Stress-induced Neuroinflammation Research Articles

Forkhead Box 1(FoxO1) mediates psychological stress-induced neuroinflammation

ABSTRACT Objectives Neuroinflammation plays a key role in cerebrovascular disease (CVD). Neuropsychiatric disorders appear to share an epidemiological association with inflammation, but the mechanisms are unclear. Forkhead box 1 (FoxO1) regulates inflammatory signaling in diabetes and cardiovascular diseases, but its role in psychological stress-induced neuroinflammation remains unknown. Therefore, we investigated the potential involvement of FoxO1 in repeated social defeat stress (RSDS)-induced neuroinflammation. Methods 6-week-old male C57BL/6 J mice were randomly divided into RSDS or control groups. In the RSDS group, mice (18–22 g) were individually subjected to social defeat by an 8-week-old CD-1 mouse (28–32 g) for 10 min daily for 10 consecutive days. At 24 h after this 10-day process, corticosterone (CORT), epinephrine (EPI), hydrogen peroxide, and inflammatory factors (TNF-α, IL-6, IL-1β, and VCAM-1) from serum and brain tissues were assayed using ELISA, real-time PCR, and Western blot. Iba-1 was determined by immunofluorescence (IF), and FoxO1 siRNA was transfected into BV2 cells to further analyze the expression of inflammatory factors. Results RSDS significantly increased the levels of TNF-α, IL-6, IL-1β, and VCAM-1 in the serum; it also increased both mRNA and protein expression of these in the brain. FoxO1 was significantly increased after stress, while its knockdown significantly suppressed stress-induced inflammation. Immunofluorescence demonstrated the activation of microglia in the setting of RSDS. Conclusion RSDS induced a measurable inflammatory response in the blood and brain, and FoxO1 was demonstrated in vitro to aggravate stress-induced inflammation.

Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1β Signaling In Stress-induced Mice.

Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1β signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1β signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1β expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.

A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats

Worldwide, millions of people suffer from treatment-resistant depression. Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant effect even in treatment-resistant patients. A proposed mechanism for the antidepressant effect of ketamine is the reduction of neuroinflammation. To further explore this hypothesis, we investigated whether a single dose of ketamine can modulate protracted neuroinflammation in a repeated social defeat (RSD) stress rat model, which resembles features of depression. To this end, male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A combination of behavioral analyses and PET scans of the inflammatory marker TSPO in the brain were performed. Rats submitted to RSD showed anhedonia-like behavior in the sucrose preference test, decreased weight gain, and increased TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195 PET. Whole brain TSPO levels correlated with corticosterone levels in several brain regions of RSD exposed animals, but not in controls. Ketamine injection 1 day after RSD disrupted the correlation between TSPO levels and serum corticosterone levels, but had no effect on depressive-like symptoms, weight gain or the protracted RSD-induced increase in TSPO expression in male rats. These results suggest that ketamine does not exert its effect on the hypothalamic–pituitary–adrenal axis by modulation of neuroinflammation.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression.

Major depressive disorder is a debilitating mental illness and a leading cause of global disease burden. While many etiological factors have been identified, social stress is a highly prevalent causative factor for the onset of depression. Unfortunately, rates of depression continue to increase around the world, and the recent COVID-19 pandemic has further exacerbated this mental health crisis. Though several therapeutic strategies are available, nearly 50% of patients who receive treatment never reach remission. The exact mechanisms by which social stress exposure promotes the development of depression are unclear, making it challenging to develop novel and more effective therapeutics. However, accumulating evidence points to a role for stress-induced neuroinflammation, particularly in treatment-resistant patients. Moreover, recent evidence has expanded the concept of the pathogenesis of depression to mitochondrial dysfunction, suggesting that the combined effects of social stress on mitochondria and inflammation may synergize to facilitate stress-related depression. In this chapter, we review evidence for neuroinflammation and mitochondrial dysfunction in the pathogenesis of social stress-induced depression and discuss these in the context of novel therapeutic targets for the treatment of depression.

Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk.

The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.

Ameliorative Effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in Mouse Model.

The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. Alzheimer's disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer's disease (AD) in the mouse model. The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+ SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

Repeated Neonatal Isoflurane Exposure is Associated with Higher Susceptibility to Chronic Variable Stress-induced Behavioural and Neuro-inflammatory Alterations

Numerous studies have reported that prolonged or multiple exposures to anaesthetics in early life lead to detrimental effects on brain function, most having focused on neurocognitive function, and relatively few on long term neuropsychiatric performance. The present study investigated the impact of repeated neonatal isoflurane exposure on chronic variable stress (CVS)-induced psychiatric and behavioural outcomes together with CVS-related neuronal activity and neuro-inflammatory reactivity in relevant brain circuits. In the present study, C57BL/6J mice received either three exposures to isoflurane at postnatal days 7, 8, and 9 or a control exposure. From postnatal day 45, mice were exposed to a mild, 3-week, CVS paradigm or none and the CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The neuronal activity in relevant brain regions was measured by ΔFosB immunopositivity and CVS-related neuroinflammation was assessed by analysing levels of pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α. In mice experiencing serial neonatal isoflurane exposure, we detected a significant enhancement in anxiety levels following CVS procedures, together with enhanced neuronal activity, and exacerbated neuroinflammation in the basolateral amygdaloid nuclei (BLA) and hippocampal dentate gyrus (DG) regions. No such change was found in control mice. These results indicate an association between early multiple isoflurane exposures in infant mice and susceptibility to a CVS-evoked anxious phenotype accompanied by enhanced neuronal activity in BLA and DG regions and high inflammatory reactivity in response to CVS.

The Immunosuppressant Cyclosporine a Attenuates Stress-Induced Neuroinflammation

We have shown that calcineurin (CLN)-meditated immunosuppressants reduce alcohol intake in mice. Calcineurin plays key roles in reward, stress, and neuroinflammatory signaling. Ethanol use causes enhanced neuroinflammation and increased stress signaling. Similarly, stress also induces neuroinflammatory responses. Here we sought to determine the effects of cyclosporine A (CsA) on stress-induced neuroinflammatory markers in brain.

Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway.

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.

Left-right asymmetry in chronic stress-induced neuroinflammation

Left-right asymmetry in chronic stress-induced neuroinflammation

Unique maternal immune and functional microbial profiles during prenatal stress

Maternal stress during pregnancy is widespread and is associated with poor offspring outcomes, including long-term mental health issues. Prenatal stress-induced fetal neuroinflammation is thought to underlie aberrant neurodevelopment and to derive from a disruption in intrauterine immune homeostasis, though the exact origins are incompletely defined. We aimed to identify divergent immune and microbial metagenome profiles of stressed gestating mice that may trigger detrimental inflammatory signaling at the maternal–fetal interface. In response to stress, maternal glucocorticoid circuit activation corresponded with indicators of systemic immunosuppression. At the maternal–fetal interface, density of placental mononuclear leukocytes decreased with stress, yet maternal whole blood leukocyte analysis indicated monocytosis and classical M1 phenotypic shifts. Genome-resolved microbial metagenomic analyses revealed reductions in genes, microbial strains, and metabolic pathways in stressed dams that are primarily associated with pro-inflammatory function. In particular, disrupted Parasutterella excrementihominis appears to be integral to inflammatory and metabolic dysregulation during prenatal stress. Overall, these perturbations in maternal immunological and microbial regulation during pregnancy may displace immune equilibrium at the maternal–fetal interface. Notably, the absence of and reduction in overt maternal inflammation during stress indicates that the signaling patterns driving fetal outcomes in this context are more nuanced and complex than originally anticipated.

Fructooligosaccharides supplementation mitigated chronic stress-induced intestinal barrier impairment and neuroinflammation in mice

Abstract Recently, accumulating evidence has suggested that gut microbiota is involved in modulating brain function and behavior through the gut-brain axis. Manipulation of gut microbiota by functional foods, such as prebiotics and probiotics, might improve mental health in stress-related psychiatric disorders. In present study, we found that supplementation of fructooligosaccharides could improve the depression-like behaviors and had a significant effect on the composition of gut flora in chronic stress mice. FOS treatment exhibited no effects on the elevated level of serum corticosterone in chronic stress mice, but significantly reversed the alterations of colonic tight junction proteins (Claudin1, Occludin, ZO-1) and reduced the pro-inflammatory cytokines (TNF-α, IL-6) in colon and brain. Thus, FOS might exert an anti-depressant effect via the prevention of intestinal barrier impairment and neuroinflammation induced by chronic stress.

Depletion of brain perivascular macrophages regulates acute restraint stress-induced neuroinflammation and oxidative/nitrosative stress in rat frontal cortex

The central nervous system can respond to peripheral immune stimuli through the activation of the neurovascular unit. One of the cellular types implicated are perivascular macrophages (PVMs), hematopoietic-derived brain-resident cells located in the perivascular space. PVMs have been implicated in the immune surveillance and in the regulation of the accumulation/trafficking of macromolecules in brain-blood interfaces. Recent studies suggested that the role of PVMs could vary depending on the nature and duration of the immune challenge applied. Here, we investigate the role of PVMs in stress-induced neuroinflammation and oxidative/nitrosative consequences.The basal phagocytic activity of PVMs was exploited to selectively deplete them by ICV injection of liposomes encapsulating the pro-apoptotic drug clodronate. Acute restraint stress-induced neuroinflammation and oxidative/nitrosative stress in rat brain frontal cortex samples were assessed by western blot and RT-PCR analyses.The depletion of PVMs: (1) decreased tumor necrosis-α levels (2) prevented the Janus kinase/signal transducers and activators of transcription pathway and increased interleukin-6 receptor protein-expression in stress conditions; (3) prevented the stress-induced Toll-like receptor 4/Myeloid differentiation primary response 88 protein signaling pathway; (4) down-regulated the pro-inflammatory nuclear factor κB/cyclooxygenase-2 pathway; (5) prevented stress-induced lipid peroxidation and the concomitant increase of the endogenous antioxidant mediators nuclear factor (erythroid-derived 2)-like 2, glutathione reductase 1 and Parkinsonism-associated deglycase mRNA expression.Our results point to PVMs as regulators of stress-induced neuroinflammation and oxidative/nitrosative stress. Much more scientific effort is still needed to evaluate whether their selective manipulation is promising as a therapeutic strategy for the treatment of stress-related neuropsychopathologies.

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

BackgroundMicroglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear.MethodsThe stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope.ResultsWe showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGEfl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia.ConclusionsCollectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM.

Benzimidazole Containing Acetamide Derivatives Attenuate Neuroinflammation and Oxidative Stress in Ethanol-Induced Neurodegeneration

Oxidative stress-induced neuroinflammation is the prominent feature of neurodegenerative disorders, and is characterized by a gradual decline of structure and function of neurons. Many biochemical events emerge thanks to the result of this neurodegeneration, and ultimately provoke neuroinflammation, activation of microglia, and oxidative stress, leading to neuronal death. This cascade not only explains the complexity of events taking place across different stages, but also depicts the need for more effective therapeutic agents. The present study was designed to investigate the neuroprotective effects of newly synthesized benzimidazole containing acetamide derivatives, 3a (2-(4-methoxyanilino)-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide) and 3b (2-(Dodecylamino)-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide) against ethanol-induced neurodegeneration in the rat model. Both derivatives were characterized spectroscopically by proton NMR (1H-NMR) and carbon-13 NMR (13C-NMR) and evaluated for neuroprotective potential using different pharmacological approaches. In vivo experiments demonstrated that ethanol triggered neurodegeneration characterized by impaired antioxidant enzymes and elevated oxidative stress. Furthermore, ethanol administration induced neuroinflammation, as demonstrated by elevated expression of tumor necrotic factor (TNF-α), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX2), and ionized calcium-binding adapter molecule-1 (Iba-1), which was further validated by enzyme-linked immunosorbent assay (ELISA). Treatment with 3a and 3b ameliorated the ethanol-induced oxidative stress, neuroinflammation, and memory impairment. The affinity of synthesized derivatives towards various receptors involved in neurodegeneration was assessed through docking analysis. The versatile nature of benzimidazole nucleus and its affinity toward several receptors suggested that it could be a multistep targeting neuroprotectant. As repetitive clinical trials of neuroprotectants targeting a single step of the pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles of neuroinflammation.

Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death.

Recent studies from our group and others have demonstrated that oxidative stress, Ca2+ signaling, and neuroinflammation are major mechanisms contributing to post-traumatic neurodegeneration. The present study investigated the mechanisms of regulation of nuclear factor E2-related factor 2 (Nrf2) and its role in regulating antioxidant genes and oxidative stress-induced neuroinflammation and neurodegeneration following TBI. Nrf2 transcriptional system is the major regulator of endogenous defense mechanisms operating within the cells. Wild-type (Nrf2+/+) and Nrf2-deficient mice (Nrf2-/-) were subjected to 15 psi fluid percussion injury and demonstrated the regulatory role of Nrf2 in the expression antioxidant genes and oxidative stress, neuroinflammation, and cell death. Immunohistochemistry, q-RT-PCR, and western blotting techniques detected downregulation of Nrf2 and antioxidant proteins such as HO-1, GPx1, GSTm1, and NQO1 in mouse brain samples. Further, our study demonstrated that the downregulation of Nrf2 and antioxidant genes in TBI correlated with the induction of free radical-generating enzyme NADPH oxidase 1 and inducible nitric oxide synthase and their corresponding oxidative/nitrosative stress markers 4-hydroxynonenal and 3-nitrotyrosine. The decrease in Nrf2 with subsequent increase in oxidative stress markers led to the activation of MMP3/9, TGF-β1, and NF-kB that further led to neuroinflammation and apoptosis. The absence of Nrf2 function in mice resulted in exacerbated brain injury as shown by the increased oxidative stress markers, pro-inflammatory cytokines, and apoptosis markers at 24 h after TBI. In conclusion, this study could establish the significance of Nrf2 in transforming into a novel preventive approach against the pathophysiology of TBI. KEY MESSAGES: • Traumatic brain injury impairs Nrf2 signaling in mouse. • Nrf2-mediated activation of antioxidant genes are altered after TBI. • Impairment of Nrf2 signaling leads to oxidative stress. • TBI-induced downregulation of Nrf2 activates MMPs, TGF-β1, and NF-kB. • Nrf2 regulates neuroinflammation and apoptotic cell death in TB.

Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors.

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 and its role in depressive-like behaviors remain poorly understood. In this study, rats were subjected to 6 h of restraint stress per day for 21 days to produce a model of stress-induced depression. Behavioral tests and serum corticosterone were used to assess the success of the model. Furthermore, HAPI cells were pretreated with dexamethasone (5 × 10–7 M) to assess stress-induced changes in microglial cells in culture. The microglial marker Iba-1, reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) and key components of the NLRP3 inflammasome and its downstream inflammatory effectors (IL-1β and IL-18) were measured. Chronic stress induced depressive-like behavior, increased serum corticosterone levels and produced hippocampal structural changes. Chronic stress and dexamethasone both increased Iba-1 expression and ROS formation and also elevated levels of NF-κB, NLRP3, cleaved caspase-1, IL-1β and IL-18. After use of the NF-κB inhibitor BAY 117082 and knocked out NLRP3 in vitro decreased ROS formation and the expression of Iba-1, NF-κB and NLRP3 as well as levels of cleaved caspase-1, IL-1β and IL-18. These findings suggest that activation of the glucocorticoid receptor-NF-κB-NLRP3 pathway in hippocampal microglia mediates chronic stress-induced hippocampal neuroinflammation and depression-like behavior.

酸化ストレス誘発されるニューロン障害およびミクログリア依存性脳炎症に対するRatanasampilの抑制作用

Generation of reactive oxygen species (ROS) causes lipids, proteins and DNA damage, resulting in neuronal damage and neruoinflammation. Ratanasampil (RNSP), a traditional Tibetan medicine, clinically used for the mild-to moderate AD patients living at high altitude. In vivo, RNSP improved the learning and memory in an AD mouse model (Tg2576). However, mechanism underlying the effects of RNSP is unknown. In SH-SY5Y cells, RNSP significantly ameliorated the H2O2 –induced cytotoxicity. Furthermore, RNSP significantly reduced the H2O2-induced 8-oxo-2′-deoxyguanosine and attenuated the phosphorylation of p38 and ERK 1/2. In MG6 microglia, RNSP significantly ameliorated the cytotoxicity induced by hypoxia-reoxygenation. Furthermore, RNSP significantly suppressed the H6/R24-induced pro-inflammatory cytokines, ROS, DNA damage and phosphorylation of IκBα. These observations suggest that RNSP suppressed the H2O2-induced neuronal death through downregulation of p38-ERK activation and regulated the H/R-induced neuroinflammation through inhibition of oxidative stress and the activation of NFκB in MG6 cells. Therefore, RNSP may be beneficial for preventing oxidative stress-induced neuronal death and neuroinflammation.

Study of Behavioral Deficits Elicited by Exposure to Lipopolysacaride /Chronic Mild Stress in Male Wistar Rats

Background: depression may be considered disease of the modern era. With a high prevalence worldwide causing significant morbidity and mortality and constituting a heavy burden on social and economic welfare. Despite decades-long research the exact pathogenesis of depression is still not fully understood. Aims: to investigate the behvioral deficits elicited by exposure to the combined model of lipopolysaccharide (LPS) then chronic mild stress (CMS) in male Wistar rats and to investigate the putative role of inflammatory cytokine production induced lipopolysaccharide exposure together with chronic stress in the pathogenesis of depressive like behaviour. Materials and Methods: Sixty five Male Wistar rats were divided into two groups; Control group (n=29): naive rats left undisturbed, not exposed to stress and LPS/CMS exposed group (n=27). Results: exposure to LPS/CMS model induced a depressive-like behavior manifested by a decline in body weight gain, alongside an increase in immobility time in FST and a decrease in time of active interaction in SIT. Conclusion: this work highlights the depressive like behaviour induced by exposure to the combined model of lipopolysaccharide and chronic mild stress. This work also underscores the putative role of lipopolysaccharide exposure in modulating the stress-induced neuroinflammation which is thought to be crucial, not only for the pathogenesis of depression, but also for a wide array of neurological diseases.