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Background: Depression is a common mental illness with more than 280 million sufferers worldwide. Inflammation, particularly the c-Jun amino-terminal kinase (JNK) pathway, contributes to depression development and neuronal apoptosis. Gardenia is a herb with therapeutic effects on depression that has been shown to inhibit neuronal apoptosis. However, one of the components in gardenia, Genipin 1-O-β-D-gentiobioside(GG), has been less studied for its mechanism on depression. Thus, in the current study, we investigate how Genipin 1-O-β-D-gentiobioside improves depression and elucidate its possible mechanism of action., Methods: In this investigation, we utilize a chronic unpredictable mild stress (CUMS) mouse model and corticosterone-induced primary cortical neurons to examine the role of GG in ameliorating depressive symptoms and neuronal apoptosis. TUNEL staining and flow cytometry assessed the effects of GG on neuronal apoptosis. Western Blot analyses and immunofluorescence assays apoptosis-related proteins in the prefrontal cortex and primary neurons. The site of action of GG in regulating homeodomain interacting protein kinase 2 (HIPK2) SUMOylation was further explored in primary neurons. We constructed siRNA-SUMO1 vectors to transfect primary neuronal cells with intracellular SUMO1 knockdown. Proximity ligation assay (PLA) experiments were performed on primary neurons according to the instructions of the assay kit to observe the physical relationship between HIPK2 and SUMO1. We predicted the HIPK2 SUMOylation modification site by an online database and constructed vectors to target and site-directed mutagenesis, then to transfected primary neuronal cells., Results: The results showed that GG effectively alleviated depressive-like behaviours, down-regulated apoptosis-related proteins (p-JNK, Bax, Cleaved-Caspase-3), and inhibited neuronal apoptosis in CUMS-induced depressed mice and corticosterone-induced primary cortical neurons. We reveal a complex mechanism underlying the link between GG, SUMOylation of HIPK2, and complex pathways of neuronal apoptosis regulation. K326 and K1189 are the key SUMOylation sites regulated by GG in intricate interactions of apoptosis-related proteins., Conclusion: Our study demonstrated that GG exerts antidepressant-like actions through neuroprotective effects by inhibiting the apoptosis of prefrontal cortex neurons, revealing the mechanism of GG inhibition of JNK phosphorylation by enhancing HIPK2 SUMOylation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is a serious mental disorder that threatens patients' physical and mental health worldwide. The activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is essential for microglia-mediated neuroinflammation and neuronal damage in depression. Numerous pathophysiological factors, such as mitochondrial dysfunction and impaired mitophagy, have an essential role in activating the NLRP3 inflammasome. AdipoRon is a potent adiponectin receptor agonist; however, its antidepressant effects have not been thoroughly investigated. In this study, we found that AdipoRon ameliorated depression-like behavior and neuronal damage induced by chronic unpredictable mild stress (CUMS). Further research demonstrated that AdipoRon inhibited the activation of the NLRP3 inflammasome and protected hippocampal neurons from microglial cytotoxicity by promoting mitophagy, increasing the clearance of damaged mitochondria, and reducing mtROS accumulation. Importantly, inhibition of mitophagy attenuated the antidepressant and neuroprotective effects of AdipoRon. Overall, these findings indicate that AdipoRon alleviates depression by inhibiting NLRP3 inflammasome activation in microglia via improving mitophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The gut microbiota has been posited as a target for the treatment of major depressive disorder. Herein, we investigated the effect of the hydroethanolic leaf extract of Mallotus oppositifolius (MOE) on the gut microbiota of mice and how this contributes to its known antidepressant-like effect. A 6-week chronic unpredictable mild stress (CUMS) procedure was employed in 7 groups of mice to induce depression. From the third week, oral MOE treatments (10, 30, 100 mg/kg) and two reference drugs, fluoxetine (12 mg/kg) and minocycline (40 mg/kg), known to affect the gut microbiota, were administered. The sixth and seventh groups were the vehicle stressed (VEH-S) and non-stressed groups (VEH-NS). Changes in depressive-like behaviors were assessed using sucrose preference test while the forced swimming test (FST) was used to assess sustained antidepressant-effect after treatment discontinuation. Moreover, changes in prefrontal cortex (PFC) and hippocampal serotonin (5-HT) levels were evaluated using enzyme-linked immunosorbent assay (ELISA). The effect of treatment on the profile of the gut microbiota of the groups was elucidated using 16S rRNA Oxford Nanopore sequencing. MOE and reference drugs reversed the depression-associated reduction in sucrose preference when compared to VEH-S. MOE (with peak effect at 30 mg/kg) reduced immobility while increasing swimming and climbing behaviors. MOE reversed CUMS-induced reduction of 5-HT concentration in PFC and hippocampus. The behavioral effects of MOE were associated with shifts in the gut microbiota of CUMS-exposed mice. The study has provided seminal evidence that MOE ameliorates CUMS-induced depressive symptoms by modulating gut microbiota and increasing brain 5-HT levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

The efficacy and tolerability of current antidepressants for adolescent depression are inadequate. S-adenosylmethionine (SAMe), known for its effectiveness and minimal side effects in adult depression, remains unstudied in adolescents. This study explored the potential of SAMe to address depression-like behaviors in juvenile rats induced by chronic unpredictable mild stress (CUMS), with a focus on gut microbiome interactions. Adolescent male Wistar rats were subjected to a 4-week CUMS regimen and received daily intraperitoneal injections of 300 mg/kg SAMe. Behavioral assessments included the sucrose preference test, elevated plus maze test, open field test, and Y-maze test. Histopathological changes of the hippocampus and colon were observed by Nissl staining and hematoxylin and eosin staining, respectively. Gut microbiome composition was analyzed using Accurate 16S absolute quantification sequencing. The results showed that SAMe significantly improved behavioral outcomes, reduced histopathological damages in hippocampal neurons and colon tissues, and modulated the gut microbiota of depressed rats. It favorably altered the ratio of Bacteroidetes to Firmicutes, decreased the absolute abundance of Deferribacteres, and adjusted levels of key microbial genera associated with depression-like behaviors. These results suggested that SAMe could effectively counter depression-like behaviors in CUMS-exposed adolescent rats by mitigating hippocampal neuronal and colon damage and modulating the gut microbiota. This supports SAMe as a viable and tolerable treatment option for adolescent depression, highlighting the importance of the gut-brain axis in therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with daily functioning and quality of life. Despite decades of research, the pathophysiology of depression remains incompletely understood. The correlation between depression and inflammation has recently attracted considerable attention. This study investigated the potential antidepressant effect of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, utilizing a chronic mild stress (CMS) model in rats. Male Wistar rats were divided into two groups; one following a non-stressed protocol and the other a stressed protocol for 5 weeks. From the beginning of the third week, rats were treated either with saline daily or with etanercept twice a week (0.3 mg/kg, i.p.) or with fluoxetine daily (10 mg/kg, i.p) as a reference. Etanercept exhibited comparable effects to those of fluoxetine in counteracting CMS-induced behavioral manifestation in the forced swimming and splash tests. Etanercept also restored serotonin and norepinephrine levels to control values in the prefrontal cortex (PFC). Moreover, the current study verified the antioxidant and anti-inflammatory effects of etanercept. Interestingly, etanercept halted the expression of both norepinephrine and serotonin transporters in stressed rats. This could be attributed to abrogation of the p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 3 (STAT-3) pathways in the PFC. The findings of the present study contribute to the understanding of the potential of etanercept as an antidepressant and provide insights into the neurobiological mechanisms underlying its therapeutic effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression currently ranks as the fourth leading cause of disability globally, affecting approximately 20% of the world's population. we established a chronic restraint stress (CRS) induced depression model in mice and employed fluoxetine as a reference drug. We assessed the therapeutic potential of saffron essential oil (SEO) and elucidated its underlying mechanisms through behavioral indices and NMR-based metabolomic analysis. The findings indicate that SEO ameliorates behavioral symptoms of depression, such as the number of entries into the central area, fecal count, latency to immobility, and duration of immobility in both the Tail Suspension Test (TST) and the Forced Swim Test (FST), along with correcting the dysregulation of 5-serotonin. Metabolomic investigations identified sixteen potential biomarkers across the liver, spleen, and kidneys. SEO notably modulated nine of these biomarkers: dimethylglycine, glycerol, adenosine, β-glucose, α-glucose, uridine, mannose, sarcosine, and aspartate, with glycerol emerging as a common biomarker in both the liver and spleen. Pathway analysis suggests that these biomarkers participate in glycolysis, glycine serine threonine metabolism, and energy metabolism, potentially implicating a role in neural regulation. In summary, SEO effectively mitigates depressive-like behaviors in CRS mice, predominantly via modulation of glycolysis, amino acid metabolism, and energy metabolism, and potentially exerts antidepressant effects through neural regulation. Our study offers insights into small molecule metabolite alterations in CRS mice through a metabolomics lens, providing evidence for the antidepressant potential of plant essential oils and contributing to our understanding of the mechanisms of traditional Chinese medicine in treating depression., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ying Zhou reports financial support was provided by Zhejiang University of Technology. Ziwei Chen reports financial support was provided by Zhejiang University of Technology. Feng Su reports financial support was provided by Zhejiang University of Technology. Yi Tao reports financial support was provided by Zhejiang University of Technology. Ping Wang reports financial support was provided by Zhejiang University of Technology. Jinping Gu reports financial support was provided by Zhejiang University of Technology. Ying Zhou, Ziwei Chen, Feng Su,Yi Tao reports a relationship with Zhejiang University of Technology that includes: employment. Ping Wang, Jinping Gu reports a relationship with Zhejiang University of Technology that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mecamylamine, a noncompetitive blocker of nicotinic acetylcholine receptors (nAChRs), is the racemic mixture of two stereoisomers: S-(+)-mecamylamine (S-mec) and R-(-)-mecamylamine (R-mec), with distinct interactions with α4β2 nAChRs. It has been shown that mecamylamine increases glutamate release and excites serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN). In this study, we separately evaluated the effects of S-mec and R-mec on 5-HT neuron excitability. S-mec (3 μM) increased firing frequency by 40 %, while R-mec (3 μM) raised it by only 22 %. S-mec acts as a positive allosteric modulator on high-sensitivity (HS) α4β2 nAChRs at glutamate terminals, enhancing spontaneous excitatory postsynaptic currents (sEPSCs) in 5-HT neurons. Conversely, R-mec decreased sEPSCs by blocking HS α4β2 nAChRs and reduced GABA-mediated inhibitory currents (sIPSCs) by blocking α7 nAChRs at GABAergic terminals. These mechanisms make S-mec more effective than R-mec in enhancing 5-HT neuron firing. Moreover, combining S-mec with TC-2559, a selective agonist of HS α4β2 nAChRs, increased firing frequency by 65 %, exceeding the effect of S-mec alone. To validate these findings, we evaluated the antidepressant effects of S-mec (1 mg/kg) combined with TC-2559 or RJR-2403, another α4β2 nAChR agonist. This combination successfully reduced depression-like behaviors, suggesting a potential treatment strategy for patients resistant to conventional antidepressants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4-10) fragment, ACTH(4-7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4-10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4-10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4-10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with brain inflammation and neuronal damage. Derived from the Aesculus chinensis Bunge fruit, escin has shown anti-inflammatory and neuroprotective effects. However, its potential as a treatment for MDD is unclear. This study investigates the antidepressant properties of escin using in vivo experimentation. The chronic unpredictable mild stress (CUMS) model was used to analyze the potential antidepressant effects and underlying mechanisms of escin. Wistar rats were exposed to CUMS for 35 consecutive days to induce MDD. The rats were then given either escin (1, 3, and 10 mg/kg) or fluoxetine (2 mg/kg) on a daily basis. Notably, escin significantly alleviated the depressive behaviors induced by CUMS, as evaluated through a series of behavioral assessments. Moreover, escin administration reduced TNF-α, IL-1β, and IL-6 levels in the hippocampus. It also decreased serum adrenal cortical hormone (ACTH) and corticosterone (CORT) levels while increasing 5-HT and Brain-derived neurotrophic factor (BDNF) levels in the CUMS rats, as measured by the enzyme-linked immunosorbent assay (ELISA). Pathological changes in the hippocampal regions were identified through Nissl staining, and Western blotting was used to quantify the protein levels of BDNF, TrkB, CREB, TLR4, MyD88, and NF-κB. Escin mitigated neuronal injury, elevated TrkB, BDNF, and CREB, and reduced TLR4, MyD88, and NF-κB protein levels in CUMS rats. The data from this study suggest that escin holds the potential for alleviating depression-like symptoms induced by CUMS. This effect may be mediated through the modulation of two signaling pathways, BDNF/TrkB/CREB and TLR4/MyD88/NF-κB., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the research and/or publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown., Methods: We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1β. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1 + microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons., Results: DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1β signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons., Conclusions: Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1β signaling pathway and alleviating hyperactivity of BLA neurons., (Copyright © 2024 Elsevier B.V. All rights reserved.)

β-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of β-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and β-arrestin2 -/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the β-arrestin2 -/- CMS group, these results of the β-arrestin2 -/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out β-arrestin2. Mass spectrometry implying that FLX promoted the binding of β-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT 2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to β-arrestin2. We further found that the lack of β-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, β-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT 2B R-β-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-β (TGF-β) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

TMP269, a class IIA histone deacetylase inhibitor with selectivity, that has a protective effect on the central nervous system, yet its specific mechanism of action remains ambiguous. Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that histone deacetylase 5 plays a key role in the pathological process of depression and the fact that preclinical studies have shown HDAC5 to be a potential antidepressant target, the search for natural drugs or small molecule compounds that can target HDAC5 may be a potential therapeutic strategy for the treatment of depression. In addition, we examined the role of the Brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for neuronal survival and growth, as a potential downstream target of HDAC5. We found downward revision of HDAC5 levels in the hippocampus ameliorated depressive-like behavior in LH (Learned helplessness) mice. Furthermore, injection of HDAC5 overexpressing adenoviral vectors in the hippocampal dentate gyrus of wild-type mice produced a somewhat depressive-like phenotype. Pharmacological, immunofluorescence and biochemical experiments showed that TMP269 could produce antidepressant effects by inhibiting mouse hippocampal HDAC5 and thus modulating its downstream BDNF. Over all, TMP269 mitigated LH-induced depressive-like behaviors and abnormalities in synapse formation and neurogenesis within the hippocampus. These findings suggest potential beneficial effects of TMP269 on depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The present research study aimed to investigate the role of Ascorbic acid (AA) on synaptic plasticity, learning, and memory impairment induced by unpredicted chronic mild stress (CUMS) in adolescent male rats. Adolescent male rats were divided into: 1) vehicle, 2) CUMS, 3-5) CUMS plus various doses of AA by oral gavage (CUMS-10/100/400 mg/kg), and 6) AA400 mg/kg by oral gavage. In Morris Water Maze, the time latency decreased, while the time spent in the target quadrant increased in CUMS group treated with AA at the dose of 400 mg/kg. In passive avoidance, the latency of entering into the dark chamber decreased in CUMS group treated with AA (400 mg/kg). In biochemical test results, nitrite and MDA significantly decreased, while thiol content, SOD, and catalase activity in CUMS group that received AA400mg/kg was increased. IL-10, BDNF and Ki67 increased, while TNF-a and AChE activity were decreased in CUMS group treated with AA simultaneously. The results of our study showed that chronic stress during adolescence could cause learning and memory disorders as well as synaptic plasticity. In addition, we showed that AA can prevent this problem by reducing oxidative stress, inflammation, increasing the amount of BDNF, and neurogenesis., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress., Competing Interests: Declaration of competing interest All authors declare that they have no competing financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present study aimed at investigating the pharmacokinetics of paroxetine, after its intranasal instillation and assessing its potential therapeutic effect on female and male mice subjected to unpredictable chronic mild stress (UCMS) protocol. IN administration revealed direct nose-to-brain paroxetine delivery but dose- and sex-dependent differences. Pharmacokinetics was nonlinear and paroxetine concentrations were consistently higher in plasma and brain of male mice. Additionally, UCMS decreased animal preference for sucrose in both male and female mice following acute (p < 0.01) and chronic stress (p < 0.05), suggesting anhedonia. Both male and female mice exhibited depressive-like behavior in the forced swimming test. UCMS females displayed a significantly longer immobility time and shorter climbing time than the control group (p < 0.05), while no differences were found between male mice. Two weeks of paroxetine intranasal administration reduced immobility time and lengthened climbing and swimming time, approaching values similar to those observed in the healthy control group. The therapeutic effect was stronger on female mice. Importantly, melatonin plasma levels were significantly decreased in female mice following UCMS (p < 0.05), while males exhibited heightened corticosterone levels. On the other hand, treatment with IN paroxetine significantly increased corticosterone and melatonin levels in both sexes compared to healthy mice (p < 0.05). Intranasal paroxetine delivery undoubtedly ameliorated the behavioral despair, characteristic of depressive-like animals. Despite its efficiency in male and female mice subjected to UCMS, females were more prone to this novel therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Baicalin has various neuroprotective effects in models of nervous system disease. Our study has shown baicalin could alleviate depressive-like behaviors in a neuroendocrine mouse model. But the systematic metabolic characteristic and particular targets of baicalin in regulating depressive behaviors have never been investigated. Therefore, this study aims to reveal the hippocampal metabolic profiling of chronic unpredictable mild stress (CUMS) induced depressive rats and the potential metabolic variations after baicalin treatment. We first used the sucrose preference test and open field test to access the antidepressant effects of baicalin. Then, metabolites of the hippocampus after baicalin therapy were monitored by widely-targeted metabolomics based on ultra-performance liquid chromatography-tandem mass spectrometry technology. Finally, the potential mechanism associated with neurogenesis obtained from metabolomics was verified by immunohistochemistry. The results showed that baicalin(40,80 mg/kg) could significantly alleviate depressive behaviors induced by CUMS as demonstrated by an increase in sucrose preference and movement distance and stand-up times in open field test. In the metabolomic analysis, a total of 733 metabolites were identified after baicalin treatment including 15 differential metabolites such as organic acid and its derivatives, heterocyclic compounds, fatty acid, bile acids, amino acid and its metabolites, and so on. Enrichment for differential metabolites showed that the differential metabolites might be involved in the process of folate and cofactor biosynthesis, cholesterol metabolism, primary bile acid biosynthesis, tyrosine metabolism and dopaminergic synapse. Moreover, immunohistochemical analysis confirmed baicalin could facilitate hippocampal neurogenesis of depressive rats in CUMS model. These results suggested baicalin might exert antidepressant effects through regulating the differential metabolites which might play a crucial role in inhibiting oxidative stress and improving neurogenesis. Our findings wish to discover the potential mechanism of baicalin on depression from the metabolomics perspective and promote its clinical application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

There is a body of evidence to suggest that chronic stress modulates neurochemical homeostasis, alters neuronal structure, inhibits neurogenesis and contributes to development of mental disorders. Chronic stress-associated mental disorders present common symptoms of cognitive impairment and depression with complex disease mechanisms. P-coumaric acid (p-CA), a natural phenolic compound, is widely distributed in vegetables, cereals and fruits. p-CA exhibits a wide range of health-related effects, including anti-oxidative-stress, anti-mutagenesis, anti-inflammation and anti-cancer activities. The current study aims to evaluate the therapeutic potential of p-CA against stress-associated mental disorders. We assessed the effect of p-CA on cognitive deficits and depression-like behavior in mice exposed to chronic restraint stress (CRS); we used network pharmacology, biochemical and molecular biological approaches to elucidate the underlying molecular mechanisms. CRS exposure caused memory impairments and depression-like behavior in mice; p-CA administration attenuated these CRS-induced memory deficits and depression-like behavior. Network pharmacology analysis demonstrated that p-CA was possibly involved in multiple targets and a variety of signaling pathways. Among them, the protein kinase A (PKA) - cAMP-response element binding protein (CREB) - brain derived neurotrophic factor (BDNF) signaling pathway was predominant and further characterized. The levels of PKA, phosphorylated CREB (pCREB) and BDNF were significantly lowered in the hippocampus of CRS mice, suggesting disruption of the PKA-CREB-BDNF signaling pathway; p-CA treatment restored the signaling pathway. Furthermore, CRS upregulated expression of proinflammatory cytokines in hippocampus, while p-CA reversed the CRS-induced effects. Our findings suggest that p-CA will offer therapeutic benefit to patients with stress-associated mental disorders., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Depressive disorder is a psychiatric condition that is characterized by the core symptoms of anhedonia and learned helplessness. Myelination loss was recently found in the prefrontal cortex (PFC) of patients with depression and animal models, but the mechanism of this loss is unclear. In our previous study, chronic restraint stress (CRS) mice showed depressive-like symptoms. In this study, we found that myelin was reduced in the PFC of CRS mice. We also observed increased mammalian target of rapamycin (mTOR) phosphorylation levels in the PFC. Chronic injections of rapamycin, a mTOR complex inhibitor, prevented depressive behavior as shown by the forced swimming test and sucrose preference test. Rapamycin also increased myelination in the PFC of CRS mice. In summary, we found that CRS enhanced mTOR signaling and reduced myelination in the PFC and that rapamycin could prevent it. Our study provides the etiology of reduced myelin in depressive symptoms and suggests that mTOR signaling could be a target for treating depression or improving myelination deficits in depressive disorders., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Microglia-mediated inflammatory process is recognized as a target in the treatment of depression. Ginsenoside Rg1 (GRg1), the active ingredient of traditional ginseng, regulates microglial phenotypes to resist stress-induced inflammatory responses. Here we used a mouse model of stress-induced depression to investigate the involvement of microglial Nod-like receptor protein 3 (NLRP3) in the antidepressant effects of GRg1. Male C57BL/6J mice were exposed to chronic mild stress (CMS) for three weeks, followed by intraperitoneal injection of GRg1 (20 mg/kg) or the antidepressant imipramine (20 mg/kg) for another three weeks. Depressive-like behaviors were assessed by sucrose preference test, forced swimming test, and tail suspension test. Microglial phenotypes were assessed in terms of morphological features and cytokine profiles; inflammasome activity, in terms of levels of complexes containing NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1; and neurogenesis, in terms of numbers of proliferating, differentiating, and mature neurons identified by immunostaining. GRg1 reduced abnormal animal behaviors caused by CMS, such as anhedonia and desperate behaviors, without affecting locomotor behaviors. GRg1 also reduced the number of ASC-specks, implying inhibition of inflammasome activation, which was associated with weaker activation of pro-inflammatory microglia. At the same time, GRg1 rescued impairment of hippocampal neurogenesis in vivo and in vitro, which correlated with modulation of microglial phenotypes. GRg1 exert antidepressant effects by preventing stress from activating the NLRP3 inflammasome in microglia, promoting a proneurogenic phenotype and allowing adult hippocampal neurogenesis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this research., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Eucommia ulmoides Oliv (EUO) is a traditional therapeutic drug that tonifies the liver and kidney and may improve depression. However, the mechanism of action of the main component, aucubin (AU), is unknown. To study the therapeutic effect of AU, we constructed a chronic unpredictable mild stress (CUMS) depression model in mice. Depression-like behaviors, pathological damage, hormonal changes, inflammation, intranuclear expression of glucocorticoidreceptor (GR), and hippocampal protein expression were assessed. Immunofluorescence staining of the hippocampus showed that CUMS decreased neuronal regeneration, and axons were observed to be reduced and broken. Intracellular GR expression decreased in the hippocampus and hypothalamus, and serum levels of stress hormones increased. Furthermore, molecular changes indicative of pyroptosis were observed. AU administration reversed these changes and significantly improved the depression-like behavior induced by CUMS. Our results suggested that AU improves depression by promoting the intranuclear expression of GR and inhibiting nuclear factor-kappa B-mediated inflammatory activation-driven cell pyroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

An absence of reward in chronic stress may impair the reward circuit in the brain, resulting in major depressive disorder (MDD). In a part of chronically stressed individuals, MDD is not present, i.e., there is resilience, implying endogenous anti-depressive mechanisms in the brain. We studied social defeat model mice and analyzed the mRNA maps of the hippocampus from a control group and social defeat (SD)-susceptible and SD-resilient mice using high-throughput sequencing techniques. It was found that the immune response was associated with depression. Existing studies have proven that microglia play an important role in the brain immune response, and their activation level increases after chronic social defeat stress (CSDS). In our study, minocycline inhibited the activation of microglia, thereby improving the depressive state of CSDS mice. In addition, minocycline combined with fluoxetine enhanced the efficacy of fluoxetine. Thus, our results propose the most probable mechanism underlying different responses to CSDS and indicate the potential of a combination of anti-inflammatory drugs and antidepressants in treating refractory depression., (Copyright © 2023. Published by Elsevier Ltd.)

Depressive disorder is a psychiatric disease characterized by its main symptoms of low mood and anhedonia. Due to its complex etiology, current clinical treatments for depressive disorder are limited. In this study, we assessed the role of the δ opioid receptor (δOR) system in the development of chronic-restraint-stressed (CRS)-induced depressive behaviors. We employed a 21-day CRS model and detected the c-fos activation and protein levels' changes in enkephalin (ENK)/δOR. It was found that the hippocampus and amygdala were involved in CRS-induced depression. The expression of pro-enkephalin (PENK), the precursors of the endogenous ligand for δOR, was significantly decreased in the hippocampus and amygdala following CRS. We then treated the mice with SNC80, a specific δOR agonist, to examine its anti-depressant effects in the tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT). SNC80 administration significantly reversed depressive-like behaviors, and this antidepressant effect could be blocked by a TrkB inhibitor: ANA-12. Although ANA-12 treatment had no significant effect on the expression of ENK/δOR, it blocked the promoting effects of brain-derived neurotrophic factor (BDNF)/tyrosine kinase B(TrkB) signaling by SNC80 in the hippocampus and amygdala. Therefore, the present study demonstrates that SNC80 exerts anti-depressant effects by up-regulating the BDNF/TrkB signaling pathway in the hippocampus and amygdala in CRS-induced depression and provides evidence that δOR's agonists may be potential anti-depressant therapeutic agents., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pimavanserin is a highly selective 5-HT 2A inverse agonist in current medical use. Prior studies suggest that 5-HT 2A serotonin receptors may play a role in anxiety and emotional memory. Therefore, pimavanserin was tested in a rat model of PTSD to determine whether it might ameliorate PTSD-like symptoms. The lifetime prevalence of PTSD is estimated to be 125% higher in women than men. Consequently, in an effort to create a robust model of PTSD that was more representative of human PTSD prevalence, 20-week old female rats of the emotionally hyperreactive Lewis strain were used for these studies. The rats were single-housed and exposed twice to restraint stress coupled with predator odor or to a sham-stressed condition. Twenty days after the second stress or sham-stress exposure, rats were injected with saline alone or with 0.3 or 1.0 mg/kg pimavanserin, doses that were confirmed to substantially block 5-HT 2A receptor activity in this study without causing any non-specific behavioral or adverse effects. One hour later, rats were tested for anxiety through acoustic startle response, the elevated plus-maze and three parameters of open field behavior. Five days later, blood was sampled for plasma corticosterone. The stressed/saline-injected rats had higher anxiety scores and corticosterone levels than sham-stressed/saline-injected rats. Pimavanserin significantly and generally dose-dependently reversed these persistent stress effects, but had no significant effect on the behavioral measures in normal, non-stressed rats. These results, consistent with a role for the 5-HT 2A receptor, suggest that pimavanserin might have potential to reduce some consequences of traumatic stress., Competing Interests: Declaration of competing interest Supported by funding from Acadia Pharmaceuticals Inc. to the University of Houston-Clear Lake, and by the University of Houston-clear Lake Biobehavioral Research Fund. Co-author Ethan S. Burstein is an employee of Acadia Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Depression is a common disorder with a complex pathogenesis. Tanshinone IIA (TAN IIA) is a botanical agent with neuroprotective and antidepressant properties., Objective: To examine the effects of TAN IIA on chronic unpredictable mild stress (CUMS)-induced depression-like behavior and cognitive impairment in rats., Methods: Rats were exposed to CUMS for 4 weeks, followed by the oral administration of TAN IIA, Deanxit (DEAN), or normal saline for an additional 4 weeks. The control rats were fed with regular chow and administered with normal saline for 4 weeks. Behavioral tests were performed to assess the effects of TAN IIA on depression-like behavior and cognitive impairment in rats with CUMS. The morphology of dendrites was analyzed by Golgi staining. Immunofluorescence staining was performed to determine protein localization., Results: TAN IIA treatment ameliorated CUMS-induced depression-like behavior and cognitive impairment in rats. TAN IIA treatment also reversed the effects of CUMS on dendritic complexity and the levels of gamma-aminobutyric acid (GABA) in the hippocampus and prefrontal cortex. Rats with CUMS showed decreased levels of brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin receptor kinase B (TrkB), upregulated expression of GABA transporter 1 (GAT1), and reduced expression of synaptic proteins in the hippocampus, while TAN IIA treatment significantly diminished the effects of CUMS exposure. In addition, GAT1 was colocalized with N-methyl-D-aspartate receptor 2B., Conclusion: TAN IIA ameliorates CUMS-induced depression-like behavior and cognitive impairment in rats by regulating the BDNF/TrkB/GAT1 signaling pathway, suggesting that TAN IIA may be a candidate drug for the treatment of depression., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The World Health Organization (WHO) recorded approximately 350 million people worldwide have suffered from mental health disorders, such as depression, anxiety, schizophrenia, and addictive behaviors. The search for new drugs from nature has drawn on many biological resources and human practices. In this study, leaves of Polygonum minus standardized extract (Biokesum®), 1 and 100 mg/L were used to evaluate the anti-stress effect in the chronic unpredictable stress (CUS) zebrafish model. Five groups of zebrafish were manipulated in this study, comprising control, chronic unpredictable stress (CUS), CUS + Biokesum® 1 mg/L (4 days, 20 min/day, immersion) CUS + Biokesum® 100 mg/L (4 days, 20 min/day, immersion) and CUS + fluoxetine 0.6 mg/L (4 days, 20 min/day, immersion). Four different behavioral tests were used, i.e. open-field test, social interaction test, light and dark test, and exploratory test. After four consecutive days of treatment, the zebrafish were sacrificed for whole-body cortisol analysis. The exploratory test showed a significant change upon P. minus treatment (one-way ANOVA; p = 0.0011). Cortisol analysis showed a decrease of cortisol level after treatment with the extract and fluoxetine, without significant difference. These results showed that zebrafish is a reliable model to study the anti-stress effect of compounds or herbal extract., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The 3-[(4-methoxyphenyl)selanyl]-2-phenylimidazo[1,2-a] pyridine (MPI), a novel organic selenium compound, has been receiving increased attention due to its antioxidant effects and its ability to protect against depression-like behaviours. However, it remains elusive whether MPI is able to reverse depressive-like symptoms and biochemical alterations in mice. In the present work, we explored the ability of MPI (10 mg/kg, i.g.) to reverse inflammation- and stress-induced depression-like behaviours in mice injected with tumour necrosis factor (TNF-α) or submitted to acute restraint stress. Depression-like behaviours were evaluated by the tail suspension and splash test and the open field test was used to evaluate the locomotor activity of mice. The prefrontal cortex and hippocampus of mice were used for the evaluation of parameters of oxidonitrosative stress. Here, we showed that a single administration of MPI abolished the depressive-like behaviours induced by TNF-α and acute restraint stress. The oxidative and nitrosative stress presented in mice with depression-like behaviours were also decreased by MPI in the prefrontal cortex and hippocampus. Our findings suggest that MPI presents antidepressant-like activity which is associated with the biochemical regulation of oxidative stress in prefrontal cortex and hippocampus of mice, arising as a promising strategy for the management of depressive symptoms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The environmental psychological stress causes depressive disorders. Stress causes many neurobiological, neurodegenerative changes in brain. Topiramate (TPM) is used in the treatment of epilepsy and psychiatric diseases. However, there are conflicting findings that TPM disrupts cognitive functions. We aimed to investigate the effects of TPM on depression, anxiety, learning and memory as well as neurobiological, morphological changes in rats exposed to chronic unpredictable mild stress (CUMS). After CUMS was formed by random application of nine mild stressors for 45 days, TPM (at doses of 0.1, 1, 10, 100 mg/kg) was administered for 21 days. Sucrose preference, locomotor activity, forced swimming, elevated plus maze and Morris water maze tests were performed. Corticosterone, BDNF (Brain-derived neurotrophic factor) and glutamate levels and volumes of hippocampus were evaluated. Body weights of the rats were measured. Immobilization time increased in CUMS, CUMS + TPM0.1 in forced swimming test and time spent in platform quadrant increased in Control + TPM1, CUMS, CUMS + TPM0.1, CUMS + TPM1 in Morris water maze test. Control + TPM1 decreased distance to platform in Morris water maze while CUMS + TPM100 increased. Learning is impaired in CUMS + TPM100 while it is improved in Control + TPM1. BDNF levels increased in CUMS and glutamate levels increased in CUMS, CUMS + TPM10. Body weight decreased in CUMS, CUMS + TPM0.1, CUMS + TPM1, CUMS + TPM100. Hippocampus volumes increased in CUMS. In conclusion, CUMS improved cognition and this finding was supported by the increase of BDNF levels and volume of hippocampus. TPM 1 mg/kg improved cognition in non-stressed rats. TPM 0.1 and 1 mg/kg improved while TPM 100 mg/kg impaired memory in rats exposed to stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although dipyrone is a widely used analgesic and antipyretic, its mechanism of action is not fully clarified. Recent studies have drawn attention to its central effects and its relationship with the endocannabinoid system. The endocannabinoid system plays important roles in processes such as anxiety, depression, fear, and learning-memory. In this study, we aimed to investigate whether endocannabinoid levels change in the amygdala in chronic unpredictable mild stress model in mice and whether cannabinoid and TRPV1 receptors mediate antidepressant and anxiolytic effects of dipyrone. Mice were submitted to chronic unpredictable mild stress protocol of 6-weeks, then behavioral test were performed. In the first part of the study, dipyrone was injected at doses of 150, 300, and 600 mg/kg (i.p.) during behavioral tests. In the second part, the CB1 antagonist AM 251 (1 mg/kg, i.p.), the CB2 antagonist AM630 (1 mg/kg, i.p.), and the TRPV1 antagonist capsazepine (3 mg/kg, i.p.) were administered alone or in combination with 300 mg/kg dipyrone to observe if these receptors mediate dipyrone effects. Endocannabinoid and N-acylethanolamines levels were measured by LC-MS/MS in amygdala. Our results showed that there were no changes in AEA, 2-AG, PEA, OAE levels in the amygdala in mice exposed to chronic unpredictable mild stress model; dipyrone exerted antidepressant and anxiolytic effects at doses of 300 and 600 mg/kg; its anxiolytic effect appears to be mediated via CB1 receptors, whereas TRPV1 receptors seems to mediate its antidepressant action., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic social isolation stress (SIS) could impair learning and memory-related behaviors. Herein, we investigated the efficacy of Melatonin in treatment of memory despair and also its possible underlying mechanism of action in an animal model of SIS. For this purpose, mice were allocated to two opposing conditions, including social condition (SC) and isolated condition (IC), for five weeks. The study consisted of three groups, including saline-treated SC, saline-treated IC, Melatonin-treated IC (10 mg/kg/day for five successive days). At the end of the isolation period, mice underwent three neurobehavioral tests: passive avoidance (PA), Morris water maze (MWM), and Y maze (YM) tests. Hippocampus samples were obtained and the expressions of BDNF, TrkB, phosphorylated TrkB (pTrkB), CREB, phosphorylated CREB (pCREB), as well as M1 and M2 microglia were assessed. Interpreting the behavioral tests, we found that isolated mice showed lower freezing response in the PA test, lower number of novel arm visits in the YM, and higher escape latency and less time spent in the target quadrant in the MWM, when compared to SC rodents (P values < 0.001). The isolated group had higher M1/M2 relative ratio (P < 0.001), as well as lower concentrations of BDNF mRNA (p < 0.001) and protein (P < 0.001), TrkB protein (P = 0.035), CREB mRNA (P < 0.001) and protein (P = 0.012), pTrkB (P < 0.001), and pCREB (P = 0.035). However, Melatonin relatively reversed the behavioral, cellular, and molecular effects of SIS. Taken together, melatonin therapy could alleviate memory impairment through switching microglial polarization from M1 to M2 phenotype along with altered expression and function in the BDNF/TrkB/CREB signaling pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is one of the most common psychiatric disorders. However, the effective drugs for MDD have not yet been developed. WS6 is originally designed with a similar structure as Resveratrol and Pterostilbene. The present study aims to investigate the neuroprotective and ameliorating effects of WS6 treatment in a rat model of chronic unpredictable mild stress (CUMS) induced depression. The results show that CUMS is effective in producing depressive-like behavior in rats as indicated by decreased responses in the locomotor activity, sucrose preference test and increased immobility time. However, WS6 treatment significantly ameliorated these behavioral alterations associated with CUMS-induced depression. Moreover, the reduction in neurogenesis, GABAergic neurons, dendrite complexity, spine density and synaptic plasticity-associate protein 95 (PSD95) by CUMS can be reversed by treatment with WS6. Taken together, this study highlights the neuroprotective and antidepressant-like effects of WS6 against CUMS-induced depression, and suggest a possible mechanism for this protection via changes in neurogenesis within the hippocampus. These finding reveal the therapeutic protection of WS6 for use in clinical trials in the treatment of neuronal deterioration in MDD., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Resilience, referring to "achieving a positive outcome in the face of adversity", is a common phenomenon in daily life. Elucidating the mechanisms of stress resilience is instrumental to developing more effective treatments for stress-related psychiatric disorders such as depression. Metabotropic glutamate receptors (mGlu2/3 and mGlu5) within the medial prefrontal cortex (mPFC) have been recently recognized as promising therapeutic targets for rapid-acting antidepressant treatment. In this study, we assessed the functional roles of the mGlu2/3 and mGlu5 within different subregions of the mPFC in modulating stress resilience and vulnerability by using chronic social defeat stress (CSDS) paradigms in mice. Our results showed that approximately 51.6% of the subjects exhibited depression- or anxiety-like behaviors after exposure to CSDS. When a susceptible mouse was confronted with an attacker, c-Fos expression in the prelimbic cortex (PrL) subregion of the mPFC substantially increased. Compared with the resilient and control groups, the expression of mGlu2/3 was elevated in the PrL of the susceptible group. The expression of mGlu5 showed no significant difference among the three groups in the whole mPFC. Finally, we found that the social avoidance symptoms of the susceptible mice were rapidly relieved by intra-PrL administration of LY341495-an mGluR2/3 antagonists. The above results indicate that mGluR2/3 within the PrL may play an important regulatory role in stress-related psychiatric disorders. Our results are meaningful, as they expand our understanding of stress resilience and vulnerability which may open an avenue to develop novel, personalized approaches to mitigate depression and promote stress resilience., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Several studies have proposed that cocoa products-enriched in flavonoids reduce anxiety and depressive symptoms. (-)-Epicatechin (Epi), a flavonoid present in high concentration in cocoa, has been associated with many dark chocolate effects and has been postulated as an exercise mimetic. Physical exercise is used as an adjuvant treatment for many depressive patients. This study aimed to evaluate the impact of Epi on resilience in depression-like behavior in a murine model. Male mice were randomly selected and divided into four groups (n = 8/group). Beginning at the age of 8-9 weeks, the mice were subjected to Chronic Mild Stress (CMS) and/or treatment Epi for five weeks. Epi was administered by oral gavage twice daily/5 weeks. The control group was housed in conditions without stress and Epi treatment. Depressive behavior was evaluated by sucrose preference and open field tests. Interestingly, Epi reduced anhedonia and anxiogenic behavior in the murine stress model. These results suggest that Epi induces resilience to stress-induced depression. Furthermore, our findings propose that muscles respond to Epi treatment according to their type of metabolism and that kynurenine aminotransferases (KATs) could play a role in modulating this response., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hippocampal neurogenesis is known to be related to depressive symptoms. Increasing evidence indicates that Wnt/β-catenin signaling regulates multiple aspects of adult hippocampal neurogenesis. Baicalin is a major flavonoid compound with multiple pharmacological effects such as anti-inflammatory, anti-apoptotic, and neuroprotective effects. The current study aimed to explore the antidepressant effects of baicalin and its possible molecular mechanisms affecting hippocampal neurogenesis via the regulation of the Wnt/β-catenin signaling pathway. A chronic mild unpredictable stress (CUMS) model of depression was used in the study. The CUMS-induced mice were treated with baicalin (50 and 100 mg/kg) for 21 days, orally, and the fluoxetine was used as positive control drug. The results indicated that baicalin alleviated CUMS-induced depression-like behaviour, and improved the nerve cells' survival of the hippocampal dentate gyrus (DG) in CUMS-induced depression of model mice and increased Ki-67- and doublecortin (DCX)-positive cells to restore CUMS-induced suppression of hippocampal neurogenesis. The related proteins in the Wnt/β-catenin signaling pathway, which declined in the CUMS-induced depression model of mice, were upregulated after baicalin treatment, including Wingless3a (Wnt3a), dishevelled2 (DVL2), and β-catenin. Further study found that the phosphorylation rate of glycogen synthase kinase-3β (GSK3β) and β-catenin nuclear translocation increased, as the levels of the β-catenin target genes cyclinD1, c-myc, NeuroD1, and Ngn2 upregulated after baicalin treatment. In conclusion, these findings suggest that baicalin may promote hippocampal neurogenesis, thereby exerting the antidepressant effect via regulation of the Wnt/β-catenin signaling pathway., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We previously reported that helicid, an active plant monomer of Helicid nilgirica Bedd, had good antidepressant pharmacological activities. However, the potential mechanism of action remains unknown. Current investigation showed the antidepressant-like effects of helicid and its effects on the neurocalcin delta (NCALD) gene, and its mechanism of action through a depression model in rats exposed to chronic unpredictable mild stress (CUMS). We evaluated depression symptoms using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). By silencing NCALD and using rescue experiments, the IL-6, iNOS, IL-1β, COX-2, and TNF-α levels in the hippocampus or peripheral blood were determined using western blotting and ELISAs. The expression of IKKβ, p-IкBα, p-IKKβ, NF-кB p65, and IкBα were tested using western blots of the cytoplasmic or nuclear samples. Helicid and silencing NCALD relieved the CUMS-irritated depressive-like actions of rats, which were shown by increased consumption of sucrose, numbers of rearings, total running distance, zone crossings, and reduced immobility times. Helicid or silencing NCALD reversed the CUMS-induced high levels of IL-1β, COX-2, IL-6, TNF-α, and iNOS in the hippocampus or peripheral blood. Helicid or silencing NCALD also reduced the expressions of p-IκBα and p-IKKβ in the cytoplasm and the expression of nuclear NF-κB p 65 in hippocampus, and simultaneously elevated cytoplasmic expressions of IκBα, IKKβ, and NF-κB p65 in the hippocampus. Notably, after NCALD overexpression, the biochemical indices of rat helicid administration were reversed. In conclusion, the antidepressant action of helicid was mediated through NCALD in rats of CUMS by repressing hippocampal neuro-inflammation and abating the activation of the IKK/IκBα/NF-κB pathway., (Copyright © 2020. Published by Elsevier B.V.)

Early life stress is associated with various complications. Auraptene has significant antioxidant and anti-inflammatory effects. This study aimed to assess the probable underlying mechanisms that mediate changes in the behavior, hippocampus, heart and serum in the mouse model of maternal separation (MS) stress. We evaluated the possible protective effects of auraptene in these changes focusing on inflammatory response and oxidative state. Mice were treated with auraptene (5, 10, and 50 mg/kg). In addition, anxiety-like behaviors were evaluated using behavioral tests; including open field test (OFT) and elevated plus maze (EPM). Hippocampus and heart samples were assessed histopathologically. Levels of malondialdehyde (MDA) and antioxidant capacity, as well as nitrite levels, were measured in serum, heart, and hippocampal tissues. Moreover, gene expression of inflammatory markers (Il-1β and Tlr-4) was evaluated in the heart and hippocampus. Results showed that auraptene reversed the negative effects of MS on behavior (increased time spent in central zone of the OFT and time and entries to the open arms of the EPM). Auraptene mitigated adverse effects of MS on the hippocampus (increased diameter and decreased percentage of dark neurons in the CA3 area). Accordingly, auraptene decreased MDA and nitrite levels and increased the antioxidant capacity in serum, and hippocampal samples. However, we observed different effects for different doses of auraptene in the heart samples. We concluded that MS is associated with anxiety-like behavior and cellular/molecular modifications in the heart, hippocampus and serum. We found that auraptene exerted protective effects against these negative effects of MS in mouse., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Clinical studies have shown that diabetes can present with underlying depression, and a combination of the two can lead to emotional, memory and cognitive disorders, closely associated with hippocampal neuroinflammation. However, the mechanism underlying the development of hippocampal neuroinflammation under the above condition remains elusive. The aims of this study were to explore the pathogenesis of diabetes combined with depression, and the effect of dexamethasone (Dex), a glucocorticoid receptor (GR) agonist, on hippocampal neuroinflammation in diabetic rats with chronic unpredictable mild stress (CUMS). Therefore, rats were intragastrically fed on a high-fat diet (10% cholesterol 10 ml/kg) for 14 days and thereafter injected with 38 mg/kg of streptozotocin on the 15th day to induce diabetes. Dex treatment of the diabetic and CUMS rats ameliorated the depression-associated behavior in the respective rats. Apart from enhanced depressive behavior, diabetes-depressed condition also up-regulated the expression of hippocampus microglia chemokine Ⅰ receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - α (TNF-α). Hematoxylin-eosin staining revealed inflammatory damages in the hippocampus. Western blot analysis further revealed repression of GR proteins converse to the nuclear factor kappa-B (NF-κB) proteins, which were up-regulated. Intriguingly, Dex reversed the above events by inhibiting inflammatory reactions in the hippocampus. Consequently, played an antidepressant effect in diabetic and CUMS model rats. Overall, findings of this research suggest that the physiopathology of diabetes with stress cormobity are mediated by inflammatory reactions in the hippocampus. In particular, the responses are associated with regulation of GR/NF-κB signaling pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Oridonin (Ori) has multiple biological properties, especially anti-inflammatory. However, its effects on chronic unpredictable mild stress (CUMS)-induced insulin resistance are still unclear. In this study, we explored the regulatory role of Ori in CUMS-triggered insulin resistance, and the underlying molecular mechanisms; Methods: SD rats were subjected to CUMS for 4 weeks, some of which were injected with Ori or fluoxetine (FLX) in durations of CUMS. After CUMS procedure, the behavioral and metabolic tests were performed. Elisa, immunofluorescence and western blotting were used to determine the inflammatory response and NLRP3 inflammasome activation. We investigated the interaction between NLRP3 and NEK7 using immunoprecipitation. Finally, we detected the proinflammatory cytokines in Lipopolysaccharide (LPS)-activated RAW264.7 cells treated with Ori; RESULTS: In this study, we found that chronic stress resulted in depressive-like behavior comorbid with insulin resistance. Ori was discovered to ameliorate insulin resistance as well as insulin signaling disturbance in the hippocampus. In addition, CUMS caused the infiltration of macrophages into the islets. And IL-1β, IL-18 and caspase-1 were elevated in pancreases of CUMS rats, which could also be reversed by Ori treatment via reducing the interaction between NLRP3 and NEK7. Furthermore, Ori dose-dependently inhibited the levels of IL-1β and IL-18 in LPS-activated RAW264.7 cells; CONCLUSIONS: All these results supported our hypothesis that Ori possesses potent anti-insulin resistant actions, which is partially correlated with inhibiting infiltration of macrophages into the islets and NLRP3 activation induced by CUMS. Therefore, our results highlighted the protective role of Ori against CUMS-elicited insulin resistance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several stress-related neuropsychiatric diseases are related to inflammatory phenomena. Thus, a better understanding of stress-induced immune responses could lead to enhanced treatment alternatives. Little is known about the possible involvement of inflammasomes in the stress-induced proinflammatory response. Antipsychotics have anti-inflammatory effects, but the possible antipsychotic treatment actions on inflammasomes remain unexplored. Our aim was to study whether inflammasomes are involved in the neuroinflammation induced by a paradigmatic model of chronic stress and whether the monoamine receptor antagonist paliperidone can modulate the possible stress-induced inflammasomes activation in the frontal cortex (FC). Thus, the effects of paliperidone (1 mg/Kg, oral gavage) administered during a chronic restraint stress protocol (6 h/day for 21 days) on the possible stress-related inflammasomes protein induction were evaluated through Western blot in the FC of male Wistar rats. Stress increased protein expression levels of the inflammasome complexes NALP1, NLRP3 and AIM2 and augmented caspase-1 and mature interleukin (IL)-1β protein levels. Paliperidone pre-treatment normalized the protein expression of the inflammasome pathway. In conclusion, our data indicate an induction of inflammasome complexes by chronic restraint stress in the FC of rats. The antipsychotic paliperidone has an inhibitory action on some of the stress-induced inflammasomes stimulation trying to normalize the neuroinflammatory scenario caused by stress. Considering the emerging role of inflammation in neuropsychiatric diseases, the development of new drugs targeting inflammasome pathways is a promising approach for future therapeutic interventions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tianeptine (Tian) has been widely used in treating mood and anxiety disorders, and recently as a nootropic to improve cognitive performance. However, its mechanisms of action are insufficiently clear. We used a comparative proteomic approach to identify sub-proteome changes in hippocampal cytosol and non-synaptic mitochondria (NSM) following chronic Tian treatment (3 weeks, 10 mg/kg/day) of adult male Wistar rats and rats exposed to chronic social isolation stress (CSIS) (6 weeks), an animal model of depression. Behavioural assessment of depressive and anxiety-like behaviours was based on sucrose preference, forced swim test and marble burying. Selected differently expressed proteins were validated by Western blot and/or immunohistochemical analysis. Tian normalized the behavioural alternations induced by CSIS, indicating its antidepressant and anxiolytic efficacy. Proteomic data showed that Tian increased the expression of proteasome system elements and redox system enzymes, enhanced energy metabolism and increased glyceraldehyde-3-phosphate dehydrogenase expression bound to NSM in control rats. Tian-treatment of CSIS-stressed rats resulted in a minor suppression of the increase in proteasome elements and antioxidative enzymes, except for an increase in Cu-Zn superoxide dismutase, and increased the level of Lactate dehydrogenase. Our results indicate on an increased NSM functionality in controls and suppression of the CSIS-induced impairment of NSM functionality by Tian treatment as well as on the CSIS-caused discrepancy in Tian effects relative to controls., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Introduction: Axonal transport deficit is a key mechanism involved in neurodegenerative conditions. Fluoxetine, a commonly used antidepressant for treatment of depression, is known to regulate several important structural and neurochemical aspects of hippocampal functions. However, the mechanisms underlying these effects are still poorly understood. This study aimed to investigate the effects of chronic fluoxetine treatment on axonal transport in the hippocampus of rat stress-induced model of depression., Methods: We have analyzed the effects of chronic fluoxetine treatment (20 mg/kg/day, 24 days) on immobility behavior (forced swimming test), hippocampal iNOS (inflammatory factor) expression (RT-PCR) as well as hippocampal BDNF, kinesin and dynein expression (RT-PCR) and hippocampal neuronal survival (Nissl staining)., Results: This study provided evidence that fluoxetine could effectively suppress iNOS expression following unpredictable chronic mild stress (P < 0.01), increase hippocampal BDNF (P < 0.01), kinesin (P < 0.05) and dynein (P < 0.01) gene expression, and control neuronal death in CA1 (P < 0.01) and CA3 regions (P < 0.01) of the hippocampus and thereby improve immobility behavior (P < 0.001)., Conclusion: Based on the findings of this study, we concluded the neuroprotective effect of fluoxetine may be due to its ability to improve axonal transmission, followed by increased energy supply and neurotrophin concentration and function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recent studies have suggested that CREB-regulated transcription coactivator 1 (CRTC1) plays a role in the pathophysiology of depression. Although imipramine is thought to prevent the reuptake of synaptic serotonin and norepinephrine, its antidepressant-like mechanisms remain elusive. In this study, the effects of imipramine on CRTC1 were studied in several models of depression, including the chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models. We examined whether repeated imipramine administration can reverse the effects of CRS, CUMS and CSDS on CRTC1 expression in both the hippocampus and medial prefrontal cortex (mPFC). Furthermore, genetic knockdown of CRTC1 by CRTC1-shRNA was used to determine whether CRTC1 is necessary for the antidepressant-like effects of imipramine in mice. Our results showed that imipramine reversed the down-regulating effects of CRS, CUMS and CSDS on CRTC1 expression in the mPFC but not the hippocampus, and that CRTC1-shRNA fully abolished the antidepressant-like actions of imipramine in mice. In conclusion, CRTC1 in the mPFC is involved in the antidepressant mechanism of imipramine., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stress-related disorders, such as depression and anxiety, present marked deficits in behavioral and cognitive functions related to reward. These are highly prevalent disabling conditions with high social and economic costs. Furthermore, a significant percentage of affected individuals cannot benefit from clinical intervention, opening space for new treatments. Although the literature data have reported limited and variable results regarding oxidative stress-related endpoints in stress-related disorders, the possible neuroprotective effect of antioxidant compounds, such as ascorbic acid (vitamin C), emerges as a possible therapy strategy for psychiatric diseases. Here, we briefly present background information on biological activity of ascorbic acid, particularly functions related to the CNS homeostasis. Additionaly, we reviewed the available information on the role of ascorbic acid in stress-related diseases, focusing on supplementation and depletion studies. The vitamin C deficiency is widely associated to stress-related diseases. Although the efficacy of this vitamin in anxiety spectrum disorders is less stablished, several studies showed that ascorbic acid supplementation produces antidepressant effect and improves mood. Interestingly, the modulation of monoaminergic and glutamatergic neurotransmitter systems is postulated as pivotal target for the antidepressant and anxiolytic effects of this vitamin. Given that ascorbic acid supplementation produces fast therapeutic response with low toxicity and high tolerance, it can be considered as a putative candidate for the treatment of mood and anxiety disorders, especially those that are refractory to current treatments. Herein, the literature was reviewed considering the potential use of ascorbic acid as an adjuvant in the treatment of anxiety and depression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The intestine and the brain are connected via the brain-gut axis and the intestinal microbiota influences the immune activation and signaling molecules that are involved in the stress response. The aim of the study was to investigate if intake of the probiotic strain Lactiplantibacillus plantarum HEAL9 (LPHEAL9) for four weeks could counteract elevated cortisol and inflammation levels in subjects with chronic stress that are exposed to an acute stress test (Trier Social Stress Test, TSST). Seventy participants were included, and 63 participants completed the study (LPHEAL9, n = 32; placebo, n  =  31). Cardiovascular reactivity and cortisol levels were affected by the TSST, but no differences between the groups were observed. Intake of LPHEAL9 did, however, result in significantly decreased plasma levels of two inflammatory markers (soluble fractalkine and CD163) compared to placebo. In conclusion, intake of LPHEAL9 for four weeks may reduce inflammatory markers coupled to acute stress in chronically stressed individuals., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to this publication. G.Ö. and C.M. are employed by Probi AB., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Accumulating evidence indicates the role of microglial activation and sustained neuroinflammation in the pathogenesis of cognitive dysfunction, a common feature associated with depressive disorders. It also indicates the role of Wnt/β-catenin pathway in regulation of microglia-mediated neuroinflammation. Amisulpride exhibits antidepressant and pro-cognitive activities in several clinical and experimental studies. Hitherto, the direct effects of amisulpride on Wnt/β-catenin signaling and microglial activity have not been thoroughly studied. This study aimed at investigating the effects of chronic amisulpride treatment on Wnt/β-catenin signaling and pro-inflammatory microglial activation and its role in alleviation of depressive-like behavior and cognitive deficits elicited by unpredictable chronic mild stress (UCMS). The effects of amisulpride (3 mg/kg/day) were investigated on behavioral/cognitive deficits, expression of Wnt/β-catenin pathway and microglial activation in the prefrontal cortex (PFC) of UCMS-exposed male Wistar rats. UCMS induced depressive-like behavior with impairment of performance in novel object recognition test and attentional set-shifting task. These behavioral deficits were associated with decreased total β-catenin and increased pro-inflammatory microglial activation. Amisulpride improved UCMS-induced behavioral/cognitive deficits, ameliorated Wnt/β-catenin signaling dysregulation and pro-inflammatory microglial activation. This work highlights the antidepressant and pro-cognitive effects of amisulpride in UCMS-exposed rats that could be mediated by modulation of Wnt/β-catenin pathway activity and amelioration of pro-inflammatory microglial activation in the prefrontal cortex. This could provide new insights into the putative mechanisms behind the antidepressant and pro-cognitive effects exerted by amisulpride., (Copyright © 2020 Elsevier B.V. All rights reserved.)