]indole at a dose of 10 mg/kg exhibited antidepressant effect in the Porsolt behavioral despair test. (Z)-8-(1-Hydrazonoethyl)-7-methoxy-1-methyl-9H-pyrido[3,4-b]indole has a pronounced analgesic activity. Modeling of biological activity using PASS software predicted HIV attachment inhibiting, antimycobacterial, antituberculosic, histamine release inhibiting, cytochrome P450 stimulating, and various antineoplastic activities for synthesized harmine derivatives with high probability. [ABSTRACT FROM AUTHOR]

Studies have found that repetitive transcranial magnetic stimulation rTMS can produce antidepressant effects by affecting inflammatory cytokines in patients with depression, which plays a key role in the therapeutic mechanism of antidepressants. This study aimed to explore the changes in inflammatory cytokine levels in patients with depression after 4 weeks of rTMS treatment to determine the possible antidepressant mechanism of rTMS. This prospective, double-blind, pseudo-stimulus-controlled study was conducted, and a total of 57 patients with depression and 30 healthy controls were recruited. Patients were randomly divided into the active rTMS (n = 29) and sham rTMS groups (n = 28). The Hamilton Depression Scale was used to evaluate depressive symptoms and their severity. The serum levels of seven inflammatory cytokines were measured using enzyme-linked immunosorbent assay. Inflammatory cytokines include high-sensitivity C-reactive protein (CRP-hc); tumor necrosis factor (TNF-α); interferon (IFN-γ); interleukin-2 (IL-2); interleukin-4 (IL-4); interleukin-6 (IL-6); and interleukin-8 (IL-8). At baseline, TNF-α (F = 36.699, p < 0.001), IFN-γ (F = 8.907, p < 0.001), IL-4 (F = 66.256, p < 0.001), and IL-2 (F = 9.162, p < 0.001) levels in the depression group were significantly different from those of healthy controls. In the self-control analysis of the active rTMS group, the levels of IL-2 and CRP-hc increased significantly after 2 and 12 weeks of treatment. In the sham-rTMS group, IFN-γ increased after 2 and 12 weeks of treatment. Our results revealed that the changes in inflammatory cytokines after rTMS treatment showed different patterns compared to the sham group, suggesting that the antidepressant effect of rTMS may be related to changes in inflammatory cytokines.

Depression is closely linked to hypothalamus-pituitary-adrenal axis hyperactivity. Honokiol, a biphenolic lignan compound obtained from the traditional Chinese medicine Magnolia officinalis, can reduce the activity of the hypothalamus-pituitary-adrenal axis and improve depression-like behavior caused by hypothalamus-pituitary-adrenal axis hyperactivity. The current study investigated the specific mechanism of action of this effect. A depression model was established by repeated injections of corticosterone to study the antidepressant-like effect of honokiol and its potential mechanism. Honokiol prevented the elevated activity of the hypothalamus-pituitary-adrenal axis and the depression-like behavior induced by corticosterone. Treatment with honokiol resulted in greater glucocorticoid receptor mRNA expression, greater glucocorticoid receptor-positive expression, and a greater ratio of glucocorticoid receptor to the mineralocorticoid receptor in the hippocampus. Moreover, honokiol treatment led to lower levels of interleukin-1β in serum and the positive expression of the interleukin-1β receptor in the hippocampus. These results demonstrate that the antidepressant-like mechanism of honokiol, which has effects on inflammatory factors, may act through restoring the typical activity of the hypothalamus-pituitary-adrenal axis by regulating the glucocorticoid receptor-mediated negative feedback mechanism and the balance between glucocorticoid and mineralocorticoid receptors.

The aim of this study was to evaluate whether an aqueous extract of Azadirachta indica A. Juss. (A. indica) flower had anxiolytic and antidepressant-like effects in the stressed rats. Male Wistar rats were randomly allocated to one of two experimental groups: control or stress. The stress groups were received restraint stress for 3 h. The stressed rats were administered a vehicle, diazepam, fluoxetine, and A. indica at doses of 250, 500, and 1000 mg/kg BW for 30 days. The elevated plus-maze test (EPMT), the forced swimming test (FST), and the open field test (OFT) were used to assess anxiolytic and antidepressant-like behaviors. In the EPMT, the percentage of the number of open arm entries and the duration spent in open arms were measured. These measurements were considerably enhanced in the stressed rats treated with diazepam and A. indica flower extract at a dose of 500 mg/kg BW. Furthermore, the stressed rats given fluoxetine and A. indica flower extract at all doses employed in this study showed a significant reduction in the amount of time the rats were immobilized in the FST. However, there was no significant difference in spontaneous locomotor activity between any of the groups. Additionally, the stressed rats treated with either positive control medications or A. indica flower extract exhibited significantly higher brain dopamine (DA) and serotonin (5-HT) levels, but lower blood cortisol levels as compared to the stressed rats treated with vehicle. Moreover, A. indica flower extract had no harmful effect on the stressed rats’ liver tissue.

• ECH inhibits oxidative stress and apoptosis and alleviates depression-like behaviors in PSD rats. • ECH exerts antidepressant effects through activation of the BDNF / TrkB signaling axis. • ECH up-regulates Nrf2 by promoting Nrf2 acetylation, enhances the transcriptional activity of BDNF and ultimately activates the BDNF/TrkB signaling axis. 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. 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. 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. 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). 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. [Display omitted] [ABSTRACT FROM AUTHOR]

The endocannabinoid 2‐arachidonoylglycerol (2‐AG) is an atypical neurotransmitter synthesized on demand in response to a wide range of stimuli, including exposure to stress. Through the activation of cannabinoid receptors, 2‐AG can interfere with excitatory and inhibitory neurotransmission in different brain regions and modulate behavioural, endocrine and emotional components of the stress response. Exposure to chronic or intense unpredictable stress predisposes to maladaptive behaviour and is one of the main risk factors involved in developing mood disorders, such as major depressive disorder (MDD). In this review, we describe the molecular mechanisms involved in 2‐AG signalling in the brain of healthy and stressed animals and discuss how such mechanisms could modulate stress adaptation and susceptibility to depression. Furthermore, we review preclinical evidence indicating that the pharmacological modulation of 2‐AG signalling stands as a potential new therapeutic target in treating MDD. Particular emphasis is given to the pharmacological augmentation of 2‐AG levels by monoacylglycerol lipase (MAGL) inhibitors and the modulation of CB2 receptors. [ABSTRACT FROM AUTHOR]

Objective: To study the antidepressant-like effect and action mechanism of geniposide and eleutheroside B combination treatment on the lipopolysaccharide (LPS)-induced depression mice model. Methods: Depression mice model was established by lipopolysaccharide (LPS) injection. Totally 48 mice were randomly divided into 6 groups (8 rats per group) according to a random number table, including normal, model, fluoxetine (20 mg/kg), geniposide (100 mg/kg) + eleutheroside B (100 mg/kg), geniposide + eleutheroside B + WAY 100635 (0.03 mg/kg), geniposide + eleutheroside B+ N-methyl-D-aspartic acid receptor (NMDA, 75 mg/kg) groups, respectively. After continuous administration for 10 days, autonomic activity tests after 30 min of administration were performed on the 10th day. On the 11th day, except for the normal group, the mice in the other groups were intraperitoneally injected with LPS (1 mg/kg), and the behavioral tests were performed 4 h later. Enzyme linked immunosorbent assay was used to detect tumor necrosis factor alpha (TNF- α) and interleukin-1 β (IL-1 β) levels in mice serum. The mRNA expression of indoleamine 2,3-dioxygenase (IDO) and nuclear transcription factor (NF- κB) were detected by real-time quantitative polymerase chain reaction. Western-blot analysis was used to detect IDO and NF- κB protein expressions in hippocampus tissue. Results: Compared with the normal group, a single administration of LPS increased the immobility time in the forced swimming test (FST) and tail suspension test (TST, P<0.01), without affecting autonomous activity. Compared with the model group, fluoxetine and geniposide + eleutheroside B administration significantly improved the immobility time of depressed mice in the FST and TST, decreased serum IL-1 β content, inhibited the expression levels of NF- κ B gene and protein in hippocampus tissues (P<0.05 or P<0.01). Compared with the model group, geniposide + eleutheroside B treatment significantly reduced serum TNF-α content and inhibited IDO mRNA and protein expressions in hippocampus (P<0.05 or P<0.01). In addition, NMDA partly prevented the inhibition of IDO mRNA expression by geniposide + eleutheroside B; NMDA and WAY-100635 also partly prevented the reduction of IL-1 ß content induced by geniposide + eleutheroside B treatment (P<0.05 or P<0.01). Conclusions: The combination of geniposide and eleutheroside B showed a certain antidepression-like effect. Its main mechanism of action may be contributed to inhibiting the activation of NF- κB, decreasing the proinflammatory cytokines such as TNF-α, IL-1 β, and inhibiting in the neuroinflammatory reaction. Additionally, it also affects tryptophan metabolism, reduces the expression of a key enzyme of tryptophan metabolism, IDO. And this antidepressant-like effect may be mediated by 5-hydroxytryptamine and glutamate systems. [ABSTRACT FROM AUTHOR]

Zhi-zi-chi Decoction (ZZCD), composed of Fructus Gardeniae (Zhizi in Chinese, ZZ in brief) and Semen sojae praeparatum (Dandouchi in Chinese, DDC in brief), has been used as a drug therapy for depression for thousands of years in China. However, the antidepressant mechanism of ZZCD still remains unknown. This study was aimed at exploring antidepressant effects of ZZCD from the aspect of neuroprotection based on herb compatibility. Glutamate-treated PC12 cells and chronic unpredictable mild stress (CUMS)-induced rats were established as models of depression in vitro and in vivo respectively. Cell viability, lactate dehydrogenase (LDH), apoptosis rate, reactive oxygen species (ROS), glutathione reductase (GR) and superoxide dismutase (SOD), and the expressions of Bax, Bcl-2 and cyclic adenosine monophosphate-response element binding protein (CREB) were measured to compare neuroprotection among single herbs and the formula in vitro. Behavior tests were conducted to validate antidepressant effects of ZZCD in vivo. Results showed that the compatibility of ZZ and DDC increased cell viability and activities of GR and SOD, and decreased the levels of LDH, apoptosis cells and ROS. Besides, the expressions of Bcl-2 and CREB were up-regulated while that of Bax was down-regulated by ZZCD. Furthermore, the compatibility of ZZ and DDC reversed abnormal behaviors in CUMS-induced rats and displayed higher efficacy than any of the single herbs. This study revealed that the antidepressant effects of ZZCD were closely associated with neuroprotection and elucidated synergistic effects of the compatibility of ZZ and DDC based on it.

We assessed the antidepressant-like effects of environmental enrichment (EE) and physical exercise (PE) compared with the selective serotonin reuptake inhibitor fluoxetine against the depression-related neurobehavioral alterations induced by postweaning social isolation (SI) in rats. After 1 month of SI, rats were submitted to PE (treadmill), EE, or fluoxetine (10 mg/kg), which were compared with naïve SI and group-housed rats. After 1 month, behavior was analyzed in the open field (OFT), the sucrose preference (SPT), and the forced swimming (FST) tests. Afterward, the hippocampal serotonin contents, its metabolite, and turnover were measured. SI induced a depression-related phenotype characterized by a marginal bodyweight gain, anxiety, anhedonia, behavioral despair, and alterations of serotonin metabolism. EE produced the widest and largest antidepressive-like effect, followed by PE and fluoxetine, which were almost equivalent. The treatments, however, affected differentially the neurobehavioral domains investigated. EE exerted its largest effect on anhedonia and was the only treatment inducing anxiolytic-like effects. Fluoxetine, in contrast, produced its largest effect on serotonin metabolism, followed by its anti-behavioral despair action. PE was a middle-ground treatment with broader behavioral outcomes than fluoxetine, but ineffective to reverse the serotonergic alterations induced by SI. The most responsive test to the treatments was the FST, followed closely by the SPT. Although OFT locomotion and body weight varied considerably between groups, they were barely responsive to PE and fluoxetine. From a translational standpoint, our data suggest that exercise and recreational activities may have broader health benefits than antidepressants to overcome confinement and the consequences of chronic stress.

One of the main tasks of modern pharmacology is the development of new methods for correcting various stress-induced states. An essential role in solving this problem can be played by herbal medicinal products. A special interest is represented by Astragalus vulpinus Willd - a plant of a large Astragalus genus of the legume family (Fabaceae),growing in the Astrakhan Region. The aim of the study is to investigate the effect of the Astragalus vulpinus Willd extract on the psychoemotional state of animals against the background of informational overload (IО). Materials and methods. The experiment was performed on nonlinear male rats. All the manipulations with the animals were carried out according to the rules and principles of work with laboratory animals. The animals were divided into groups: Group 1 - control rats; Group 2 – the animals exposed to IО for 20 days; Group 3 – the animals treated with intragastric liquid extract of Astragalus vulpinus Willd in the dose of 50 mg / kg /a day for 14 days and exposed to IО;Group 4 – the animals treated with the comparative drug of Phenibut in the dose of 25 mg / kg for 14 days against the background of informational overload. The IO model was a multi-alternative labyrinth in which food-producing skills were formed. The psychoemotional state of rats was studied in the “Suok-test” (ST), which is a complex of several classical behavioral models. Results and discussion. The study of laboratory animals’ behavior in the “Suok-test” against the background of informational overload showed the formation of the state of increased anxiety, which was manifested by a decrease in the motor and research activity of white rats. It was established that the Astragalus vulpinus Willd extract has an anxiolytic and antidepressant effect, eliminating manifestations of an anxiety-depressive state developing against the background of informational overload. Conclusion. Estimating the influence of the Astragalus vulpinus Willd extract in comparison with the activity of Phenibutum, it can be concluded that the investigated drugs eliminate the changes in the psychoemotional state of the anxiety-depressive character, demonstrating a practically comparable anxiolytic and antidepressant effect.

Valproic acid, beside its anticonvulsant action, is widely used as a mood stabilizer in the therapy of bipolar disorder. The potential antidepressant action of valproic acid has not been sufficiently characterized so far. The aim of the present study was to evaluate the antidepressant effect of valproic acid in an aldosterone model of depression. Subchronic treatment with valproic acid resulted in a reduction of the time spent in immobility in the forced swim test. In conclusion, the present study provides evidence on antidepressant effects of valproic acid using a classical behavioral approach for testing the efficacy of antidepressant drug in animal models.

Depression is a significant health issue with treatment resistance reported in about one third of patients. Treatment resistance results in significant disability, impaired quality of life, and increased healthcare costs. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for treatment resistant depression (TRD) with response and remission rates in open-label studies being as high as 58% and 37% respectively. Theta-burst is a faster and novel rTMS paradigm that has shown promise as a treatment for TRD in some preliminary studies. In a naturalistic design, we evaluated the response, remission and tolerability of bilateral sequential (right then left) prefrontal theta-burst rTMS (bsTBS) in 50 patients with TRD (600 pulses/session, 20 sessions, 100% of resting motor threshold (80% if intolerant to 100%, n = 2), F4/F3 of 10-20-20 EEG localization). Data was collected over 36 months from a specialized academic TMS clinic. Patients had multiple-treatment resistance with at least two failed trials of different antidepressants with 20% also having failed electroconvulsive therapy and 66% having received professional therapy. We found a 28% remission rate (HAMD-17 score of ≤7) and a 52% response rate (≥50% reduction in HAMD-17) with a 42% reduction in average HAMD-17 score. The treatment was well tolerated, with muscle contractions, mild pain or discomfort, headache, scalp irritation, and changes to vitals being captured as occasional adverse events with two instances of syncope (0.22% of treatments). This naturalistic study shows that bsTBS is a promising paradigm for a multiple-TRD patient population with approximately one-third of treatments achieving remission and over half achieving significant response. [ABSTRACT FROM AUTHOR]

Ginsenoside Rk1, a saponin component produced by heat-processed ginseng, possesses anti-inflammatory and antitumor activities. The aim of our study was to explore the effects of Rk1 on Lipopolysaccharide (LPS)-induced depression-like behavior in mice and to observe its effects on oxidative stress, the inflammatory response and brain-derived neurotrophic factor (BDNF) - tropomyosin-related kinase B (TrkB) signaling. After mice were pretreated with Rk1 (5, 10, and 20 mg/kg), the immobility time in both the forced swimming test (FST) and the tail suspension test (TST) was reduced, suggesting that Rk1 effectively improved depression-like symptoms. Rk1 (10 and 20 mg/kg) and Fluoxetine (Flu, 20 mg/kg) increased the activity of the antioxidant enzyme SOD in the brain and protected against lipid peroxidation. Different concentrations of Rk1 (10 and 20 mg/kg) and Flu significantly decreased the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 in serum, while Rk1 (5, 10, and 20 mg/kg) and Flu reduced the concentrations of IL-6 in a dose-dependent manner. Western blot analysis showed that the administration of Rk1 (20 mg/kg) and Flu significantly downregulated the level of Sirt1 and that Rk1 (5, 10, and 20 mg/kg) and Flu inhibited the p-NF-κb/NF-κb and p-IκB-α/IκB-α ratios, which indicated that the neuroprotective effect of Rk1 may be related to the suppression of inflammation. In addition 5, 10 and 20 mg/kg Rk1 significantly attenuated the LPS-induced decreases in BDNF and TrkB. These results indicated that Rk1 acts as an antidepressant through its antioxidant activity, the inhibition of neuroinflammation, and the positive regulation of the BDNF-TrkB pathway. This study may help develop active ginsenoside-based compounds for neurodegenerative diseases. • Ginsenoside Rk1 ameliorates LPS-induced depressive behavior in mice. • Ginsenoside Rk1decreses oxidative damage and neuroinflammation. • The effect of Ginsenoside Rk1 on protein change of NF-κB and BDNF-TrKB induced by lipopolysaccharide was studied. [ABSTRACT FROM AUTHOR]

Gastrodigenin, also known as 4-hydroxybenzyl alcohol (HBA), is one of the main components of Gastrodia elata, which is a perfect lead compound of natural products. In order to get new active compounds, we modified the structure of HBA through esterification with carboxylic acid, and got a series of derivatives in which 4-hydroxybenzyl alcohol 2-naphthoate (NHBA) showed stronger antidepressant activity than HBA. In this paper, we firstly evaluated the antidepressant activity of NHBA by tail suspension test (TST) and forced swimming test (FST). Then, we carried out the biochemical assay and western blot to determine its mechanism. The results displayed that NHBA could increase the content of serotonin, dopamine, norepinephrine, γ-aminobutyric acid, brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in mice brain. It suggested that NHBA exhibited an antidepressant-like effect through monoaminergic system, GABAergic system and BDNF/TrkB signaling pathways. [ABSTRACT FROM AUTHOR]

We assessed the antidepressant-like effects of environmental enrichment (EE) and physical exercise (PE) compared with the selective serotonin reuptake inhibitor fluoxetine against the depression-related neurobehavioral alterations induced by postweaning social isolation (SI) in rats. After 1 month of SI, rats were submitted to PE (treadmill), EE, or fluoxetine (10 mg/kg), which were compared with naïve SI and group-housed rats. After 1 month, behavior was analyzed in the open field (OFT), the sucrose preference (SPT), and the forced swimming (FST) tests. Afterward, the hippocampal serotonin contents, its metabolite, and turnover were measured. SI induced a depression-related phenotype characterized by a marginal bodyweight gain, anxiety, anhedonia, behavioral despair, and alterations of serotonin metabolism. EE produced the widest and largest antidepressive-like effect, followed by PE and fluoxetine, which were almost equivalent. The treatments, however, affected differentially the neurobehavioral domains investigated. EE exerted its largest effect on anhedonia and was the only treatment inducing anxiolytic-like effects. Fluoxetine, in contrast, produced its largest effect on serotonin metabolism, followed by its anti-behavioral despair action. PE was a middle-ground treatment with broader behavioral outcomes than fluoxetine, but ineffective to reverse the serotonergic alterations induced by SI. The most responsive test to the treatments was the FST, followed closely by the SPT. Although OFT locomotion and body weight varied considerably between groups, they were barely responsive to PE and fluoxetine. From a translational standpoint, our data suggest that exercise and recreational activities may have broader health benefits than antidepressants to overcome confinement and the consequences of chronic stress. [ABSTRACT FROM AUTHOR]

Carnitine is synthesized both by endogenous biosynthesis in the body and is taken from foods with daily diet. Carnitine (trimethyl amino-ß-hydroxybutyrate) is present in cells and tissues as both free carnitine and acylcarnitins, including acetyl-L-carnitine. Carnitine acts as a carrier of mitochondria for the ß-oxidation of long chain fatty acids. Carnitine is also important in the transport of other metabolites due to its ability to form esters with carboxylic acids. Carnitine also plays a role in the nervous system by modulating the activity of neurotransmitters. Depression is a disorder associated with a significant decrease in quality of life, increased physical comorbidities, and increased mortality. It is thought that changes in fatty acids and lipid metabolism occur in individuals with depression. Therefore, when carnitine is thought to modulate the activity of various neurotrophic factors, cell membranes, lipid metabolism and neurotransmitters in nerve tissues, carnitine supplementation has been suggested to have a potential role as an alternative therapeutic agent to antidepressants. Carnitine is common in the brain and has a stimulating effect on cholinergic receptors. In addition, carnitine exhibits neuromodulatory effect and increases dopamine release and increases gamma-aminobutyric acid. Carnitine has antioxidant and neurotrophic effects in nervous system. Animal and human model clinical studies have shown positive effects of carnitine on depression. Studies have shown that L-carnitine has similar effects with antidepressant drugs and has lower side effects. It is thought that carnitine supplementation may have an effective role in the treatment of depression due to its antidepressant and neurotrophic effects. [ABSTRACT FROM AUTHOR]

• IV ketamine is effective and tolerable in the management of TRD in clinic. • IV ketamine is effective and tolerable in the management of suicidal ideation. • Age, sex, marital status, or pharmacotherapy did not impact IV ketamine effect. Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen's D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice. [ABSTRACT FROM AUTHOR]

Magnetic seizure therapy is a novel form of focal convulsive treatment wherein magnetic field passes through the scalp and skull without impedance. In many ways, it has the potential to be superior to electroconvulsive therapy (ECT) as the anesthesia-associated side effects and cognitive impairments are less. It also may be an alternative for those who do not opt for ECT because of the stigma associated with it.

Bright light treatment is a treatment modality that leads elevation of mood due to attenuation in depressive symptoms, regulation in circadian rhythm activity, increase the effect of antidepressants and amelioration in sleep quality. Bright light treatment is considered among the first-line treatments for seasonal affective disorder because of high response rates. Additionally, bright light treatment being extended to other conditions, including non-seasonal mood disorders, Alzheimer's disease, circadian rhythm sleep disorders, eating disorders, attention deficit hyperactivity disorder and other behavioral syndromes is likely to have a far reached use. Side effects are often temporary and can generally be overcome by reducing exposure time. The central focus on this paper is to review the action mechanisms, efficacy, usage areas, the ways of administration and side effects of the light treatment. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2017; 9(2.000): 177-188]

3-iodothyroacetic acid (TA1), an end metabolite of thyroid hormone, has been shown to produce behavioral effects in mice that are dependent on brain histamine. We now aim to verify whether pharmacologically administered TA1 has brain bioavailability and is able to induce histamine-dependent antidepressant-like behaviors. TA1 brain, liver and plasma levels were measured by LC/MS-MS in male CD1 mice, sacrificed 15 min after receiving a high TA1 dose (330 μgkg–1). The hypothalamic mTOR/AKT/GSK-β cascade activation was evaluated in mice treated with 0.4, 1.32, 4 μgkg–1 TA1 by Western-blot. Mast cells were visualized by immuno-histochemistry in brain slices obtained from mice treated with 4 μgkg–1 TA1. Histamine release triggered by TA1 (20–1000 nM) was also evaluated in mouse peritoneal mast cells. After receiving TA1 (1.32, 4 or 11 μgkg–1; i.p.) CD1 male mice were subjected to the forced swim (FST) and the tail suspension tests (TST). Spontaneous locomotor and exploratory activities, motor incoordination, and anxiolytic or anxiogenic effects, were evaluated. Parallel behavioral tests were also carried out in mice that, prior to receiving TA1, were pre-treated with pyrilamine (10 mgkg–1; PYR) or zolantidine (5 mgkg–1; ZOL), histamine type 1 and type 2 receptor antagonists, respectively, or with p-chloro-phenylalanine (100 mgkg–1; PCPA), an inhibitor of serotonin synthesis. TA1 given i.p. to mice rapidly distributes in the brain, activates the hypothalamic mTOR/AKT and GSK-3β cascade and triggers mast cells degranulation. Furthermore, TA1 induces antidepressant effects and stimulates locomotion with a mechanism that appears to depend on the histaminergic system. TA1 antidepressant effect depends on brain histamine, thus highlighting a relationship between the immune system, brain inflammation and the thyroid.