Intracerebroventricular Injection Of Lipopolysaccharide Research Articles

Protective Effect of Hop Ethyl Acetate Extract on Corticosterone-Induced PC12 and Improvement of Depression-like Behavior in Mice.

Depression is a common mental disorder. In recent years, more and more attention has been paid to depression and its etiology and pathogenesis. This review aims to explore the neuroprotective and antidepressant effects of hop components. By establishing an in vitro cell damage model using PC12 cells induced by corticosterone (CORT) and an in vivo depression model through the intracranial injection of lipopolysaccharide (LPS) in mice, hop ethyl acetate extract (HEA) was used to study the protective effect and mechanism of HEA on neuronal cells in vitro and the antidepression effect and mechanism in vivo. The results showed that HEA increased the survival and decreased the rate of lactate dehydrogenase (LDH) release, apoptosis, and the ROS and NO content of CORT-induced PC12 cells. HEA alleviated depressive-like behavior, neuroinflammation, reduction of norepinephrine, and dendritic spines induced by intracerebroventricular injection of LPS in mice and increases the expression levels of BDNF, SNAP 25, and TrkB proteins without any significant side effects or toxicity. Hops demonstrated significant comprehensive utilization value, and this work provided an experimental basis for the role of hops in the treatment of depression and provided a basis for the development of HEA for antidepressant drugs or dietary therapy products.

Neuroprotective Effects of Dammarane Sapogenins Against lipopolysaccharide-induced Cognitive Impairment, Neuroinflammation and Synaptic Dysfunction.

Neuroinflammation is a critical driver in the pathogenesis and progression of neurodegenerative disorders. Dammarane sapogenins (DS), a deglycosylated product of ginsenoside, possess a variety of potent biological activities. The present study aimed to explore the neuroprotective effects of DS in a rat model of neuroinflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS). Our study revealed that DS pretreatment effectively improved LPS-induced associative learning and memory impairments in the active avoidance response test and spatial learning and memory in Morris water maze test. DS also remarkably inhibited LPS-induced neuroinflammation by suppressing microglia overactivation, pro-inflammatory cytok ine release (TNF-α and IL-1β) and reducing neuronal loss in the CA1 and DG regions of the hippocampus. Importantly, pretreatment with DS reversed LPS-induced upregulation of HMGB1 and TLR4 and inhibited their downstream NF-κB signaling activation, as evidenced by increased IκBα and decreased p-NF-κB p65 levels. Furthermore, DS ameliorated LPS-induced synaptic dysfunction by decreasing MMP-9 and increasing NMDAR1 expression in the hippocampus. Taken together, this study suggests that DS could be a promising treatment for preventing cognitive impairments caused by neuroinflammation.

Insulin alleviates lipopolysaccharide-induced cognitive impairment via inhibiting neuroinflammation and ferroptosis

Neuroinflammation is regarded to be a key mediator in cerebral diseases with attendant cognitive decline. Ferroptosis, characterized by iron-dependent lipid peroxidation, participates in neuroinflammation and cognitive impairment. Recent studies have revealed insulin's neuroprotective effects and involvement in the regulation of numerous central functions. But the effect of insulin on cognitive impairment induced by neuroinflammation has been rarely explored. In this study, we constructed a cognitive impairment model by intracerebroventricular injection of lipopolysaccharide (LPS) and a single dosage of insulin was mixed in the LPS solution to explore the potential mechanisms through which insulin treatment could improve LPS-induced cognitive dysfunction. At 24 h after treatment, we found that insulin treatment significantly improved LPS-induced cognitive decline, neuronal injuries, and blood-brain barrier (BBB) disruption. Insulin treatment could also inhibit the LPS-induced activation of microglia and astrocytes, and the release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampus. Furthermore, insulin treatment inhibited LPS-induced ferroptosis in the hippocampus by decreasing iron accumulation levels, regulating ferroptosis-related proteins including transferrin, glutathione peroxidase 4 (GPX4), ferritin heavy chin 1 (FTH1) and cystine/glutamate antiporter (xCT), inhibiting oxidative stress injuries and lipid peroxidation in the hippocampus. In conclusion, our finding that insulin treatment could alleviate LPS-induced cognitive impairment by inhibiting neuroinflammation and ferroptosis provides a new potential therapeutic method to ameliorate cognitive decline.

Mechanism of the Mongolian medicine Eerdun Wurile basic formula in improving postoperative cognitive dysfunction by inhibiting apoptosis through the SIRT1/p53 signaling pathway.

The Mongolian medicine Eerdun Wurile is a commonly used Mongolian in folk medicine used to treat cerebral nervous system diseases such as cerebral hemorrhage, cerebral thrombosis, nerve injury and cognitive function, cardiovascular diseases such as hypertension and coronary heart disease. Eerdun wurile may effect anti-postoperative cognitive function. To investigate the molecular mechanism of the Mongolian medicine Eerdun Wurile Basic Formula (EWB) in improving postoperative cognitive dysfunction (POCD) based on Network pharmacology, and to confirm involvement of the SIRT1/p53 signal pathway, one of the key signal pathways, by using the POCD mouse model. Obtain compounds and disease-related targets through TCMSP, TCMID, PubChem, PharmMapper platforms, GeneCards, and OMIM databases, and screen intersection genes; Use Cytoscape software to build a "drug-ingredient-disease-target" network, and the STRING platform for protein interaction analysis.; R software was used to analyze the function of gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment.; AutoDock Vina software for active components and core targets to Perform molecular docking. The POCD mouse model was prepared by intracerebroventricular injection of lipopolysaccharide (LPS), and the morphological changes of hippocampal tissue were observed by hematoxylin-eosin (HE) staining, Western blot, immunofluorescence and TUNEL were used to verify the results of network pharmacological enrichment analysis. There were 110 potential targets for improving POCD by EWB, 117 items were enriched by GO, and 113 pathways were enriched by KEGG, among which the SIRT1/p53 signaling pathway was related to the occurrence of POCD. Quercetin, kaempferol, vestitol, β-sitosterol and 7-methoxy-2-methyl isoflavone in EWB can form stable conformations with low binding energy with core target proteins IL-6, CASP3, VEGFA, EGFR and ESR1. Animal experiments showed that compared with the POCD model group, the EWB group could significantly improve the apoptosis in the hippocampus of the mice, and significantly down-regulate the expression of Acetyl-p53 protein (P<0.05). EWB can improve POCD with the characteristics of multi-component, multi-target, and multi-pathway synergistic effects. Studies have confirmed that EWB can improve the occurrence of POCD by regulating the expression of genes related to the SIRT1/p53 signal pathway, which provides a new target and basis for the treatment of POCD.

Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimer's disease neuroinflammatory type: Early approaches for therapeutic intervention.

Alzheimer's disease (AD) is a predominantly heterogeneous disease with a highly complex pathobiology. The presence of amyloid-beta (Aβ) depositions and the accumulation of hyperphosphorylated tau protein remain the characteristic hallmarks of AD. These hallmarks can be detected throughout the brain and other regions, including cerebrospinal fluid (CSF) and the spinal cord. Microglia cells, the brain-resident macrophage type of the brain, are implicated in maintaining healthy brain homeostasis. The localized administration of primary healthy microglia (PHM) is suggested to play a role in mitigating AD hallmark depositions and associated cognitive dysfunction. Carbenoxolone (CBX) is the most common gap junction blocker. It cannot effectively cross the blood-brain barrier (BBB) under systemic administration. Therefore, localized administration of CBX may be a recommended intervention against AD by acting as an antioxidant and anti-inflammatory agent. This study aims to determine whether the localized intracerebroventricular (ICV) administration of PHM and CBX may act as an effective therapeutic intervention for AD neuroinflammatory type. In addition, this study also aims to reveal whether detecting AD hallmarks in the spinal cord and CSF can be considered functional and effective during AD early diagnosis. Male albino rats were divided into four groups: control (group 1), lipopolysaccharide (LPS)-induced AD neuroinflammatory type (group 2), ICV injection of LPS + isolated PHM (group 3), and ICV injection of LPS + CBX (group 4). Morris water maze (MWM) was conducted to evaluate spatial working memory. The brain and spinal cord were isolated from each rat with the collection of CSF. Our findings demonstrate that the localized administration of PHM and CBX can act as promising therapeutic approaches against AD. Additionally, Aβ and tau toxic aggregates were detected in the spinal cord and the CSF of the induced AD model concomitant with the brain tissues. Overall, it is suggested that the ICV administration of PHM and CBX can restore normal brain functions and alleviate AD hallmark depositions. Detecting these depositions in the spinal cord and CSF may be considered in AD early diagnosis. As such, conducting clinical research is recommended to reveal the benefits of related therapeutic approaches compared with preclinical findings.

The intracerebroventricular injection of lipopolysaccharide may induce neurogenic detrusor overactivity symptoms in mice.

We aimed to explore if the intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS) was able to evoke the cognitive and locomotive impairment and detrusor overactivity (DO) symptoms in mice. This study compared the bladder function of mice that received the i.c.v. injection of LPS or saline. Specifically, basal pressure (BP), threshold pressure (TP), micturition pressure (MP), bladder capacity (BC), micturition volume (MV), bladder compliance (COM), frequency of micturition (MF), detrusor overactive index (DOI), frequency of non-voiding contractions (FNVCs), and amplitude of non-voiding contractions (ANVCs) were assessed by cystometry. The spontaneous voiding spot assay (VSA) was exerted to further assess the micturition patterns of mice. The Morris water maze (MWM) and the open field test (OFT) were used to detect the cognition and locomotive behaviors, respectively. Hematoxylin and eosin staining was conducted to evaluate the changes in morphology and histology of mice. The extent of injury in the prefrontal cortex was tested by using Nissl staining. The LPS-treated mice exhibited evidently DOcharacterized by the increase of MF, FNVCs, ANVCs, and DOI and the decrease of BC. The VSA further suggested that LPS induced urinary frequency and urinary incontinence in mice. Furthermore, neither signs of bladder inflammation nor the damage of bladder smooth muscle and urothelium in LPS-exposed mice was observed. LPS induced deficits in spatial learning, memory, and locomotor activity in mice. Neuronal cells in the prefrontal cortex were obviously lost in the LPS-treated mice. Acute neuroinflammation induced the cognitive and locomotive impairment and the neurogenic overactive bladder (NOAB) symptoms in mice. This novel animal model may contribute to further study the mechanisms of NOAB in neurodegenerative patients and assess the novel therapeutic strategies in the future.

Dihydroquercetin ameliorates LPS-induced neuroinflammation and memory deficit

Dihydroquercetin (DHQ) is a pentahydroxyflavanone that has been used as an important suppliment against oxidative stress related inflammation and neuroinflammation. Neuroinflammation, which is the activation of the defense mechanism of the central nervous system, upon exposure to stimuli like amyloid β, Lewy bodies, lipopolysaccharide (LPS) and reactive oxygen species. It is an important pathophysiological mediator of a number of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis and others. The objective of the present study is to evaluate the neuroprotective effect of DHQ, a potent antioxidant molecule, against LPS induced neuroinflammation. On the first day of the experiment (day-1), neuroinflammation was induced through intracerebroventricular injection of LPS (5 ​μg/5 μl) into each lateral ventricle in the rats. DHQ-0.5, 1 and 2 ​μg/kg was injected into the tail vein in respective groups from day-2 to day-10. Behavioral studies showed that DHQ attenuated the LPS-induced loss in long-term memory and working memory as evaluated by elevated plus maze and Y-maze test, respectively.Further, the biochemical estimations revealed that DHQ dose-dependently attenuated the LPS-induced decrease in acetylcholine level and increased in the acetylcholine-esterase activity in the hippocampal region. DHQ also increased the catalase activity and decreased nitric oxide and lipid peroxidation altered by LPS injection. DHQ also attenuated interleukin-6 in the brain, which has elevated upon LPS induction. The decrease in IL-6 is attributed to its antioxidant activity. Hence, DHQ could be a potential therapeutic candidate in the management of neuroinflammation and related neurodegenerative disorders.

Rosmarinic acid attenuates lipopolysaccharide-induced neuroinflammation and cognitive impairment in rats

It has been recently demonstrated that rosmarinic acid (RA) through modulation in the amyloidogenic pathway exhibit neuroprotective potential in Alzheimer’s disease. However, its effects on non-amyloidogenic pathways such as neuroinflammation (NI) and oxidative stress have not been elucidated carefully. Hence, this study aimed to investigate the effect of RA on cognitive function, cortical and hippocampal oxidant-antioxidant balance, and proinflammatory cytokines production in lipopolysaccharide (LPS)-induced NI in rats. NI was induced by intracerebroventricular injection of LPS (50 μg/20 μL; 10 μL into each ventricle) in Wistar rats. RA (25 and 50 mg/kg.) was intraperitoneally administrated to the experimental groups 30 min before the LPS injection and continued once per day for seven days. Cognitive function was investigated by the Y-maze test, and the production of proinflammatory cytokines and oxidative stress markers were evaluated in their hippocampi (HIP) and prefrontal cortex (PFC). In addition, neuronal damage was evaluated in the HIP subfields histologically. The RA administration could alleviate cognitive impairments caused by NI in LPS-treated rats as evidenced by improved working memory and attenuated neuronal injury in the HIP subfields. RA treatment in a dose-dependent manner prevented the overproduction of tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6 in both the HIP and PFC. RA significantly alleviated the HIP and PFC levels of malondialdehyde (MDA) and nitric oxide (NOx) and enhanced the superoxide dismutase (SOD) activity. These findings demonstrated that RA could also exert its neuroprotective effects by modulating non-amyloidogenic pathways such as inflammation and oxidative stress.

Interaction between extracellular ATP5A1 and LPS alleviates LPS-induced neuroinflammation in mice

Neuroinflammation is one of the main causes of Alzheimer’s disease (AD). The presence of Lipopolysaccharide (LPS) in senile plaques (SP) of AD suggests that it plays a role in AD pathogenesis. ATP5A1 (F1F0-ATP synthase F1 α subunit) is abundant in SP. Further, the protein has recently been found to have an anti-infection role in zebrafish embryos. In the present study, we observed that LPS levels were higher in the brains of APP/PS1 mice than in control mice, and LPS co-localised with ATP5A1 in amyloid plaques. The interaction of recombinant ATP5A1(rATP5A1) and LPS was evidenced by cellular thermal shift assay and enzyme-linked immunosorbent assay-based binding assay in vitro. Neuroinflammation in the brain of a mouse model was induced by intracerebroventricular injection of LPS. The addition of rATP5A1 relieved LPS-induced reduction of spontaneous locomotor ability, depressive-like behaviour, and working memory impairment. Furthermore, rATP5A1 suppressed the activation of astrocytes and microglia, IL-1β accumulation, and tau phosphorylation induced by LPS. Taken together, findings suggest that ATP5A1 is involved in the regulation of LPS-mediated neuroinflammation in AD.

Neuroinflammation decreased hippocampal microtubule dynamics in the acute behavioral deficits induced by intracerebroventricular injection of lipopolysaccharide in male adult rats.

Neuroinflammation plays a vital role in the pathology of depression. Microtubule dynamics produces an immediate response to stress, but the effect of microtubule dynamics in the rats with acute behavioral deficits following a central immune challenge remains elusive. Adult male Sprague-Dawley rats were subjected to the intracerebroventricular (icv) injection of lipopolysaccharide (. Behavioral tests, including bodyweight, sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), were performed to evaluate anxiety-like and depressive-like phenotypes at 24 h after injection, and some neuroinflammation biomarkers and microtubule dynamics in the hippocampus were detected. Lipopolysaccharide decreased the bodyweight, sucrose preference in SPT (depressive-like behavior), spontaneous activity in OFT (anxiety-like behavior) and increased the immobility time in FST (depressive-like behavior). Besides, lipopolysaccharide increased the mRNA levels of hippocampal CD11b and ionized calcium binding adaptor molecule (Iba1), which suggest microglial activation, and also upregulated hippocampal NLR Family Pyrin Domain Containing 3 inflammasome/interleukin-18/nuclear factor kappa-B mRNA. Lipopolysaccharide injection(icv) reduced the ratio of Tyr-/Acet-tubulin, an important marker of microtubule dynamics, in the acute behavioral deficit rats. Specifically, a decrease in Tyr-tubulin and an increase in the expression of Acet-tubulin were observed, indicating weakened microtubule dynamics. Pearson correlation analysis further showed that there was a significant negative correlation between hippocampal microtubule dynamics and neuroinflammatory activity. This study confirmed that hippocampal microtubule dynamics was decreased in the rats with acute behavioral deficits following a central immune challenge.

Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity

BackgroundOxidative stress and neuroinflammation are central pathogenic mechanisms common to many neurological diseases. Isoliquiritigenin (ISL) is a flavonoid in licorice with multiple pharmacological properties, including anti-inflammatory activity, and has demonstrated protective efficacy against acute neural injury. However, potential actions against cognitive impairments have not been examined extensively. We established a rat model of cognitive impairment by intracerebroventricular injection of lipopolysaccharide (LPS), and examined the effects of ISL pretreatment on cognitive function, hippocampal injury, and hippocampal expression of various synaptic proteins, antioxidant enzymes, pro-inflammatory cytokines, and signaling factors controlling anti-oxidant and pro-inflammatory responses.ResultsRats receiving LPS alone demonstrated spatial learning deficits in the Morris water maze test as evidenced by longer average escape latency, fewer platform crossings, and shorter average time in the target quadrant than untreated controls. ISL pretreatment reversed these deficits as well as LPS-induced decreases in the hippocampal expression levels of synaptophysin, postsynaptic density-95, brain-derived neurotrophic factor, superoxide dismutase, glutathione peroxidase, and BCL-2. ISL pretreatment also reversed LPS-induced increases in TUNEL-positive (apoptotic) cells, BAX/BCL-2 ratio, and expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 3. Pretreatment with ISL increased the expression levels of phosphorylated (p)-GSK-3β, nuclear NRF2, HO-1 mRNA, and NQO1 mRNA, and reversed LPS-induced nuclear translocation of nuclear factor (NF)-κB.ConclusionsISL protects against LPS-induced cognitive impairment and neuronal injury by promoting or maintaining antioxidant capacity and suppressing neuroinflammation, likely through phosphorylation-dependent inactivation of GSK-3β, enhanced expression of NRF2-responsive antioxidant genes, and suppression of NF-κB-responsive pro-inflammatory genes.

Madecassoside ameliorates lipopolysaccharide-induced neurotoxicity in rats by activating the Nrf2-HO-1 pathway

Neuroinflammation is a predisposing factor for several neurodegenerative diseases. The purpose of this study was to evaluate the protective effect of madecassoside (MA) in lipopolysaccharide (LPS)-induced cognitive impairment and neuroinflammation in rats. MA has many protective effects such as antioxidant and anti-inflammatory properties. We investigated whether MA could improve neurocognitive dysfunction caused by intracerebroventricular injection of LPS. We examined the effects and mechanisms of action of MA on LPS-induced neuroinflammation in the cortex and hippocampus. Our study revealed that MA (120 mg/kg, i.g) treatment for 14 days reduced LPS-induced neurotoxicity by reducing cognitive impairments and suppressing the production of inflammatory cytokines such as interleukin 1 beta (IL-1β), tumor necrosis factor alpha(TNF-α), and interleukin 6(IL-6) via activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Furthermore, MA treatment enhanced protein levels of heme oxygenase (HO)-1 by upregulating Nrf2 in LPS-stimulated neurotoxicity. Collectively, these results suggest that MA is effective in preventing neurodegenerative diseases by improving memory functions due to its anti-inflammatory activities and activation of Keap1-Nrf2/HO-1 signaling. As such, MA may be a potential therapy for addressing memory impairment caused by neuroinflammation.

Nootkatone, a neuroprotective agent from Alpiniae Oxyphyllae Fructus, improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer's disease

Neuroinflammatory responses play a crucial role in the pathogenesis of Alzheimer's disease (AD). Our previous study demonstrated that petroleum ether extracts from Alpiniae Oxyphyllae Fructus(AOF) could attenuate lipopolysaccharide (LPS)-induced learning and memory impairment in mice, which could be associated with its inhibitory effect on neuroinflammation. Therefore, our present study is to investigate the potential therapeutic neuroprotective effects of nootkatone (NKT) on an AD mouse model induced by intracerebroventricular injection of LPS. We found that NKT (10 mg/kg) group showed good performance in behavior experiments including Y-maze test and Morris water maze test. The results of histopathological examination and immunohistochemical analysis showed that LPS induced degeneration of neurons and activation of microglia particularly in hippocampus and NKT (10 mg/kg) reversed these changes. Enzyme linked immunosorbent assay and western blot analysis also demonstrated that the model group had increased expression of IL-1β, IL-6, TNF-α, NLRP3 and NF-κB p65, especially in hippocampus relative to sham-operated group, and NKT (10 mg/kg) decreased the high expression of these inflammatory cytokines. Collectively, these data indicated that LPS-induced learning and memory impairments in mice could be improved by NKT, which was associated with attenuating neuroinflammatory responses. Our study indicated that NKT could act as a potential therapeutic agent for the treatment of neuroinflammation and AD.

Increased brain docosahexaenoic acid has no effect on the resolution of neuroinflammation following intracerebroventricular lipopolysaccharide injection

Resolution of inflammation in the periphery was once thought to be a passive process, but new research now suggests it is an active process mediated by specialized pro-resolving lipid mediators (SPM) derived from omega-3 polyunsaturated fatty acids (n-3 PUFA). However, this has yet to be illustrated in neuroinflammation. The purpose of this study was to measure resolution of neuroinflammation and to test whether increasing brain docosahexaenoic acid (DHA) affects the resolution of neuroinflammation.C57Bl/6 mice, fat-1 mice and their wildtype littermates, fed either fish oil or safflower oil, received lipopolysaccharide (LPS) in the left lateral ventricle. Animals were then euthanized at various time points for immunohistochemistry, gene expression, and lipidomic analyses.Peak microglial activation was observed at 5 days post-surgery and the resolution index was 10 days. Of the approximately 350 genes significantly changed over the 28 days post LPS injection, 130 were uniquely changed at 3 days post injection. No changes were observed in the bioactive mediator pools. However, a few lysophospholipid species were decreased at 24hr post surgery. When brain DHA is increased, microglial cell density did not resolve faster and did not alter gene expression.In conclusion, resolution of neuroinflammation appears to be independent of SPM. Increasing brain DHA had no effect in this model.

Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons

BackgroundThe primary cilium is an organelle that can act as a master regulator of cellular signaling. Despite the presence of primary cilia in hippocampal neurons, their function is not fully understood. Recent studies have demonstrated that the primary cilium influences interleukin (IL)-1β-induced NF-κB signaling, ultimately mediating the inflammatory response. We, therefore, investigated ciliary function and NF-κB signaling in lipopolysaccharide (LPS)-induced neuroinflammation in conjunction with ciliary length analysis.MethodsSince TLR4/NF-κB signaling is a well-known inflammatory pathway, we measured ciliary length and inflammatory mediators in wild type (WT) and TLR4−/− mice injected with LPS. Next, to exclude the effects of microglial TLR4, we examined the ciliary length, ciliary components, inflammatory cytokine, and mediators in HT22 hippocampal neuronal cells.ResultsPrimary ciliary length decreased in hippocampal pyramidal neurons after intracerebroventricular injection of LPS in WT mice, whereas it increased in TLR4−/− mice. LPS treatment decreased primary ciliary length, activated NF-κB signaling, and increased Cox2 and iNOS levels in HT22 hippocampal neurons. In contrast, silencing Kif3a, a key protein component of cilia, increased ARL13B ciliary protein levels and suppressed NF-κB signaling and expression of inflammatory mediators.ConclusionsThese data suggest that LPS-induced NF-κB signaling and inflammatory mediator expression are modulated by cilia and that the blockade of primary cilium formation by Kif3a siRNA regulates TLR4-induced NF-κB signaling. We propose that primary cilia are critical for regulating NF-κB signaling events in neuroinflammation and in the innate immune response.

Follistatin-like protein 1 suppressed pro-inflammatory cytokines expression during neuroinflammation induced by lipopolysaccharide.

Follistain-like protein 1 (FSTL1), has been recently demonstrated to be involved in the embryo development of nervous system and glioblastoma. However, the role of FSTL1 in neuroinflammation remains unexplored. In this study, the expression of FSTL1 in astrocytes was verified and its role was studied in neuroinflammation induced by in vivo intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) or LPS treatment to astrocytes in vitro. FSTL1 was significantly induced after ICV LPS injection or LPS treatment. FSTL1 suppressed upregulation of pro-inflammatory cytokines in astrocytes after LPS treatment. Moreover, FSTL1 downregulated expression of pro-inflammatory cytokines through suppressing MAPK/p-ERK1/2 pathway in astrocytes. Our results suggest that FSTL1 may play an anti-inflammatory role in neuroinflammation mediated by astrocytes.

Central histaminergic system interplay with suppressive effects of immune challenge on food intake in chicken

The aim of the current study was to investigate the interaction of the lipopolysaccharide (LPS) and histaminergic systems on appetite regulation in broilers. Effects of intracerebroventricular (ICV) injection of α-fluoromethylhistidine (α-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptor antagonist), famotidine (histamine H2 receptor antagonist) and thioperamide (histamine H3 receptor antagonist) on LPS-induced hypophagia in broilers were studied.A total of 128 broilers were randomly allocated into 4 experiments (4 groups and 8 replications in each experiment). A cannula was surgically implanted into the lateral ventricle. In Experiment 1, broilers were ICV injected with LPS (20 ng) prior to α-FMH (250 nmol). In Experiment 2, chickens were ICV injected with LPS followed by chlorpheniramine (300 nmol). In Experiment 3, broilers were ICV injected with famotidine (82 nmol) after LPS (20 ng). In Experiment 4, ICV injection of LPS was followed by thioperamide (300 nmol). Then, cumulative food intake was recorded until 4 h post-injection.According to the results, LPS significantly decreased food intake. Chlorpheniramine significantly amplified food intake, and LPS-induced hypophagia was lessened by injection of chlorpheniramine. α-FMH, famotidine and thioperamide had no effect on LPS-induced hypophagia.These results suggest that there is an interaction between central LPS and the histaminergic system where LPS-induced hypophagia is mediated by H1 histamine receptors in 3 h food-deprived broilers.

Lipopolysaccharide and histaminergic systems interact to mediate food intake in broilers.

1. The aim of the current study was to investigate the interaction of the lipopolysaccharide and histaminergic systems on appetite regulation in broilers. The effects of intracerebroventricular (ICV) injection of α-fluoromethylhistidine (α-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptor antagonist), famotidine (histamine H2 receptor antagonist) and thioperamide (histamine H3 receptor antagonist) on lipopolysaccharide (LPS)-induced hypophagia in broilers were studied. 2. A total of 128 broilers were randomly allocated into 4 experiments (4 groups and 8 replications in each experiment). A cannula was surgically implanted into the lateral ventricle. In Experiment 1, broilers were ICV injected with LPS (20 ng) prior to α-FMH (250 nmol). In Experiment 2, chickens were ICV injected with LPS followed by chlorpheniramine (300 nmol). In Experiment 3, broilers were ICV injected with famotidine (82 nmol) after LPS (20 ng). In Experiment 4, ICV injection of LPS was followed by thioperamide (300 nmol). The cumulative food intake was recorded until 4 h post injection. 3. LPS decreased food intake; chlorpheniramine amplified food intake and LPS-induced hypophagia was lessened by injection of chlorpheniramine. α-FMH, famotidine and thioperamide had no effect on LPS-induced hypophagia. 4. The results suggest that there is an interaction between central LPS and the histaminergic system where LPS-induced hypophagia is presumably mediated by H1 histamine receptors in 3 h food-deprived broilers.

Brain Endoplasmic Reticulum (ER) Stress Mediates Lipopolysaccharide‐Induced Central Inflammation and Sympathetic and Cardiovascular Excitation

Inflammation in central cardiovascular regulatory regions has recently emerged as an essential contributor to increased sympathetic nerve activity in hypertension and heart failure. However, the mechanisms are poorly understood and are a topic of intense investigation. Endoplasmic reticulum (ER) stress is an important pathophysiological mechanism in various cardiovascular diseases including heart failure and hypertension. We hypothesized that ER stress contributes to the central inflammation and sympathetic excitation induced by intracerebroventricular (ICV) administration of lipopolysaccharide (LPS). In anesthetized rats, ICV injection of LPS (5 μg) increased (p&lt;0.05, vs baseline) renal sympathetic nerve activity, mean blood pressure and heart rate. ICV infusion of the ER stress inducer thapsigargin (TG, 5 μg/hr) elicited similar responses, but with smaller amplitude. LPS significantly increased paraventricular nucleus (PVN) mRNA for tumor necrosis factor‐α, interleukin‐1β, and cyclooxygenase‐2. ICV infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 5 μg/hr) significantly attenuated all of these TG‐ and LPS‐induced responses. These data suggest that therapeutic interventions targeting brain ER stress may modulate the sympatho‐excitatory effects of central inflammation in heart failure and hypertension.

A comprehensive study on long‐term injury to nigral dopaminergic neurons following intracerebroventricular injection of lipopolysaccharide in rats

Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Lipopolysaccharide (LPS) can induce chronic inflammation and has been widely used to study the pathogenesis of PD. In this study, a single intracerebroventricular injection of LPS was used to induce neurotoxic effects on dopaminergic neurons in Sprague-Dawley rats. The long-term neurotoxic effects of LPS were evaluated at different time points. Microglia were activated in the hippocampus and striatum at 4 weeks, and in the SN at 24 weeks. Astrocytes were activated in the hippocampus and nigrostriatal system at 2 and 24 weeks. The expression of brain-derived neurotrophic factor in the SN increased at 4 weeks and decreased after 12 weeks, and tyrosine hydroxylase-positive neurons in the SN were shown to have an atrophic appearance, with cell loss evident after 24 weeks. Phospho-α-synuclein expression, a reflection of parkinsonian pathogenesis, increased at 12 weeks, and peaked at 24 weeks. Abnormal motor behavior appeared at 16 weeks and lasted up to 48 weeks. These results indicate that microglia are activated for several months after a single, low dose injection of LPS, which eventually results in progressive and selective damage to dopaminergic neurons in the SN.