Depressive-like Symptoms In Mice Research Articles

Colistin treatment causes neuronal loss and cognitive impairment via ros accumulation and neuronal plasticity alterations.

The rise of antimicrobial resistance has made necessary the increase of the antibacterial arsenal against multidrug-resistant bacteria. In this context, colistin has re-emerged as a first-line antibiotic in critical situations despite its nephro- and neuro- toxicity at peripheral level. However, the mechanism underlying its toxicity remains unknown, particularly in relation to the central nervous system (CNS). Therefore, this study aimed to characterize the molecular mechanisms underlying colistin-induced neurotoxicity in the CNS through a combination of in vitro and in vivo molecular studies along with several in vivo behavioral tests. Following colistin treatment, mice exhibited a significant reduction in body weight together with renal impairment, and locomotor dysfunction. Moreover, our results demonstrated that colistin disrupted the blood-brain barrier, inducing astrogliosis, and triggering apoptosis-related processes probably through the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction. Further analysis on mice and primary neuronal cultures revealed that colistin administration altered neuronal plasticity by reducing the number of immature neurons in adult neurogenesis and altering the synaptic function through a reduction of the post-synaptic protein PSD95. All these alterations together finally lead to cognitive impairment and depression-like symptoms in mice. These findings provide novel insights into the mechanisms of colistin-induced neurotoxicity in the CNS, highlighting the need for careful monitoring of cognitive function in patients undergoing colistin treatment.

T-2 toxin triggers depression-like behaviors via upregulation of dopamine transporter in nucleus accumbens of male mice

The T-2 toxin is a frequent contaminant in the global environment and agricultural production. Existing evidence suggests that the ingested T-2 toxin can enter the brain and exhibit neurotoxicity. However, it is still unknown whether T-2 toxin causes the depression-like behaviors. In this study, the mice were orally administrated with 1.5 mg/kg T-2 toxin daily for 14 d, and the depression-like behaviors were assessed by the tail suspension test (TST) and sucrose preference test (SPT). Here, the results showed that T-2 toxin exposure induced depression-like behaviors, manifested as behavioral despair and anhedonia, without anxiety-like behaviors. In addition, the reduced dopamine (DA) level and elevated dopamine transporter (DAT) level were found in reward center nucleus accumbens (NAc) receiving DAergic projection from ventral tegmental area (VTA) in brain after T-2 toxin administration, while there was no significant alteration in DA synthesis-related tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) in VTA and DA storage-related vesicle monoamine transporter 2 (VMAT2) in NAc. The local administration of DAT inhibitor AHN 1–055 hydrochloride into NAc alleviated T-2 toxin caused the depression-like behaviors. Importantly, the chemogenetic activation of the VTADA-NAc circuit increased the DA content in NAc and reversed the T-2 toxin-produced behavioral despair and anhedonia. Thus, our study for the first time illustrates DA dysregulation by upregulated DAT in NAc mediates T-2 toxin-triggered depression-like symptoms in mice. Meanwhile, this study establishes a novel causal relation between the neurotoxicant T-2 toxin exposure and the etiology of depression-like behaviors, and provides reference for the prevention and treatment for mycotoxin-induced depression-like symptoms.

Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor via HDAC5 in Depression.

Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of Bdnf transcripts II, IV, and Bdnf CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine. Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at Bdnf II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine. Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of Bdnf expression in the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.

A study on the effects of metacinnabar (β-HgS) on weight and appetite recovery in stressed mice

Ethnopharmacological relevanceDepression is a prevalent stress disorder, yet the underlying physiological mechanisms linking stress to appetite and weight loss remain elusive. While most antidepressants are associated with excessive weight and appetite gain, sertraline (SER) exhibits a lower risk of these side effects. Metacinnabar (β-HgS), the primary component of Tibetan medicine Zuotai, has been shown to enhance mice's resilience against external stress without causing excessive increases in weight or appetite. However, the precise physiological pathway through which β-HgS restores appetite and weight in stressed mice remains unclear. Aim of the studyThe objective of this study is to assess the efficacy of β-HgS in ameliorating weight loss and appetite suppression induced by pressure stimulation in mice, as well as elucidate its potential mechanisms of action. MethodsThe present study employed chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) as experimental models to simulate environmental stress encountered in daily life. Subsequently, a series of experiments were conducted, including behavior tests, HE staining of rectal and hippocampal pathological sections, detection of depression-related biological indicators, analysis of intestinal flora diversity, as well as metabolomics analysis of hippocampal and intestinal contents. ResultDysregulation of glycerophospholipid metabolism may represent the principal pathway underlying reduced appetite, body weight, neurotransmitter and appetite hormone levels, heightened inflammatory response, hippocampal and rectal tissue damage, as well as altered composition of intestinal microbiota in stressed mice. Following intervention with SER and β-HgS in stressed mice, the deleterious effects induced by stress can be ameliorated, in which the medium-dose β-HgS exhibited superior performance. ConclusionThe aforementioned research findings suggest that the stress-induced decrease in appetite and body weight in mice may be associated with dysregulation in glycerophospholipid metabolism connecting the gut-brain axis. β-HgS exhibits potential in ameliorating depressive-like symptoms in mice subjected to stress, while concurrently restoring their body weight and appetite without inducing excessive augmentation. Its therapeutic effect may also be attributed to its ability to modulate glycerophospholipid metabolism status and exert influence on the gut-brain axis.

Exploratory studies of the antidepressant effect of Cordyceps sinensis polysaccharide and its potential mechanism

Cordyceps sinensis, a traditionally prized medicinal fungus, contains polysaccharides as one of its main bioactive constituents, known for their significant immunomodulatory properties. In this study, we systematically investigated the composition and structure of Cordyceps sinensis polysaccharide, followed by an evaluation of its therapeutic effect on depression using a chronic restraint stress-induced depression model. The polysaccharide CSWP-2, extracted via hot water, precipitated with ethanol, and purified using DEAE-cellulose column chromatography from Cordyceps sinensis, is primarily composed of glucose, mannose, and galactose, with α-1,4-D-glucan as its major structural component. Behavioral tests, immunological profiling, metabolomics, and gut microbiota analyses indicated a notable ameliorative effect of CSWP-2 on depressive-like symptoms in mice. Furthermore, the action of CSWP-2 may be attributed to the modulation of the gut microbiome's abundance and its metabolic impacts, thereby transmitting signals to the host immune system and exerting immunomodulatory activity, ultimately contributing to its antidepressant effects.

Prophylactic Effects of n-Acethylcysteine on Inflammation-induced Depression-like Behaviors in Mice

Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.

Running exercise improves astrocyte loss, morphological complexity and astrocyte-contacted synapses in the hippocampus of CUS-induced depression model mice

Although the antidepressant effects of running exercise have been widely reported, further research is still needed to determine the structural bases for these effects. Astrocyte processes physically contact many synapses and directly regulate the numbers of synapses, but it remains unclear whether running exercise can modulate astrocyte morphological complexity and astrocyte-contacted synapses in the hippocampus of the mice with depressive-like behavior. Male C57BL/6 J mice underwent four weeks of running exercise after four weeks of chronic unpredictable stress (CUS). The sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess anhedonia in mice. Western blotting was used to measure the expression of astrocyte- and synapse-related proteins. Immunofluorescence and 3D reconstruction were used to quantify the density and morphology of astrocytes, and astrocyte-contacted synapses in each hippocampal subregion. Four weeks of running exercise alleviated depressive-like symptoms in mice. The expression of astrocyte- and synapse-related proteins in the hippocampus; astrocyte process lengths, process numbers, and dendritic arborization; and the number of astrocyte-contacted PSD95 positive synapses in the CA2–3 and DG regions were significantly decreased in the mice with depressive-like behavior, and running exercise successfully reserved these changes. Running exercise improved the decreases in astrocyte morphological complexity and astrocyte-contacted PSD95 positive synapses in the CA2–3 and DG regions of the mice with depressive-like behavior, suggesting that the physical interactions between astrocytes and synapses can be increased by running exercise, which might be an important structural basis for the antidepressant effects of running exercise.

Ghrelin/GHSR signaling in the lateral septum ameliorates chronic stress-induced depressive-like behaviors

Ghrelin is a gastrointestinal hormone on feeding and metabolism regulation, and acts through its receptor-growth hormone secretagogue receptor (GHSR), which is widely distributed throughout the central nervous system. Recent studies have suggested that ghrelin plays an important role in the regulation of depression, but the underlying mechanisms remain uncertain. Lateral septum (LS) is a critical brain region in modulating depression. Therefore, we investigated the role of ghrelin/GHSR signaling in the LS on the depressive-like behaviors of mice under conditions of chronic stress by using behavioral tests, neuropharmacology, and molecular biology techniques. We found that infusion of ghrelin into the LS produced antidepressant-like responses in mice. Activation of LS GABAergic neurons was involved in the antidepressant effect of ghrelin. Importantly, GHSR was highly expressed and distributed in the LS neurons. Blockade of GHSR in the LS reversed the ghrelin-induced antidepressant-like effects. Molecular knockdown of GHSR in the LS induced depressive-like symptoms in mice. Furthermore, administration of ghrelin into the LS alleviated depressive-like behaviors induced by chronic social defeat stress (CSDS). Consistent with the neuropharmacological results, overexpression of GHSR in the LS reversed CSDS-induced depressive-like behaviors. Our findings clarify a key role for ghrelin/GHSR signaling in the regulation of chronic stress-induced depressive-like behaviors, which could provide new strategies for the treatment of depression.

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression.

Vindeburnol (VIND, RU24722, BC19), a synthetic molecule derived from the eburnamine-vincamine alkaloid group, has many neuropsychopharmacological effects, but its antidepressant-like effects are poorly understood and have only been described in a few patents. To reliably estimate this effect, vindeburnol was studied in a model of long-term variable-frequency ultrasound (US) exposure at 20-45 kHz in male Wistar rats and BALB/c mice. Vindeburnol was administered chronically for 21 days against a background of simultaneous ultrasound exposure at a dose of 20 mg/kg intraperitoneally (IP). Using four behavioral tests, the sucrose preference test (SPT), the social interaction test (SIT), the open field test (OFT), and the forced swimming test (FST), we found that the treatment with the compound diminished depression-like symptoms in mice and rats. The compound restored the ultrasound-related reduced sucrose consumption to control levels and increased social interaction time in mice and rats compared with those in ultrasound-exposed animals. Vindeburnol showed contraversive results of horizontal and vertical activity in both species and generally did not increase locomotor activity. At the same time, the compound showed a specific effect in the FST, significantly reducing the immobility time. Moreover, we found an increase in norepinephrine, dopamine, and its metabolite levels in the brainstem, as well as an increase in dopamine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid levels in the striatum. We also observed a statistically significant increase in tyrosine hydroxylase (TH) levels in the region containing the locus coeruleus (LC). We suggest that using its distinct chemical structure and pharmacological activity as a starting point could boost antidepressant drug discovery.

The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice.

The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function. To specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1Vip; Vax1fl/fl:VipCre). We found that Vax1Vip females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1Vip males and females presented with a shortened circadian period in locomotor activity and ex vivo SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes Bmal1 and Per2. Interestingly, Vax1Vip females presented with increased expression of arginine vasopressin (Avp) in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1Vip mice, we assessed GnRH sensitivity to a kisspeptin challenge in vivo. We found that GnRH neurons in Vax1Vip females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1Vip males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1Vip mice were fertile and generated litters comparable in size and frequency to controls. Together, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.

Neurobehavioral protective effects of Japanese sake yeast supplement against chronic stress-induced anxiety and depression-like symptoms in mice: Possible role of central adenosine receptors.

Using routine synthetic drugs in the treatment of psychiatric disorders may have some restrictions due to serious side effects and pharmacoresistance. Some natural agents may be promising alternatives in this case. The neuroprotective activity of the neuromodulator adenosine and its receptor, A1 receptor (A1R) in the central nervous system has been mentioned in different studies. We aimed to determine the anxiolytic, antidepressant and sedative effects of Japanese sake yeast as the first report. Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose levels of 100, 200 and 300 mg kg-1 once daily for a week. The anxiolytic, antidepressant, and sedative actions of sake yeast were evaluated with the related tests. In all dose regiments, sake yeast significantly improved functions in the EPM and FST. 200 and 300 mg/kg of sake yeast significantly increased sleep duration and reduced sleep latency. Anxiolytic and antidepressant-like activities of sake yeast were maintained by the injection of ZM241385 (15 mg kg-1), a selective adenosine A2AR antagonist but completely counteracted by the injection of 8-cyclopentyltheophylline (10 mg kg-1), a selective adenosine A1R antagonist. 300 mg/kg of the yeast significantly increased the BDNF levels. Amygdala corticosterone levels did not show any significant changes at any dosage. Amygdala TNF-α, IL-6 and IL-1β levels also decreased significantly with all the sake regiments compared to the control group. We conclude that oral sake yeast supplement exerts a neurobehavioral protective effect predominantly by activating central A1Rs.

The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice.

Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos+ cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.

Depressive-like behavior associated with colitis is altered after treatment with aryl hydrocarbon receptor ligand

Abstract Colitis is a chronic inflammatory disease with no cure and an overall reduction in patient quality of life. Due to decreased mucous production and weakening of the colonic epithelial lining, gut -microbiota and their metabolites can invade the intestinal lamina propria and circulate systemically, a term known as “leaky gut”. Recent studies show a relationship exists between peripheral inflammation and depression. The gut-brain axis (GBA) acts as a bidirectional communication pathway between the enteric and central nervous system (CNS), and colitis patients are known to have increased incidence of depression. In the current study, we aimed to investigate the relationship between colitis, and its impact on depressive-like symptoms in mice. Colitis was chemically induced in mice and treated with indole-3-carbinol (I3C), a naturally-occurring aryl hydrocarbon receptor (AhR) our lab previously showed reduced colitis severity. Untargeted metabolomic profiles of over 200 metabolites revealed that during disease induction a potential neurotoxic and kynurenine pathway metabolite, quinolinic acid (QA), was upregulated in colitis models, but reduced after I3C treatment. As high QA levels are linked to depression, we performed tail suspension tests (TST) over the course of disease and treatment to assess depressive-like behavior in experimental mice. Our results show that colitis- induced mice had a higher immobility time as compared to healthy controls, but this was reversed upon treatment with I3C. These results suggest that colonic inflammation can lead to altered behavior and increased depressive-like symptoms through dysregulation of the gut metabolome, but restored after treatment with AhR ligand, I3C. NIH P20GM103641

Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice.

Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NFkB, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS.

Flavonoids from Seabuckthorn (Hippophae rhamnoides L.) restore CUMS-induced depressive disorder and regulate the gut microbiota in mice.

Seabuckthorn (Hippophae rhamnoides L.), which is enriched with flavonoids, including isorhamnetin, quercetin and kaempferol, is a representative example of "medicine food homology" targeting several diseases. Major depressive disorders seriously threaten mental health worldwide and may even lead to death. Chronic unpredictable mild stress (CUMS)-induced depressive-like symptoms in mice are usually considered as the highest similarity to the situation in humans. Herein, we determined the potential functions of the flavonoid-enriched fraction from Seabuckthorn, which was named SBF, in treating major depressive disorder in mice. In the CUMS-induced mouse model, the intake of SBF reversed their depressive behaviors and relieved the CUMS-disturbed levels of neurotrophins, neurotransmitters, stress-related hormones, and inflammation-related cytokines. Additionally, the treatment of depressive mice with SBF showed ability to regulate the gut microbiota, especially in decreasing the abundance of Lactobacillaceae, while increasing the abundance of Lachnospiraceae at the family level. The results suggest the beneficial effects of Seabuckthorn flavonoids in functioning as a health food supplement to treat major depressive disorders.

Effects of Tibetan medicine metacinnabar (β-HgS) combined with imipramine or sertraline on depression-like symptoms in mice.

Depression is a common mood disorder that has exhibited an increased incidence rate worldwide, but the overall clinical efficacy of antidepressants remains unsatisfactory. In traditional Ayurveda and Tibetan medicines, β-HgS-containing medicines have been used to treat neurological diseases for thousands of years, and our previous study found that β-HgS ameliorated depression-like behaviors in chronic restraint stress (CRS)-treated or chronic unpredictable mild stress (CUMS)-treated mice. Hence, present study investigated the effects of β-HgS combined with the clinical first-line antidepressants, imipramine (IMI) and sertraline (SER), on depression-like symptoms in CRS- and CUMS-co-treated mice. Our results revealed that β-HgS promoted the antidepressant effect of SER on depression-like behavior in mice, and enhanced its effects on promoting glucocorticoid receptor (GR) expression and neuronal proliferation in key hippocampal subregions, as well as increasing interleukin 10 (IL-10) levels and decreasing malondialdehyde levels in the sera of stress-stimulated mice. As for IMI, β-HgS enhanced its effects on preventing atrophy and severe structural damage in the hippocampus, as well as in promoting hippocampal GR levels and neuronal proliferation and serum IL-10 and superoxide dismutase (SOD) levels. Additionally, combination therapy resulted in the increased diversity of important intestinal microbiota compared to that of monotherapy, which may help sustain the health of the digestive tract and reduce inflammation to further enhance the antidepressant effects of IMI and SER in mice.

The effect and mechanism of Jiao-tai-wan in the treatment of diabetes mellitus with depression based on network pharmacology and experimental analysis

BackgroundThe incidence of diabetes mellitus (DM) and depression is increasing year by year around the world, bringing a serious burden to patients and their families. Jiao-tai-wan (JTW), a well-known traditional Chinese medicine (TCM), has been approved to have hypoglycemic and antidepressant effects, respectively, but whether JTW has such dual effects and its potential mechanisms is still unknown. This study is to evaluate the dual therapeutic effects of JTW on chronic restraint stress (CRS)-induced DM combined with depression mice, and to explore the underlying mechanisms through network pharmacology.MethodsCRS was used on db/db mice for 21 days to induce depression-like behaviors, so as to obtain the DM combined with depression mouse model. Mice were treated with 0.9% saline (0.1 ml/10 g), JTW (3.2 mg/kg) and Fluoxetine (2.0 mg/kg), respectively. The effect of JTW was accessed by measuring fasting blood glucose (FBG) levels, conducting behavioral tests and observing histopathological change. The ELISA assay was used to evaluate the levels of inflammatory cytokines and the UHPLC-MS/MS method was used to determine the depression-related neurotransmitters levels in serum. The mechanism exploration of JTW against DM and depression were performed via a network pharmacological method.ResultsThe results of blood glucose measurement showed that JTW has a therapeutic effect on db/db mice. Behavioral tests and the levels of depression-related neurotransmitters proved that JTW can effectively ameliorate depression-like symptoms in mice induced by CRS. In addition, JTW can also improve the inflammatory state and reduce the number of apoptotic cells in the hippocampus. According to network pharmacology, 28 active compounds and 484 corresponding targets of JTW, 1407 DM targets and 1842 depression targets were collected by screening the databases, and a total of 117 targets were obtained after taking the intersection. JTW plays a role in reducing blood glucose level and antidepressant mainly through active compounds such as quercetin, styrene, cinnamic acid, ethyl cinnamate, (R)-Canadine, palmatine and berberine, etc., the key targets of its therapeutic effect include INS, AKT1, IL-6, VEGF-A, TNF and so on, mainly involved in HIF-1 signal pathway, pathways in cancer, Hepatitis B, TNF signal pathway, PI3K-Akt signal pathway and MAPK signaling pathway, etc.ConclusionOur experimental study showed that JTW has hypoglycemic and antidepressant effects. The possible mechanism was explored by network pharmacology, reflecting the characteristics of multi-component, multi-target and multi-pathway, which provides a theoretical basis for the experimental research and clinical application of JTW in the future.

Antidepressant-like effects of 1-methylnicotinamide in a chronic unpredictable mild stress model of depression

Depression is one of the most common psychiatric disorders, and there is strong demand for developing novel antidepressants with better efficacy and less adverse effects. 1-Methylnicotinamide (MNA) is a main metabolite of nicotinamide and has been demonstrated to possess biological effects in the brain. This study aimed to evaluate the antidepressant-like effects of MNA in mice, and the possible antidepressant mechanism was also determined. The forced swim test (FST), tail suspension test (TST), chronic unpredictable mild stress (CUMS) model of depression, western blotting method and K252a (a pharmacological inhibitor of the BDNF receptor) were used together in the present study. It was found that a single injection of MNA (100 and 200 mg/kg) displayed notable antidepressant-like potential in the FST and TST without affecting the locomotor activity of mice. Repeated administration of MNA (100 and 200 mg/kg) for 2 weeks fully reversed not only the CUMS-induced depressive-like symptoms in mice but also the CUMS-induced decrease in the hippocampal BDNF signaling pathway. Furthermore, the usage of K252a fully blocked the antidepressant-like effects of MNA in the FST, TST and CUMS model of depression. Collectively, MNA possess an antidepressant-like effect in mice which is mediated, at least in part, through promoting the hippocampal BDNF signaling pathway.

Effect of adzuki bean sprout fermented milk enriched in γ-aminobutyric acid on mild depression in a mouse model

This study focused on the ability of adzuki bean (Vigna angularis) sprout fermented milk, which is rich in γ-aminobutyric acid (GABA), to relieve anxiety and mild depression. A high-yield GABA-producing strain, Lactobacillus brevis J1, from a healthy cow was screened, and its physiological and probiotic properties were evaluated. The effect of adzuki bean sprout fermented milk was investigated in vivo in a chronic depression mouse model. The results showed that Lb. brevis J1 had excellent probiotic properties, grew well at low pH and 3% NaCl, and adhered to the surface of HT-29 cells. The GABA-enriched (241.30 ± 1.62 µg/mL) adzuki bean sprout fermented milk prepared with Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactobacillus plantarum, and Lb. brevis J1 can reduce and possibly prevent mild depression-like symptoms in mice (C57/B6) by increasing social interaction and enhancing the pleasure derived from movement. The research revealed that the GABAB-cyclic AMP-protein kinase A-cAMP-response element binding protein (GABAB-cAMP-PKA-CREB) signaling pathway was related to the depression-like symptoms and that levels of 5-hydroxytryptamine, norepinephrine, and dopamine in the hippocampus of mice increased after treatment with the adzuki bean sprout fermented milk. Our results suggest that GABA-enriched dairy products have the potential to prevent or treat mild depression-like symptoms in mice, which suggests a new approach for a dietary therapy to treat chronic social stress.

Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-κB-NLRP3 inflammation activation.

Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Metformin has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. We used a chronic mild stress model of depression and cultured primary macrophage to investigate the effects of metformin on depression and its underlying mechanisms. We demonstrated that metformin alleviated depressive-like behaviors in the chronic mild stress-induced anhedonia model of depression. We further found that metformin significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in both peripheral macrophages and central hippocampus. Our findings reveal that metformin confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation. In light of metformin favorable properties, it should be evaluated in the treatment of depression and related neurologic disorders characterized by NLRP3 inflammasome activation.