Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression

Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5 mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression-targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFα, IL-1β and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression.     

Etazolate rescues behavioral deficits in chronic unpredictable mild stress model: Modulation of hypothalamic–pituitary–adrenal axis activity and brain-derived neurotrophic factor level

Preliminary study in our laboratory showed that etazolate produced antidepressant- and anxiolytic-like effects in rodent models, however, the ability of etazolate to produce antidepressant- and anxiolytic-like effects and underlying mechanism(s) in chronic unpredictable mild stress (CUMS) model have not been adequately addressed. This study was aimed to investigate the beneficial effects of etazolate on CUMS-induced behavioral deficits (depression- and anxiety-like behaviors). In addition, the possible underlying mechanism(s) of etazolate in CUMS model was also investigated by measuring serum corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels. Mice were subjected to a battery of stressors for 28 days. Etazolate (0.5 and 1 mg/kg, p.o.) and fluoxetine (20 mg/kg, p.o.) were administered during the last 21 days (8–28th) of the CUMS paradigm. The results showed that 4-weeks CUMS produces significant depression-like behavior in tail suspension test (TST) and partial anxiety-like behavior in elevated plus maze (EPM) and open field test (OFT). Stressed mice have also shown a significant high serum CORT and low BDNF level. Chronic treatment with etazolate (0.5 and 1 mg/kg., p.o.) and fluoxetine (20 mg/kg., p.o.) produced significant antidepressant-like behavior in TST (decreased duration of immobility), whereas, partial anxiolytic-like behavior in EPM (increased percentage of open arm entries) and OFT (increased % central ambulation score, total ambulation score and time spent in center zone). In addition, etazolate and fluoxetine treatment significantly (p < 0.05) increased the BDNF level and inhibited the hypothalamic–pituitary–adrenocortical (HPA) axis hyperactivity, as evidenced by low serum CORT level in stressed mice. In addition, etazolate and fluoxetine also showed significant antidepressant- and anxiolytic-like effects in normal control mice. In this study no significant changes were observed in locomotor activity in actophotometer test. Moreover, we did not find any effect of etazolate and fluoxetine on CORT and BDNF levels in normal control mice. In conclusion, the results of the present study suggested compelling evidences that etazolate has more marked effect on depression-like behavior in mice, which is atleast in part may be related to their modulating effects on the HPA axis and BDNF level.     

Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress.     

Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine

J. Neurochem. (2012) 122, 995-1009. ABSTRACT: Up-regulation of proinflammatory cytokines and chemokines in brain ("neuroinflammation") accompanies neurological disease and neurotoxicity. Previously, we documented a striatal neuroinflammatory response to acute administration of a neurotoxic dose of methamphetamine (METH), i.e. one associated with evidence of dopaminergic terminal damage and activation of microglia and astroglia. When we used minocycline to suppress METH-induced neuroinflammation, indices of dopaminergic neurotoxicity were not affected, but suppression of neuroinflammation was incomplete. Here, we administered the classic anti-inflammatory glucocorticoid, corticosterone (CORT), in an attempt to completely suppress METH-related neuroinflammation. METH alone caused large increases in striatal proinflammatory cytokine/chemokine mRNA and subsequent astrocytic hypertrophy, microglial activation, and dopaminergic nerve terminal damage. Pre-treatment of mice with acute CORT failed to prevent neuroinflammatory responses to METH. Surprisingly, when mice were pre-treated with chronic CORT in the drinking water, an enhanced striatal neuroinflammatory response to METH was observed, an effect that was accompanied by enhanced METH-induced astrogliosis and dopaminergic neurotoxicity. Chronic CORT pre-treatment also sensitized frontal cortex and hippocampus to mount a neuroinflammatory response to METH. Because the levels of chronic CORT used are associated with high physiological stress, our data suggest that chronic CORT therapy or sustained physiological stress may sensitize the neuroinflammatory and neurotoxicity responses to METH.     

A Possible Link between Food and Mood: Dietary Impact on Gut Microbiota and Behavior in BALB/c Mice

Major depressive disorder is a debilitating disease in the Western World. A western diet high in saturated fat and refined sugar seems to play an important part in disease development. Therefore, this study is aimed at investigating whether saturated fat or sucrose predisposes mice to develop behavioral symptoms which can be interpreted as depression-like, and the possible influence of the gut microbiota (GM) in this. Fourty-two mice were randomly assigned to one of three experimental diets, a high-fat, a high-sucrose or a control diet for thirteen weeks. Mice on high-fat diet gained more weight (p = 0.00009), displayed significantly less burrowing behavior than the control mice (p = 0.034), and showed decreased memory in the Morris water maze test compared to mice on high-sucrose diet (p = 0.031). Mice on high-sucrose diet burrowed less goal-oriented, showed greater latency to first bout of immobility in the forced swim test when compared to control mice (p = 0.039) and high-fat fed mice (p = 0.013), and displayed less anxiety than mice on high-fat diet in the triple test (p = 0.009). Behavioral changes were accompanied by a significant change in GM composition of mice fed a high-fat diet, while no difference between diet groups was observed for sucrose preferences, LPS, cholesterol, HbA1c, BDNF and the cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12(p70), IL-17 and TNF-α. A series of correlations was found between GM, behavior, BDNF and inflammatory mediators. In conclusion, the study shows that dietary fat and sucrose affect behavior, sometimes in opposite directions, and suggests a possible association between GM and behavior.     

Long-term effects of combined neonatal and adolescent stress on brain-derived neurotrophic factor and dopamine receptor expression in the rat forebrain

Altered brain-derived neurotrophic factor (BDNF) signalling and dopaminergic neurotransmission have been shown in the forebrain in schizophrenia. The ‘two hit’ hypothesis proposes that two major disruptions during development are involved in the pathophysiology of this illness. We therefore used a ‘two hit’ rat model of combined neonatal and young-adult stress to assess effects on BDNF signalling and dopamine receptor expression. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. At adulthood the medial prefrontal cortex (mPFC), caudate putamen (CPu) and nucleus accumbens (NAc) were analysed by qPCR and Western blot. The ‘two hit’ combination of MS and CORT treatment caused significant increases in BDNF mRNA and protein levels in the mPFC of male, but not female rats. BDNF mRNA expression was unchanged in the CPu but was significantly reduced by CORT in the NAc. DR3 and DR2 mRNA were significantly up-regulated in the mPFC of two-hit rats and a positive correlation was found between BDNF and DR3 expression in male, but not female rats. DR2 and DR3 expression were significantly increased following CORT treatment in the NAc and a significant negative correlation between BDNF and DR3 and DR2 mRNA levels was found. Our data demonstrate male-specific two-hit effects of developmental stress on BDNF and DR3 expression in the mPFC. Furthermore, following chronic adolescent CORT treatment, the relationship between BDNF and dopamine receptor expression was significantly altered in the NAc. These results elucidate the long-term effects of ‘two hit’ developmental stress on behaviour.     

PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions

Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro‐apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron–microglia co‐cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine‐month‐old double‐mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double‐mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double‐mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia‐induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.     

Nrf2 Signaling Pathway Mediates the Antioxidative Effects of Taurine Against Corticosterone-Induced Cell Death in HUMAN SK-N-SH Cells

Substantial evidence has shown that elevated circulating corticosteroids or chronic stress contributes to neuronal cell death, cognitive and mental disorders. However, the underlying mechanism is still unclear. Taurine is considered to protect neuronal cells from apoptotic cell death in neurodegenerative diseases and neuropsychiatric disorders. In the present study, the protective effects of taurine against corticosterone (CORT)-induced oxidative damage in SK-N-SH neuronal cells were investigated. The results showed that CORT significantly induced cell death, which was blocked by pretreatment with taurine. Similarly, pretreatment with taurine suppressed CORT-induced apoptotic cell death decreasing the levels of intracellular reactive oxygen species and improving mitochondrial function. Pretreatment with taurine increased the expression of phosphorylated extracellular regulated protein kinases (ERK) as well as the nuclear translocation of nuclear factor (erythroid 2-derived)-like 2 (Nrf2) in the CORT rich environment. Furthermore, administration of the ERK inhibitor U0126 or transient (siRNA) silencing of Nrf2 blocked the protective effects of taurine on cell viability and expression levels of Nrf2 and heme oxygenase-1 (HO-1) in the CORT model of neuronal damage. These results suggest that the Nrf2 signaling pathway may play a role in the protection mechanism of taurine against CORT-induced neuronal oxidative damage.     

锌离子调节皮质酮对原代培养大鼠海马神经元的损伤

探讨皮质酮对原代培养大鼠海马神经元的损伤效应及锌的调节作用。用原位染色和RT-PCR方法,分别检测神经元的损伤情况及NMDA受体三种亚基(NRl、NR2A、NR2B)mRNA的表达。皮质酮(5μmol／L)作用2,4h可明显降低海马神经元的存活率,导致神经元凋亡,并随着作用时间的延长而加重;锌离子明显影响皮质酮对海马神经元的损伤效应：同时加入皮质酮和低、中浓度Zn^2 (10、100μmol／L),可明显降低神经元凋亡率,而加入高浓度Zn^2 (250μmol／L)则加重神经元损伤。皮质酮作用24h后,海马神经元NRl、NR2BmRNA的表达水平增高,而同时加入低、中浓度Zn^2 (10、100μmol／L)的海马神经元NRl、NR2BmRNA表达水平与对照组接近;NR2AmRNA表达无明显变化。这些结果表明,锌对皮质酮所致应激损伤的调节具有双向性;NMDA受体亚基水平的变化可能是其中重要环节之一。     

<Emphasis Type="Italic">Trans</Emphasis>-cinnamaldehyde Modulates Hippocampal Nrf2 Factor and Inhibits Amyloid Beta Aggregation in LPS-Induced Neuroinflammation Mouse Model

Trans-cinnamaldehyde (CNM) has recently drawn attention due to its potent anti-inflammatory and antioxidant properties. The current study explored the memory enhancing effects of CNM against lipopolysaccharide (LPS)-induced neuroinflammation in mice. CNM and curcumin (a reference antioxidant) were administered at a dose of 50 mg/kg i.p. 3 h after a single LPS injection (0.8 mg/kg, i.p.) and continued daily for 7 days. Our results displayed that CNM and curcumin significantly ameliorated the LPS-induced impairment of learning and memory, neuroinflammation, oxidative stress and neuronal apoptosis. Memory functions and locomotor activity were assessed by Morris water maze, object recognition test and open field test. Both CNM and curcumin activated the nuclear factor erythroid 2 related factor 2 (Nrf2) and restored levels of downstream antioxidant enzymes superoxide dismutase and glutathione-S-transferase (GST) in the hippocampus. They also attenuated LPS-induced increase in hippocampal contents of interleukin-1β (IL-1β), malondialdehyde and caspase-3. Immunohistochemistry results showed that both CNM and curcumin reduced Aβ_1–42 protein accumulation in brain of mice. Remarkably CNM’s effect on IL-1β was less pronounced than curcumin; however it showed higher GST activity and more potent anti-apoptotic and anti-amylodogenic effect. We conclude that, CNM produces its memory enhancing effects through modulation of Nrf2 antioxidant defense in hippocampus, inhibition of neuroinflammation, apoptosis and amyloid protein burden.     

Effect of dexmedetomidine on rats with convulsive status epilepticus and association with activation of cholinergic anti-inflammatory pathway

Convulsive status epilepticus (CSE) is a neurological disease with contraction and extension of limbs, leading to damage of hippocampus and cognition. This study aimed to explore the effects of dexmedetomidine (DEX) on the cognitive function and neuroinflammation in CSE rats. All rats were divided into control group, CSE group and DEX group. Morris water maze test was used to measure cognitive function. Acute hippocampal slices were made to detect long-term potentiation (LTP). Immunohistochemistry was used to determine the expression of α7-nicotinic acetylcholine receptor (α7-nAChR) and interleukin-1β (IL-1β). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of IL-1β, tumor necrosis factor-α (TNF-α), S-100β and brain-derived neurotrophic factor (BDNF). Our results showed that DEX improved the memory damage caused by CSE. DEX reduced seizure severity and increased the amplitudes and sustainable time of LTP, and also inhibited the hippocampal expression of α7-nAChR and IL-1β in CSE rats. DEX treatment decreased serum IL-1β, TNF-α and S-100β levels and increased BDNF levels. The effects of DEX on seizure severity and LTP could be simulated by nicotine or attenuated by concurrent α-bungarotoxin (α-BGT) treatment. In conclusions, DEX significantly improved spatial cognitive dysfunction, reduced seizure severity and increased LTP in CSE rats. Improvements by DEX were closely related to enhancement of cholinergic anti-inflammatory pathway.     

Prolonged depression-like behavior caused by immune challenge: influence of mouse strain and social environment

Immune challenge by bacterial lipopolysaccharide (LPS) causes short-term behavioral changes indicative of depression. The present study sought to explore whether LPS is able to induce long-term changes in depression-related behavior and whether such an effect depends on mouse strain and social context. LPS (0.83 mg/kg) or vehicle was administered intraperitoneally to female CD1 and C57BL/6 mice that were housed singly or in groups of 4. Depression-like behavior was assessed with the forced swim test (FST) 1 and 28 days post-treatment. Group-housed CD1 mice exhibited depression-like behavior 1 day post-LPS, an effect that leveled off during the subsequent 28 days, while the behavior of singly housed CD1 mice was little affected. In contrast, singly housed C57BL/6 mice responded to LPS with an increase in depression-like behavior that was maintained for 4 weeks post-treatment and confirmed by the sucrose preference test. Group-housed C57BL/6 mice likewise displayed an increased depression-like behavior 4 weeks post-treatment. The behavioral changes induced by LPS in C57BL/6 mice were associated with a particularly pronounced rise of interleukin-6 in blood plasma within 1 day post-treatment and with changes in the dynamics of the corticosterone response to the FST. The current data demonstrate that immune challenge with LPS is able to induce prolonged depression-like behavior, an effect that depends on genetic background (strain). The discovery of an experimental model of long-term depression-like behavior after acute immune challenge is of relevance to the analysis of the epigenetic and pathophysiologic mechanisms of immune system-related affective disorders.     

不同方法建立C57BL/6J小鼠抑郁症模型的探讨

目的用不同方法建立C57BL/6J小鼠抑郁症模型,为探讨GalR蛋白对小鼠抑郁症的治疗作用打下基础。方法 C57BL/6J小鼠经体重、敞箱实验及反抗抓获实验初筛后,随机分为4组:Ⅰ.CUMS组,Ⅱ.CUMS+CORT组,Ⅲ.CORT组,Ⅳ.正常对照组。每天记录小鼠体重及摄食量。28d后进行液体消耗及强迫游泳实验测试。结果小鼠抑郁模型在第28d建立成功。Ⅱ组小鼠短期内体重迅速下降并死亡。与Ⅰ组小鼠相比,Ⅲ组小鼠液体消耗和强迫游泳实验指标改变更明显。结论成功建立C57BL/6J小鼠抑郁症模型。CUMS和CORT模型结合,小鼠不能耐受,短期内死亡。单独CORT模型造模效果要优于CUMS模型。在后续试验中,将用CORT法建立C57BL/6J小鼠抑郁症模型。     

Effect of anti-dementia drugs on LPS induced neuroinflammation in mice

Inflammation has been recently implicated in pathogenesis of dementia disorders. Effect of anti-dementia (Acetylcholinesterase inhibitor) drugs tacrine, rivastigmine and donepezil were studied on neuroinflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) in mice. Interleukin-2 (IL-2) and isoforms of acetylcholinesterase (AChE) were estimated in different brain areas as marker for neuroinflammation and cholinergic activity respectively. LPS significantly increased the level of IL-2 in all the brain areas while enhancement of AChE activity varied in brain areas. It was found that administration of tacrine, rivastigmine and donepezil in mice significantly attenuated the LPS induced increased levels of IL-2 along with the significant reduction of AChE activity predominantly in salt soluble (SS) fraction as compared to the detergent soluble (DS) fraction in a dose dependent manner. In vitro effect of LPS was also studied in different brain areas. LPS significantly increased the AChE activity in SS fractions but the significant increase was not found in DS fractions. The present study indicate that cholinesterase inhibitor anti-dementia drugs are effective against LPS induced neuroinflammation that may be linked to enhanced cholinergic activity.     

Impairment of long-term depression induced by chronic brain inflammation in rats

Although deficits in synaptic plasticity have been identified in aged or neuroinflamed animals with memory impairments, few studies have examined the cellular basis of plasticity in such animals. Here, we examined whether chronic neuroinflammation altered long-term depression (LTD) and studied the underlying mechanism of LTD impairment by neuroinflammation. Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) to the fourth ventricle. Excitatory postsynaptic potentials were recorded extracellularly in the rat hippocampal CA1 area to examine alterations in synaptic plasticity. Chronic administration of LPS induced remarkable memory impairment in the Morris water maze test. N-methyl-d-aspartate receptor (NMDAR)-dependent LTD was almost absent in LPS-infused animals. The AMPA receptor (AMPAR)-mediated synaptic response was reduced in the LPS-infused group. These results suggest that reduction in NMDAR-dependent LTD might arise because of alterations in postsynaptic AMPARs as well as NMDARs and that such changes may be present in mild and early forms of Alzheimer-type dementia.     

Up-regulation of IL-18BP,but not IL-18 mRNA in rat liver by LPS

Interleukin (IL)-18 is a pro-inflammatory cytokine that plays a critical role in inflammation leading to liver damage, through promotion of Fas-mediated apoptosis. Inhibition of IL-18 activity protects against LPS-induced lethality in mice and against liver damage induced by LPS after sensitisation of mice with Proprionibacterium acnes. A specific, potent, endogenous inhibitor of IL-18 (IL-18BP) has been identified in mice and humans, and IL-18BP mRNA is expressed constitutively in liver. The objectives of this study were to compare changes in IL-1beta and IL-18 mRNA expression in the liver of rats in response to peripheral injection of LPS, using real-time PCR, and also to investigate whether IL-18BP mRNA expression is affected by this treatment. LPS rapidly up-regulated IL-1beta mRNA expression, but IL-18 mRNA expression was unaffected by LPS treatment. Unlike IL-18, IL-18BP mRNA was up-regulated dramatically by approximately 12-fold above nai;ve levels, peaking 3 h after LPS injection. This ability of LPS to up-regulate expression of the endogenous IL-18 inhibitor may indicate a mechanism by which the inflammatory response to LPS is regulated.     

Protective effects of dihydromyricetin on primary hippocampal astrocytes from cytotoxicity induced by comorbid diabetic neuropathic pain and depression

Activated astrocytes play a key role in diabetic neuropathic pain and depression. We aimed to assess the protective effects of dihydromyricetin (DHM) on primary hippocampal astrocytes cultured with high glucose (HG), substance P (SP), and corticosterone (CORT). Culturing with HG + SP + CORT resulted in damage to primary hippocampal astrocytes, which simulates the clinical damage caused by comorbidity of diabetic neuropathic pain and depression. Western blot, qPCR, and immunofluorescence analyses revealed that HG + SP + CORT increased P2X₇ receptor expression in primary hippocampal astrocytes, which was reversed by DHM treatment. Further, HG + SP + CORT elevated TNF-α, IL-1β, free Ca²⁺, and ERK1/2 phosphorylation levels, which was inhibited by DHM or P2X₇ shRNA treatment. Moreover, DHM significantly reduced the P2X₇ agonist-activated currents in HEK293 cells transfected with the P2X₇ receptor. These findings suggest that DHM can protect primary hippocampal astrocytes cultured with HG + SP + CORT from P2X₇ receptor-mediated damage. Culturing cells with HG + SP + CORT might be a viable cell model for cellular injury exploration of diabetic comorbid pain and depression.

     

Gypenosides attenuate lipopolysaccharide-induced neuroinflammation and anxiety-like behaviors in rats

Neuroinflammation is considered a major factor in several neuropsychiatric disorders. Gypenosides (GPS) have pharmacological properties with multiple beneficial effects including antiinflammatory, antioxidative, and protective properties. The present study was performed to examine whether GPS shows anxiolytic-like effects in a model of chronic inflammation induced by injection of lipopolysaccharide (LPS) into the rat hippocampus. The effects of GPS on inflammatory factors in the hippocampus and the downstream mechanisms of these effects were also examined. Introduction of LPS into the lateral ventricle caused inflammatory reactions and anxiety-like symptoms in the rats. Daily treatment with GPS (25, 50, and 100?mg/kg) for 21 consecutive days significantly increased the time spent and number of visits to the open arm in the elevated plus maze test, and significantly increased the number of central zone crossings in the open field test. Moreover, GPS administration significantly reduced the freezing response to contextual fear conditioning, and significantly decreased the levels of proinflammatory mediators, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and nuclear factor-kappaB (NF-κB), levels in the brain. Furthermore, GPS reduced LPS-induced elevated levels of Toll-like receptor 4 (TLR4) mRNA and inhibition of brain-derived neurotrophic factor (BDNF) mRNA levels. Taken together, these results suggest that GPS may have anxiolytic-like effects and may have novel therapeutic potential for anxiety-like behaviors caused by neuroinflammation. GPS may be useful for developing an agents for the treatment of neuropsychiatric disorders, such as anxiety, due to its antiinflammatory activities and the modulation of NF-κB/iNOS/TLR4/BDNF.