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| The Wistar rats were challenged with chronic restraint stress with 6 h each day during 21 consecutive days. (A) Images of restrained rats (n = 12) for behavioral testing, (B) Image of restrained rats (n = 18) for subsequent experiments, (C) Schematic diagram showing the schedule of Body weight, Fecal pellet output (FPO), Sucrose preference test (SPT), Open field test (OFT), Forced swimming test (FST).
Source publication
Chronic stress is a key risk factor for depression, and microglia have been implicated in the pathogenesis of the disease. Recent studies show that the Nod-like receptor protein 3 (NLRP3) inflammasome is expressed in microglia and may play a crucial role in depression. However, the mechanism of NLRP3 inflammasome activation in hippocampal microglia...
Contexts in source publication
Context 1
... chronic restraint stress procedure was performed between 9:00 and 15:00, as previously described (Zhao et al., 2013;Seo et al., 2017). Briefly, except rats in C group, all rats were daily restrained into a transparent plexiglass tube (26 cm long and 8 cm in diameter) for 6 h over 21 consecutive days (Figures 1A,B). During CS group rats were restrained, the rats in the C group stay in their home cages without water and food. ...
Context 2
... behavioral experiments started on day 22 to 24 after 21 consecutive days restrained. At least 24 h between each behavior ( Figure 1C). ...
Context 3
... further clarify the roles of NF-κB and the NLRP3 inflammasome in depression, we inhibited NF-κB and knocked out the NLRP3 gene in vitro. Western blot results confirmed successful knockdown of NLRP3 gene (Supplementary Figure S1). Downregulation of NF-κB and NLRP3 reduced ROS levels, inhibited microglial activation, decreased Iba-1 expression, inhibited NF-κB nuclear translocation, and reduced NLPR3 inflammasome activation. ...
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Dexamethasone, a corticosteroid, has been approved for use in the treatment of severe COVID-19, which is characterised by hyperinflammation and associated lung damage. However, dexamethasone shows no clinical benefit in the treatment of less severe disease, and prolonged treatment may lead to immunosuppression and an increased risk of opportunistic...
Citations
... It is able to activate caspase-1 to produce inflammatory factors such as IL-1β (Dong et al., 2020). Feng et al. found that glucocorticoids can increase NF-kB nuclear transcription in hippocampal microglia, which then activates the NLRP3 inflammasome, disrupting the homeostasis of hippocampal microglia (Feng et al., 2019). Therefore, in vitro experiments, we used corticosterone to stimulate BV2 cells to mimic the effects of dark blue light at night on hippocampal microglia. ...
Objectives
Dim light at night contributes to neurodegenerative diseases by causing neuroinflammation. In the central nervous system, the activation of microglia is a significant contributor to neuroinflammation. Therefore, there is an urgent need to find an intervention to treat the neuroinflammatory response caused by dim light at night. Melatonin is a rhythmic hormone whose synthesis is suppressed during the day. In this study, we attempt to explore whether and how melatonin improves hippocampal neuroinflammation in mice exposed to dim blue light at night.
Materials and Methods
In vivo, a total of 36 male C57BL6/J mice that exposed to no light at night, dim blue light at night, and dim blue light at night with melatonin treatment. In vitro, the corticosterone-induced BV2 cells with or without melatonin treatment were used.
Results
Both in vivo and in vitro experiments showed melatonin treatment significantly reduced dim blue light -induced hippocampal microglial activation and the expression of inflammatory factors IL-1β and TNF-α. This improved effect of melatonin is related to its receptor MT2 rather than MT1. The MT2 blockers significantly increased mRNA levels of M1-type activation marker CD86 and inflammatory cytokines IL-1β and TNF-α in melatonin-treated BV2 cells. Binding of melatonin to its receptor MT2 downregulated the expression of inflammatory proteins P-P65 and NLRP3, consequently inhibited the CD80 expression and M1-type activation in microglia. Furthermore, consistent with the decrease in microglial activation and inflammatory response after melatonin treatment, we also observed a reduction in hippocampal neuron loss and damage to the HT22 cells.
Conclusion
Our findings suggested that melatonin may regulate microglial polarization through MT2/NF-kB-NLRP3 pathway and improves dim blue light -induced hippocampal neuroinflammation in mice.
... The interaction of these stimuli with NLRP3 causes the formation and activation of NLRP3 inflammasome, which results in the release of proinflammatory cytokines IL-1 and IL-18 in a caspase 1-dependent manner as well as the occurrence of gasdermin D-mediated pyroptotic cell death 7 . In view of these facts, it has been reported that a range of inhibitors have been developed to inhibit NLRP3 inflammasome such as dexamethasone (DEX) [8][9][10] . ...
Dexamethasone (DEX) is used to treat ocular surface diseases. However, regulating DEX duration in tears while preventing its absorption into the anterior chamber is critical for balancing its therapy effects and the side effects. In this study, a novel magnetic nanoparticle (MNP)-micelle (MC) codelivery
system (MMDS) was developed. The MC moiety in the MMDS served as the carrier for DEX and the MNP part endowed the MMDS with magnetic-responsive properties. To extend its residency, the MMDS was magnetically attracted by an external magnet after instilling, which acted as a precorneal drug-depot enabling a sustainable release of DEX in tears. With combination of magnet treatment, the topical instillation of MMDS@DEX significantly prolonged the DEX-retention in tears and increased the DEX-concentration in the cornea and conjunctiva, as well as concurrently reduced the DEX-level in the aqueous humor, when compared with the commercial DEX eye drop treatment. The combination of MMDS@DEX and magnet treatment exerted significantly better therapeutic effects against DED with smaller side effects than conventional treatments including DEX suspension, commercial DEX eye drops, as well as the MMDS@DEX treatment alone. The present work provided a new method for the effective delivery of DEX to ocular surface tissues while reducing its side effects, which will be beneficial to the treatments of a wide range of ocular surface diseases.
... In the histological assessment, CRS exhibited evident neuronal loss and appearance of apoptotic pyramidal neurons with pyknotic nuclei in the prefrontal cortex and hippocampus. Such findings were supported by Salama et al. [91], Jayakumar et al. [92], Feng et al. [93], Chandrasekhar et al. [94], Becerril-Chavez et al. [1] and de Lima et al. [95]. They can be explained by the occurrence of reactive gliosis in the prefrontal cortex and hippocampus in response to neuroinflammation [95], which is evidenced by high prefrontal cortical and hippocampal TNF-α levels in our study. ...
Chronic stress induces changes in the prefrontal cortex and hippocampus. Selenium nanoparticles (SeNPs) showed promising results in several neurological animal models. The implementation of SeNPs in chronic restraint stress (CRS) remains to be elucidated. This study was done to determine the possible protective effects of selenium nanoparticles on behavioral changes and brain oxidative stress markers in a rat model of CRS. 50 rats were divided into three groups; control group (n = 10), untreated CRS group (n = 10) and CRS-SeNPs treated group (n = 30). Restraint stress was performed 6 h./day for 21 days. Rats of CRS-SeNPs treated group received 1, 2.5 or 5 mg/kg SeNPs (10 rats each) by oral gavage for 21 days. Rats were subjected to behavioral assessments and then sacrificed for biochemical and histological analysis of the prefrontal cortex and hippocampus. Prefrontal cortical and hippocampal serotonin levels, oxidative stress markers including malondialdehyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx), tumor necrosis factor alpha (TNF-α) and caspase-3 were assessed. Accordingly, different doses of SeNPs showed variable effectiveness in ameliorating disease parameters, with 2.5 mg/kg dose of SeNPs showing the best improving results in all studied parameters. The present study exhibited the neuroprotective role of SeNPs in rats subjected to CRS and proposed their antioxidant, anti-inflammatory and anti-apoptotic effects as the possible mechanism for increased prefrontal cortical and hippocampal serotonin level, ameliorated anxiety-like and depressive-like behaviors and improved prefrontal cortical and hippocampal histological architecture.
... Notably, both chronic stress and dexamethasone administration resulted in elevated expression levels of Iba-1, reactive oxygen species (ROS) formation, as well as increased levels of NF-κB, cleaved caspase-1, NLRP3, IL-1β, and IL-18. These findings suggest that the glucocorticoid receptor-NF-κB-NLRP3 pathway in hippocampal microglia modulates chronic stress-induced inflammation in the HPC and contributes to the manifestation of depression-like behavior [182]. ...
Endometriosis (EM) is a gynecological inflammatory disease often accompanied by stress, chronic pelvic pain (CPP), anxiety, and depression, leading to a diminished quality of life. This review aims to discuss the relationship between systemic and local inflammatory responses in the central nervous system (CNS), focusing on glial dysfunctions (astrocytes and microglia) as in critical brain regions involved in emotion, cognition, pain processing, anxiety, and depression. The review presents that EM is connected to increased levels of pro-inflammatory cytokines in the circulation. Additionally, chronic stress and CPP as stressors may contribute to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, depleting the production of inflammatory mediators in the circulatory system and the brain. The systemic cytokines cause blood-brain barrier (BBB) breakdown, activate microglia in the brain, and lead to neuroinflammation. Furthermore, CPP may induce neuronal morphological alterations in critical regions through central sensitization and the activation of glial cells. The activation of glial cells, particularly the polarization of microglia, leads to the activation of the NLRP3 inflammasome and the overproduction of inflammatory cytokines. These inflammatory cytokines interact with the signaling pathways involved in neural plasticity. Additionally, persistent inflammatory conditions in the brain lead to neuronal death, which is correlated with a reduced volume of key brain regions such as the hippocampus. This review highlights the involvement of glial cells in the pathogenesis of the mental comorbidities of EM (i.e., pain, anxiety, and depression) and to discuss potential therapeutic approaches for targeting the inflammation and activation of microglia in key brain regions.
... The underlying mechanism of depression was suggested to be mediated by chronic hypercortisolemia, which results in excessive release of reactive oxygen species (ROS), increased NF-B transcriptional activity, and decreased synthesis of neurotrophic factors in many glucocorticoid receptor rich brain areas, such as the prefrontal cortex, amygdala, and hippocampus, with subsequent induction of structural and functional deficits. This sustained "stress responsive" HPA axis hyperactivity has been linked to the pathophysiology of depression and its associated cognitive dysfunction [38,39]. PDE inhibitors were, also, suggested to modulate brain functions by altering the cAMP/cGMP/BDNF signaling [40]. ...
Depression is a common stress disability disorder that affects higher mental functions including emotion, cognition, and behavior. It may be mediated by inflammatory cytokines that interfere with neuroendocrine function, and synaptic plasticity. Therefore, reductions in inflammation might contribute to treatment response. The current study aims to evaluate the role of Protein Kinase (PKA)- cAMP response element-binding protein (CREB)- brain derived neurotropic factor (BDNF) signaling pathway in depression and the effects of roflumilast (PDE4 inhibitor) as potential antidepressant on the activity of the PKA-CREB-BDNF signaling pathway, histology, and pro-inflammatory cytokine production. Forty Adult male Wistar rats were divided into 4 groups: Control group, Positive Control group: similar to the controls but received Roflumilast (3 mg / kg / day) by oral gavage for the last 4 weeks of the experiment, Depressed group which were exposed to chronic stress for 6 weeks, and Roflumilast-treated group which were exposed to chronic stress for 6 weeks and treated by Roflumilast (3 mg / kg / day) by oral gavage for the last 4 weeks of the experiment. The depressed group showed significant increase in immobility time with significant decrease in swimming and struggling times, significant decrease in hippocampal PKA, CERB, BDNF, Dopamine, Cortisone, and Superoxide dismutase while hippocampal Phosphodiesterase-E4, Interleukin-6, and Malondialdhyde levels were significantly elevated. These findings were significantly reversed upon Roflumilast treatment. Therefore, it could be concluded that depression is a neurodegenerative inflammatory disease and oxidative stress plays a key role in depression. Roflumilast treatment attenuated the depression behavior in rats denoting its neuroprotective, and anti-inflammatory effects.
... In contrast, A strong positive correlation was found between the expression of the CRF gene and brain immunoexpression of caspase-3, COX2, IL6, GFAP, IBA-1, NFκB, serum corticosterone, proinflammatory cytokines, and brain lipid peroxidation marker. It is also documented that the chronic stress elevated serum corticosterone concentrations and IBA-1, cleaved caspase-1, NFκB, IL-1β immunoexpression 114 . ...
Chronic immobilization stress plays a key role in several neuropsychiatric disorders. This investigation assessed the possible ameliorative effect of chia seed oil (CSO) against the neurodisturbance-induced in rats by chronic immobilization. Rats were randomly allocated into control, CSO (1 ml/kg b.wt./orally), restrained (6 h/day), CSO pre-restraint, and CSO post-restraint for 60 days. Results revealed a significant reduction in serum corticosterone level, gene expression of corticotrophin-releasing factor, pro-inflammatory cytokines, and oxidative biomarkers in restrained rats treated with CSO. The histopathological findings revealed restoring necrosis and neuronal loss in CSO-treated-restraint rats. The immunohistochemical evaluation revealed a significant reduction in the immuno-expression of caspase-3, nuclear factor kappa B, interleukin-6, and cyclooxygenase-2 (COX-2), and an elevation of calbindin-28k and synaptophysin expression compared to non-treated restraint rats. The molecular docking showed the CSO high affinity for several target proteins, including caspase-3, COX-2, corticotropin-releasing hormone binding protein, corticotropin-releasing factor receptors 1 and 2, interleukin-1 receptor types 1 and 2, interleukin-6 receptor subunits alpha and beta. In conclusion, CSO emerges as a promising candidate against stress-induced brain disruptions by suppressing inflammatory/oxidative/apoptotic signaling pathways due to its numerous antioxidant and anti-inflammatory components, mainly α-linolenic acid. Future studies are necessary to evaluate the CSO therapeutic impacts in human neurodisturbances.
... Corticosterone binds to the glucocorticoid receptor (GR), inducing increased Iba-1, NF-κB, NLRP3, cleaved caspase-1, IL-18, and IL-1β contents in the hippocampus of rats. Findings have suggested that the activation of the GR-NF-κB-NLRP3 pathway mediates chronic stress-induced depression-like behaviors and microglial neuroinflammation in rats (Feng et al., 2019). TLR4 has also been shown to mediate neuroinflammation. ...
... Several cellular components, including lipids, proteins, and DNA, can be damaged by this. As previously mentioned, chronic restraint stress causes an increase in the GC level, which binds to the GR and then promotes ROS formation in the hippocampus of rats (Feng et al., 2019). ROS production can promote the NLRP3 inflammasome activation, also called protein complex assembly (Martinon, 2010;Harijith et al., 2014). ...
... Further, Cli-095, a TLR4 inhibitor, exerted antidepressant effects via the suppression of the TLR4-NF-κB-NLRP3 pathway in CUMS mice (Fu et al., 2019). BAY 117082, an inhibitor of NF-κB, decreased levels of NF-κB, IL-18, IL-1β, NLRP3, ASC, and cleaved caspase-1 (Feng et al., 2019). Additionally, both Brilliant Blue G and A438079, P2X7 receptor inhibitors, alleviated depressionlike behaviors by inhibiting the ATP-P2X7 receptor-NLRP3 signaling pathway in CUMS rats (Yue et al., 2017). ...
Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.
... The relationship between the two (i.e., emotional disorders and metabolic diseases) seems to be mediated by inflammation. For instance, some evidence stressed a mediating role of NLRP3 inflammatory bodies in hippocampal neuroinflammation and depression-like behavior (16,17). Thus, the metabolic alteration, would be preceded by an altered inflammatory status. ...
Background
In recent decades, the relationship between emotional disorders (i.e., depression and anxiety) and alterations in physiological functions (i.e., inflammation or metabolism) have been well supported. However, studies on a symptom-based approach have provided mixed results. Our study aims to gain insight into how subclinical statuses, featured by elevated depressive and/or anxious symptoms, may influence immunometabolic alterations in the concurrent relationship; and the development of metabolic diseases at 10-year follow-up: diabetes, hypertension and hypercholesterolemia.
Methods
Data from 758 Greek adults [394 men (aged 41 ± 10 years) and 364 women (aged 37 ± 12 years)] were used. Four groups were created according to the levels of depressive and anxiety symptoms: (1) control group (CG), (2) depressive group (DG), (3) anxiety group (AG) and (4) depressive and anxiety group (DAG). Multi-indicator multi-causes (MIMIC) modeling was used to estimate metabolic function and inflammatory response scores, on a wide selection of blood biomarkers. Finally, a binary logistic regression was carried out to study the influence of symptoms on the development of the aforementioned metabolic diseases on a 10-year follow-up.
Results
Group membership was not associated with metabolic function score. Conversely, DAG membership was related with higher inflammatory response score (B = 0.20, CI95 = 0.01, 0.40), with respect to the CG (p < 0.05). Both age and sex were significant variables in the calculation of both scores. Regarding disease at 10-year follow-up effect, risk of developing diabetes, hypertension and hypercholesterolemia was associated with age and socioeconomic status. Moreover, DG membership was significant for diabetes risk (OR = 2.08, CI95 = 1.00, 4.22) and DAG for hypercholesterolemia (OR = 1.68, CI95 = 1.16, 2.43).
Limitations
Data on anti-inflammatory drugs and psychopharmacological medication were not collected in this study.
Conclusions
Elevated symptoms of depression and anxiety accounts for inflammatory alterations at concurrent relationship and a higher risk of 10-year follow-up metabolic diseases.
... From a neuroendocrine perspective, stress activates the HPA axis, during which it releases glucocorticoids. In a study incorporating dexamethasone, it was demonstrated that this glucocorticoid induces inflammation via the nuclear factor-kappa-B (NF-kB)/NLRP3 pathway and activates proinflammatory genes and cytokines (Feng et al., 2019). This may seem contradictory to the notion of immune suppression by the HPA axis; however, chronic inflammation drives glucocorticoid resistance both in the immune system as well as target cells, eventually decreasing inhibitory feedback on the production of the corticotropin-releasing hormone that could stir up stress response ( Fig. 1 section B) (Nikkheslat et al., 2015). ...
... Thus, restraint stress-driven corticosterone may explain how restraint stress stimulates FXR/NLPR3 signaling. Previous reports have shown that chronic stress can activate the NLRP3 inflammasome by inducing glucocorticoid release and activating glucocorticoid receptors (GRs) to increase the nuclear transcription of NF-κB [48]. Additionally, GR interacts with FXR to inhibit its transcriptional activity [49]. ...
Psychological stress promotes nonalcoholic steatohepatitis (NASH) development. However, the pathogenesis of psychological stress-induced NASH remains unclear. This study aims to explore the underlying mechanism of restraint stress-induced NASH, which mimics psychological stress, and to discover potential NASH candidates. Methionine choline deficient diet- and high fat diet-induced hepatosteatotic mice are subjected to restraint stress to induce NASH. The mice are administrated with Xiaoyaosan granules, NOD-like receptor family pyrin domain containing 3 (NLRP3) inhibitors, farnesoid X receptor (FXR) agonists, or macrophage scavengers. Pathological changes and NLRP3 signaling in the liver are determined. These results demonstrate that restraint stress promotes hepatic inflammation and fibrosis in hepatosteatotic mice. Restraint stress increases the expressions of NLRP3, Caspase-1, Gasdermin D, interleukin-1β, cholesterol 7α-hydroxylase, and sterol 12α-hydroxylase and decreases the expression of FXR in NASH mice. Xiaoyaosan granules reverse hepatic inflammation and fibrosis and target FXR and NLRP3 signals. In addition, inhibition of NLRP3 reduces the NLRP3 inflammasome and liver damage in mice with restraint stress-induced NASH. Elimination of macrophages and activation of FXR also attenuate inflammation and fibrosis by inhibiting NLRP3 signaling. However, NLRP3 inhibitors or macrophage scavengers fail to affect the expression of FXR. In conclusion, restraint stress promotes NASH-related inflammation and fibrosis by regulating the FXR/NLRP3 signaling pathway. Xiaoyaosan granules, NLRP3 inhibitors, FXR agonists, and macrophage scavengers are potential candidates for the treatment of psychological stress-related NASH.
