The Matrine Derivative MASM Alleviates LPS-Induced Depressive-Like Behavior in Mice by Modulating Hippocampal Inflammation, Oxidative Stress, and Autophagy

Metformin, an AMPK activator, is a widely used medicine for type II diabetes, which has been considered to exert the anti-inflammatory effects. It has been reported that inflammation plays an important role in the pathogenesis of depression. Lipopolysaccharide (LPS) is often utilized to induce depressive-like behavior in mice with respect to recent studies. However, whether metformin alleviates the symptoms of depressive-like behaviors and its mechanisms remain unexplored. The present study investigates whether metformin alleviates LPS-induced depressive-like behavior in mice and aims to explore the mechanisms. We first treated adult mice with LPS (0.83 mg/kg, intraperitoneal) to induce depressive-like behavior model for 24 hours after treatment with or without metformin. Then, the effects of metformin on depressive-like behaviors were detected by tail suspension test and forced swim test. Moreover, quantitative RT-PCR was used to determine the mRNA expression levels of lipocalin 2 (Lcn-2) and inflammatory molecules including IL-1β, IL-6 and von Willebrand factor (vWF), which are concerned with inflammation and Lcn-2. It was shown that LPS-induced mouse depressive-like behaviors, as indicated by the increased time of immobility in tail suspension test and forced swim test, were reversed by metformin. It was also shown that LPS increased the mRNA expression levels of Lcn-2 and inflammation-related molecules such as IL-1β in the amygdala tissue, which could be alleviated by metformin. Taken together, metformin mitigates LPS-induced depressive-like behavior in mice by regulating the expression level of Lcn-2 and inflammation-related molecules, including IL-1β, IL-6 and vWF.Video abstract: http://links.lww.com/WNR/A568.

Neuroinflammation plays crucial role in the development and progression of depression. Large conductance calcium- and voltage-dependent potassium (BK) channels mediate the activation of microglia. Herein, we investigated whether BK channels could serve as a target for the treatment of inflammation-associated depression. Lipopolysaccharide (LPS, 0.83mg/kg) was injected intraperitoneally (i.p.) to induce neuroinflammation and depressive-like behavior in 6-8week ICR mice. Adeno-associated virus (AAV) constructs (AAV9-Iba1p-BK shRNA-EGFP (BK shRNA-AAV) or AAV9-Iba1p-NC shRNA-EGFP (NC shRNA-AAV)) were unilaterally injected intracerebroventricularly to selectively knock down BK channels in microglia. The tail suspension test (TST) and forced-swim test (FST) were used to evaluate depressive-like behavior in mice 24h after LPS challenge. The morphology of microglia, expression of BK channels, levels of cytokines, and expression and activity of indoleamine 2,3-dioxygenase (IDO) were measured by immunohistochemistry, western blot, quantitative real time PCR, and enzyme-linked immunosorbent assay (ELISA), respectively. Either paxilline (i.p.), a specific BK channel blocker, or BK shRNA-AAV effectively inhibited the activation of microglia, reduced the production of IL-1β in the hippocampus and suppressed the expression and activity of IDO in the hippocampus and prefrontal cortex, resulting in the amelioration of depressive-like behavior in mice. These data suggest for the first time that BK channels are involved in LPS-induced depressive-like behaviors. Thus, microglia BK channels may be a potential drug target for the depression treatment.

Enhanced inflammatory and immune responses have been observed in patients with major depressive disorder, pointing to anti-inflammatory substances as potential seeds for developing novel antidepressants. Omega-3 polyunsaturated fatty acid metabolites, such as resolvin D and E series, maresins, and protectins (collectively known as specialized pro-resolving mediators) demonstrate anti-inflammatory effects. This study examined the antidepressant-like effects of maresin-1 (MaR1) on lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Using the tail suspension test (TST) and the forced swim test (FST), we assessed depression-like behaviors 26 and 28 h after intraperitoneal injection of LPS (0.8 mg/kg), respectively. An open field test (OFT) was also conducted to evaluate locomotor activity 24 h after LPS injection. Intracerebroventricular (i.c.v.) injection of MaR1 (10 ng/mouse) immediately after the LPS challenge mitigated the increased immobility time in the TST and FST, without affecting locomotor activity in the OFT, indicating the preventive effects of MaR1 on LPS-induced depression-like behaviors. Furthermore, i.c.v. injection of MaR1 23 h after the LPS challenge reduced the immobility time in both tests, underscoring its therapeutic potential. These findings suggest that MaR1 could be a promising seed for developing novel antidepressants.

BackgroundEmerging evidence suggests a connection between mitophagy-a key mitochondrial quality control mechanism-and depression. Furthermore, sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, has been implicated in the pathophysiology of depression, though its precise role remains elusive. This study aimed to investigate how SIRT1 modulates depressive-like behaviors in mice and to determine whether mitophagy mediates this process.MethodsMale BALB/c mice were administered lipopolysaccharide (LPS) to mimic depressive-like behaviors. The treatment group received a pre-administration of SRT1720 (50 mg/kg, i.p.), a specific SIRT1 activator. Depressive-like behaviors were assessed by sucrose preference test (SPT) and forced swimming test (FST). Additionally, hippocampal neuronal and mitochondrial ultrastructure was detected via transmission electron microscopy (TEM), and mitophagy-related protein expression was examined by western blotting.ResultsResults demonstrated that activation of SIRT1 significantly mitigated LPS-induced depressive-like behaviors in mice. Moreover, it was observed that SIRT1 activation protected against LPS-induced neuronal and mitochondrial damage in the hippocampus. TEM analysis revealed a marked increase in hippocampal autophagosomes following SIRT1 activation, accompanied by significantly elevated expression of LC3II and Parkin, suggesting enhanced mitophagy. In vitro experiment using HT-22 cells provided additional evidence that SIRT1 activation ameliorated LPS-induced mitochondrial dysfunction and promoted mitophagy via Parkin-mediated pathway.ConclusionsThese findings suggested that activation of SIRT1 could alleviate depressive-like behaviors in mice following LPS challenge, potentially through a Parkin-dependent mitophagy mechanism.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12868-025-00968-2.

Depression-like behaviors and heme oxygenase-1 are regulated by Lycopene in lipopolysaccharide-induced neuroinflammation

BACKGROUNDThe association between hypothyroidism and depression is well established, but the underlying mechanisms remain unclear.AIMTo explore the potential role of the gut microbiota in depressive-like behaviors in a mouse model of hypothyroidism, with a focus on bacterial composition.METHODSHypothyroidism was induced in mice using propylthiouracil. Depressive-like behaviors were assessed using the sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT). Inflammatory cytokines, including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α, and IL-10, were quantified, together with colon histopathology scores, brain-derived neurotrophic factor, nuclear factor κB, inhibitor of nuclear factor κB, and tight junction proteins (occludin, claudin-1, zonula occludens-1). Gut microbial composition was determined by 16S rRNA gene sequencing of fecal samples.RESULTSPropylthiouracil-treated mice exhibited pronounced depressive-like behaviors, intestinal barrier dysfunction, elevated peripheral and central inflammation, and gut microbiota dysbiosis. Pearson correlation analysis showed that Bilophila and Psychrobacter abundance positively correlated with sucrose preference in the SPT and locomotor activity in the OFT, and negatively correlated with immobility times in the FST and TST. Gordonibacter abundance was positively correlated with locomotion in the OFT and negatively correlated with immobility in the FST and TST. Prevotellaceae_UCG_001 was inversely correlated with immobility in the FST and TST. Streptococcus was positively associated with sucrose preference in the SPT.CONCLUSIONThe observed associations between specific bacterial taxa and behavioral indices support a potential connection between gut microbiota composition and depressive symptoms in mice with hypothyroidism.

Fluoride exposure caused anxiety- and depression-like behavior in mice. Meanwhile, exercise contributes to relieve anxiety and depression. However, the effects of exercise on anxiety- and depression-like behavior in fluorosis mice remain unclear. In the current study, thirty-six Institute of Cancer Research (ICR) female mice were randomly assigned to four groups: control group (C, gavage with distilled water); exercise group (E, gavage with distilled water and treadmill exercise (speed, 10 m/min; time, 30 min/day)); fluoride group (F, gavage with 24 mg/kg sodium fluoride (NaF)); and exercise plus fluoride group (EF, gavage with 24 mg/kg NaF and treadmill exercise). All treatments lasted for 8 weeks. A number of entries into and time spent in the open zone in the elevated zero maze (EZM), resting time in the tail suspension test (TST) and levels of serotonin (5-HT) and gamma-aminobutyric acid (GABA), were significantly altered in F when compared to C. Meanwhile, the anxiety-like behavior in the EZM and the depression-like behavior in the TST were significantly improved in EF when compared to group F. Exercise significantly enhanced fluoride-induced low GABA level, with less effect on the concentration of 5-HT. Moreover, the mRNA and protein expressions of GABA synthesis and transport-related proteins of glutamic acid decarboxylase (GAD) 65 and GAD67 and vesicular GABA transporter (VGAT) were all strikingly decreased in F, while those in EF were increased. In conclusion, exercise ameliorates anxiety- and depression-like behavior in fluorosis mice through increasing the expressions of GABA synthesis and transport-related proteins, rather than 5-HT system.

The unfixed light pattern contributes to depressive-like behaviors in male mice

Prebiotic inulin alleviates anxiety and depression-like behavior in alcohol withdrawal mice by modulating the gut microbiota and 5-HT metabolism

Chronic trans-astaxanthin treatment exerts antihyperalgesic effect and corrects co-morbid depressive like behaviors in mice with chronic pain.

ObjectiveDepression is a significant mental disorder that damages human health. Jiannao Pills (JNW) as a commercial mediation has demonstrated its effectiveness in depression treatment but the mechanism remains elusive. This research endeavored to examine the effects of JNW on the depression-like behavior in mice subjected to chronic unpredictable mild stress (CUMS) and to elucidate the underlying molecular mechanism.MethodsThe CUMS-induced mice were utilized to evaluate the antidepressant efficacy of JNW. JNW was intragastric administered at the dosage of 0.375, 0.75 and 1.5 g/kg for 32 consecutive days. The following tests were employed to assess depression-like behavior: sucrose preference test (SPT), coat state assessment (CSA), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). The concentrations of Hypothalamic-pituitary-adrenal (HPA) axis hormone, monoamine neurotransmitter and pro-inflammation cytokine was quantified by ELISA. The transcriptional levels of pro-inflammation cytokine, Bcl-2, Bax, NLRP3 and Caspase-1 was assessed by qRT-PCR. The protein expression level of Bcl-2, Bax, NF-κB p65, IκBα, p-IκBα, NLRP3 and Caspase-1 was determined by Western blot.ResultsJNW could significantly enhance the sucrose preference, decrease CSA score, reduce immobility time of TST and FST and improve various aspects of behavior in OFT, including an increase in the number of entries to the central zone, the duration spent in the central zone, and the total movement distance. JNW could also suppress IL-1β, IL-6, and TNF-α production and mRNA expression, and lower the level of CRH in the hypothalamus and ACTH and CORT in the serum, increase the level of monoamine neurotransmitter in both serum and hippocampus, upregulate the mRNA and protein expression of Bcl-2 while downregulate the mRNA and protein expression of Bax. Furthermore, JNW notably suppressed NLRP3 and Caspase-1 mRNA and protein, inhibited the expression of NF-κB p65, and increased phosphorylation and degradation of IκBα.ConclusionJNW could alleviate depression-like behavior in mice subjected to CUMS, and these effects may be mediate through NF-κB/NLRP3 pathway.

Depression is one of the most common psychiatric symptoms in Alzheimer's disease (AD), and considerable evidence indicates that major depressive disorder increases the risk of AD.1, 2, 3 To date, however, the molecular mechanisms underlying the clinical association between depression and AD have remained elusive. Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of AD patients and are increasingly recognized as the proximal neurotoxins responsible for synapse failure and memory deficits in AD.4, 5 We have hypothesized that AβOs might be mechanistically linked to behavioral changes in AD. In order to test this hypothesis, mice were given a single intracerebroventricular (i.c.v.) injection of 10 pmol AβOs and were subsequently evaluated in the Porsolt forced swim test (FST) for assessment of depressive-like behavior. Compared with vehicle-injected control mice, AβO-injected mice exhibited a significant increase in immobility in the FST, both 24 h and 8 days after AβO injections (Figure 1a). Similar results were obtained when animals were assessed in the tail suspension test, another classical task to evaluate depressive-like behavior in rodents (Supplementary Figure S1a). AβO-induced immobility in the FST was blocked by anti-depressant (fluoxetine) treatment (Figure 1a). An important feature of depressive disorder is anhedonic behavior, including decreased interest for pleasurable sensorial experiences. Whereas vehicle-injected mice exhibited an expected preference for sucrose solution over plain water, AβO-injected mice did not exhibit such preference, indicating that AβOs instigate anhedonic behavior (Figure 1b). Figure 1 Amyloid-β oligomers (AβOs) induce depressive-like behavior, memory deficits and hippocampal recruitment of microglia and astrocytes in mice. Three-month-old Swiss mice received a single intracerebroventricular (i.c.v.) injection of AβOs ... As memory deficit is the main clinical symptom of AD, we investigated the impact of AβOs on mice memory using the novel object recognition (OR) task. Results showed that 24 h after i.c.v. injection, AβO-treated mice spent equal amounts of time exploring both old (familiar) and new (novel) objects, indicating a deficit in declarative recognition memory, whereas vehicle-injected animals exhibited a significant preference for the novel object (Figure 1c). Treatment with fluoxetine prevented the memory deficit induced by AβOs (Figure 1c). Control measurements showed no changes in spontaneous exploratory or locomotor activities of fluoxetine-, saline-, vehicle- or AβO-injected animals during the training phase of the OR test (Supplementary Figure S1c–e). As the hippocampus is a key anatomical structure for OR memory, we sought to determine whether AβOs injected i.c.v. reached the hippocampus. Indeed, robust AβO immunoreactivity was verified using an anti-oligomer monoclonal antibody (NU4)6 in hippocampi from AβO-injected mice, but not in hippocampi from control vehicle-injected animals (Supplementary Figure S1b). Together, these results indicate that AβOs have an acute impact on memory, learning and mood in mice, and that fluoxetine treatment prevented both cognitive impairment and depressive-like behavior induced by AβOs. The beneficial actions of fluoxetine have been partly ascribed to its anti-inflammatory effect. This led us to ask whether AβOs triggered an inflammatory response in the mouse brain. The brains of mice used in the tests described above were analyzed for levels of pro-inflammatory cytokines after i.c.v. injection of AβOs or vehicle. AβO-injected animals showed significantly elevated brain levels of interleukin-1β and tumor necrosis factor-α compared with vehicle-injected animals (Figure 1d, e). Sections from the hippocampus and cortex of AβO- or vehicle-injected mice were further immunostained for the presence of microglia (anti-Iba-1 antibody) and astrocytes (anti-GFAP antibody). Compared with vehicle-injected animals, AβO-injected mice showed markedly increased immunoreactivities for both Iba-1 and GFAP in the hippocampus and cortex 24 h after injection (Figure 1f–o, and Supplementary Figure 1f–o). The increase in glial cell numbers instigated by AβOs was blocked by fluoxetine treatment of the animals before AβO injection (Figure 1f–o, and Supplementary Figure 1f–o). The current findings establish that AβOs link memory impairment and depressive-like behavior in mice, providing molecular mechanistic support to clinical evidence connecting AD and depressive disorder. The impact of AβOs on mood, learning and memory, and its prevention by fluoxetine, can likely be attributed to the activation of inflammatory pathways (as shown here) and, possibly, to the deregulation of the serotonergic axis. The latter possibility is in line with the observation that pro-inflammatory cytokines impact serotonin metabolism7, 8 and that increased serotonin levels are associated with lower brain Aβ levels in transgenic mouse models of AD and in humans.9 Moreover, 5-HT1A and 5-HT2A receptors have been reported to be reduced in post-mortem AD brain,10 and 5-HT1A receptors have been found to be reduced in vivo in AD.11 Brain disturbances that place a person at risk for developing depression and AD are still largely unknown. By revealing that AβOs underlie both cognitive and depressive-like symptoms in mice, our results suggest a mechanism by which elevated brain levels of AβOs may be linked to changes in cognition and mood in AD.

The effects of curcumin on depressive-like behavior in mice after lipopolysaccharide administration

Depression is one of the most important mental illnesses and is closely related to inflammation. Betaine is a natural product with an anti-inflammatory and antioxidant activities. However, the mechanism by which betaine ameliorates depression-like behaviors induced by lipopolysaccharide (LPS) is poorly understood. The purpose of this study was to investigate the neuroprotective effect of betaine on LPS-induced depression-like behavior in mice and its mechanism of action. ICR mice were randomly divided into four groups: the control group, the LPS model group (0.83 mg/kg), the positive drug group (MIDO, 50 mg/kg), and the betaine group (5% and 1% in drinking water). The betaine group was administered for 21 days, and on the 22nd day, except for the blank group, LPS (0.83 mg/kg) was intraperitoneally injected to establish a lipopolysaccharide-induced mice depression-like model. Twenty-four hours after LPS injection, the tail suspension test (TST), open field test (OFT), and sucrose preference test (SPT) were performed to evaluate the effect of betaine on LPS-induced depressive behavior in mice. After the behavioral study, the mouse brain, hippocampus, and serum were taken for detection. The expressions of cytokines and inflammatory mediators were detected by ELISA, HE staining, immunofluorescence, immunohistochemistry, and western blotting. Western blotting was used to detect the protein expression levels of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), caspase-1, and ASC, the protein expression levels of the microglial polarization markers COX-2, inducible nitric oxide synthase (iNOS), and CD206. The results showed that betaine significantly ameliorated the depression-like behavior in LPS-induced mice, significantly attenuated the production of proinflammatory cytokines and increased the release of an anti-inflammatory cytokines. Betaine decreased the expression of the NLRP3 inflammasome, decreased the expression of M1 polarization markers, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), COX-2, and iNOS and promoted the expression of M2 polarization marker CD206. Our study suggests that betaine may promote the transition of microglia from the M1 to the M2 phenotype by inhibiting NLRP3 inflammasome activation, thereby attenuating lipopolysaccharide-induced depression-like behavior.

Depression is a frequent and serious illness, and 30% of depressed patients are resistant to antidepressants1. Teneurin-4 (Tenm4) is a protein encoded by ODZ4, and Tenm4 has been shown to contribute to myelin formation by being involved in cell adhesion2,3. Our previous study has been reported that mice with hippocampal Tenm4 knockdown show depressive-like behaviors4. However, detailed mechanisms of induction of the depressive-like behavior are not clarified in the hippocampal Tenm4 knockdown mice. We aim to elucidate the mechanisms of induction of the depressive-like behavior in the hippocampal Tenm4 knockdown mice, and identify novel therapeutic targets for depression.We hypothesized that reduction of myelination in the hippocampus is resulted in the induction of depressive-behaviors in the Tenm4-knockdown mice. To examine whether the reduction of myelination is occurred in the hippocampus-specific Tenm4 knockdown mice we investigated the recovery effects of clemasitne, a myelination-promoting agents, against the deperessive-behaviors. 8-week-old male C57BL/6J mice were injected AAVgRNA vectors using the CRISPR-Cas9 system bilaterally into the mice hippocampus, were knockdown Tenm4 (Tenm4KD group). Mock vectors were injected (mock group) into the mice hippocampus as control group. Clemastine was identified by a functional screen of compounds that promote myelin sheath remodeling in mice with damaged myelin sheath5. Tenm4KD group and mock group were intraperitoneally injected clemastine in 10% DMSO as a solvent at a dosage of 10 mg/kg (clemastine group) or 10% DMSO (vehicle group) for 2 weeks. Four groups (Tenm4KD-clemasitine, Tenm4KD-vehicle, mock-clemastine, mock-vehicle) performed behavioral tests including sucrose preference test, tail suspension test and forced swim test. After their behavioral tests, brain sections were prepared, and immunofluorescence staining for myelin basic protein (MBP) expressed in the myelin sheath was performed. In the sucrose preference test, sucrose preference in the Tenm4KD-vehicle group was significantly reduced comparing with the mock-vehicle group, while the Tenm4KD-clemastine group significantly suppressed the reduction of the preference. In the tail suspension test, the immobility time of the Tenm4KD-vehicle group was significantly prolonged comparing with the mock-vehicle group, while the Tenm4KD-clemastine group significantly suppressed the prolonged time. In the forced swimming test, the immobility time of the Tenm4KD-vehicle group was significantly prolonged comparing with the mock-vehicle group, while the Tenm4KD-clemastine group was tended to suppress the prolonged time.Immunohistochemical staining of hippocampal sections showed that MBP in the Tenm4KD-vehicle group was significantly reduced comparing with that of the mock-vehicle group, while the decrease was significantly suppressed in the Tenm4KD-clemastine group. In conclusion, the depressive-like behavior in mice with hippocampus-specific Tenm4 knockdown was suppressed by clemastine, a myelination- promoting agent. Myelination was decreased by hippocampus specific Tenm4 knockdown and increased by clemastine administration. These findings suggest that hippocampus Tenm4 is involved in depressive-like behavior via its function to promote myelination. These results of this study may provide insight into the development of new treatments for depression.