Lipopolysaccharide-induced Neuroinflammation Research Articles

Gastrodin ameliorates the lipopolysaccharide-induced neuroinflammation in mice by downregulating miR-107-3p.

Background: Neuroinflammation plays a pivotal role in the pathogenesis of Central Nervous System (CNS) diseases. The phenolic glucoside gastrodin (GAS), has been known to treat CNS disorders by exerting anti-inflammatory activities. Our aim was to investigate the potential neuroprotective mechanisms of GAS on lipopolysaccharide (LPS)-induced mice. Methods: Male C57BL/6J mice were treated by LPS, before which GAS was adminisrated. The behavior tests such as forced swim test, tail suspension test, and elevated plus maze were performed to evaluate depressive-anxiety-like behaviors. A high-throughput sequencing (HTS) analysis was performed to screen out distinctive miRNAs which were validated using quantitative real-time PCR. Then, miRNA agomir or NC was injected stereotaxically into hippocampus of mice to explore the role of miRNA on GAS in response to LPS. Furthermore, Immunofluorescence and the hematoxylin and eosin (H&E) staining were employed to observe the cellular morphology. The protein levels of pro-inflammatory factors were evaluated by western blot. Finally, the target mRNA of miRNA was predicted using bioinformatics analysis. GO and KEGG enrichment analyses were conducted to clarify the potential function of target protein, which were visualized by bubble charts. Results: The behavioral data showed that mice in the LPS group had obvious depressive-anxiety-like behaviors, and 100mg/kg GAS could improve these behavioral changes and alleviate the levels of pro-inflammatory cytokines in the hippocampus when mice were exposed to LPS for 6h. Meanwhile, LPS-induced microglia and astrocyte activation in the CA1, CA2, CA3, and DG regions of the hippocampus were also reversed by GAS. Furthermore, miR-107-3p were screened out and verified for GAS in response to LPS. Importantly, miR-107-3p overexpression negatively abrogated the neuroprotective effects of GAS. Moreover, KPNA1 might be the target molecular of miR-107-3p. KPNA1 might regulate 12 neuroinflammation-related genes, which were mainly involved in cytokine-mediated signaling pathway. Conclusion: These results suggested that GAS might alleviate the LPS-induced neuroinflammation and depressive-anxiety-like behaviors in mice by downregulating miR-107-3p and upregulating the downstream target KPNA1. The indicates miR-107-3p may provide a new strategy for the treatment of CNS diseases.

Curcumin Attenuates Lipopolysaccharide-Induced Neuroinflammation and Memory Deficiency by Inhibiting Microglia Activation in Mice Hippocampus

Background. Curcumin has a variety of properties, including antioxidant and anti-inflammatory ones, and has demonstrated some protective prospects on neurological conditions.
 Aim: This study explored the neuroprotective ability of curcumin in lipopolysaccharide-induced neuroinflammation in an animal model.
 Methods. A total of thirty-two adult male mice were randomly assigned to four groups (A, B, C, and D, n=8): Group A (Control) received distilled water; Group B was administered lipopolysaccharide (LPS) only to induce neuroinflammation for seven days; Group C was treated with both LPS and curcumin simultaneously for fourteen days; Group D received only curcumin for fourteen days. After appropriate exposure to the mice, their cognitive abilities were assessed using the Y-maze and novel object recognition tests. At the termination of the administration period, the mice were sacrificed, and the hippocampi were dissected for histology and immunostaining using GFAP and Iba1. Statistical analysis for the data generated was done with GraphPad prism. Tests of significance were with one-way ANOVA and Tukey tests for post-hoc.
 Results. Curcumin significantly (p < 0.05) increased object recognition, mean alternation, and markedly restored neuronal distortion caused by LPS toxicity in the CA3 region and the dentate gyrus of the hippocampus of Group C animals as compared to Group B. In addition, curcumin significantly down-regulated Iba1 expression and GFAP cell activities of both the CA3 region and the dentate gyrus.
 Conclusions. Curcumin showed a promising role in attenuating LPS-induced neuroinflammation in the brain by inhibiting microglial activation and improving memory of neurotoxic mice.

Gastrodin improves neuroinflammation-induced cognitive dysfunction in rats by regulating NLRP3 inflammasome

Neuroinflammation is the main pathological mechanism of cognitive dysfunction caused by neurodegenerative diseases, and effective preventive and therapeutic measures are not available. We predicted the key targets of gastrodin’s effects upon neuroinflammation through Network Pharmacology and molecular docking. Then the predicted targets were used to study how gastrodin affected cognitive dysfunction triggered by lipopolysaccharide-induced neuroinflammation in rats and its mechanisms. Three-month-old male rats were intraperitoneally injected with lipopolysaccharide for 3 days (d), 7 d and 14 d respectively. Gastrodin improved learning and memory ability of rats with neuroinflammation. Lipopolysaccharide enhanced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, in rat hippocampus, which could be reversed by gastrodin. Gastrodin also inhibited the activation of microglia. Our findings suggested that gastrodin exerted neuroprotective effects in rats with neuroinflammation by impacting the TLR4-NF-kB-NLRP3 pathway. Therefore, gastrodin may be a potential therapeutic agent for neuroinflammation-induced cognitive dysfunction.

Chronotherapeutic neuroprotective effect of verapamil against lipopolysaccharide-induced neuroinflammation in mice through modulation of calcium-dependent genes

BackgroundNeuroinflammation is a major mechanism in neurodegenerative diseases such as Alzheimer’s disease (AD), which is a major healthcare problem. Notwithstanding of ample researches figured out possible molecular mechanisms underlying the pathophysiology of AD, there is no definitive therapeutics that aid in neuroprotection. Therefore, searching for new agents and potential targets is a critical demand. We aimed to investigate the neuroprotective effect of verapamil (VRP) against lipopolysaccharide (LPS)-induced neuroinflammation in mice and whether the time of VRP administration could affect its efficacy.MethodsForty male albino mice were used and were divided into normal control, LPS only, morning VRP, and evening VRP. Y-maze and pole climbing test were performed as behavioral tests. Hematoxylin and eosin together with Bielschowsky silver staining were done to visualize neuroinflammation and phosphorylated tau protein (pTAU); respectively. Additionally, the state of mitochondria, the levels of microglia-activation markers, inflammatory cytokines, intracellular Ca2+, pTAU, and Ca2+-dependent genes involving Ca2+/ calmodulin dependent kinase II (CAMKII) isoforms, protein kinase A (PKA), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF), with the level of VRP in the brain tissue were measured.ResultsLPS successfully induced neuroinflammation and hyperphosphorylation of tau protein, which was indicated by elevated levels of microglia markers, inflammatory cytokines, and intracellular Ca2+ with compromised mitochondria and downregulated CAMKII isoforms, PKA, CREB and BDNF. Pretreatment with VRP showed significant enhancement in the architecture of the brain and in the behavioral tests as indicated by the measured parameters. Moreover, morning VRP exhibited better neuroprotective profile compared to the evening therapy.ConclusionsVRP highlighted a multilevel of neuroprotection through anti-inflammatory activity, Ca2+ blockage, and regulation of Ca2+-dependent genes. Furthermore, chronotherapy of VRP administration should be consider to achieve best therapeutic efficacy.Graphical

Monocytes maintain central nervous system homeostasis following helminth-induced inflammation

Neuroimmune interactions are crucial for regulating immunity and inflammation. Recent studies have revealed that the central nervous system (CNS) senses peripheral inflammation and responds by releasing molecules that limit immune cell activation, thereby promoting tolerance and tissue integrity. However, the extent to which this is a bidirectional process, and whether peripheral immune cells also promote tolerance mechanisms in the CNS remains poorly defined. Here we report that helminth-induced type 2 inflammation promotes monocyte responses in the brain that are required to inhibit excessive microglial activation and host death. Mechanistically, infection-induced monocytes express YM1 that is sufficient to inhibit tumor necrosis factor production from activated microglia. Importantly, neuroprotective monocytes persist in the brain, and infected mice are protected from subsequent lipopolysaccharide-induced neuroinflammation months after infection-induced inflammation has resolved. These studies demonstrate that infiltrating monocytes promote CNS homeostasis in response to inflammation in the periphery and demonstrate that a peripheral infection can alter the immunologic landscape of the host brain.

Apelin-13 reduces lipopolysaccharide-induced neuroinflammation and cognitive impairment via promoting glucocorticoid receptor expression and nuclear translocation

Neuroinflammation is usually associated with cognitive decline, which is involved in neurodegenerative diseases. Apelin, a neuropeptide, exerts various biological roles in central nervous system. Recent evidence showed that apelin-13, an active form of apelin, suppresses neuroinflammation and improves cognitive decline in diverse pathological processes. However, the underlying mechanism of apelin-13 in neuroinflammation remains largely unknown. The present study aimed to determine underlying mechanism of apelin-13 on neuroinflammation-related cognitive decline. The lipopolysaccharide (LPS) intracerebroventricular (i.c.v.) to is used to establish a rat model of neuroinflammation-related cognitive decline. The results showed that apelin-13 inhibits LPS-induced neuroinflammation and improves cognitive impairment. Apelin-13 upregulates the GR level and nuclear translocation in hippocampus of rats. Moreover, glucocorticoid receptor inhibitor RU486 prevents apelin-13-mediated neuroprotective actions on cognitive function. Taken together, apelin-13 could exert a protective effect in neuroinflammation-mediated cognitive impairment via the activation of GR expression and nuclear translocation.

Histamine H3R antagonist counteracts the impaired hippocampal neurogenesis in Lipopolysaccharide-induced neuroinflammation

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with numerous neurodegenerative diseases such as aging and Alzheimer's disease (AD). Overactivation of microglia induced neuroinflammation is well acknowledged to contribute to the impaired neurogenesis in pathologies of these diseases and then leading to cognitive dysfunction. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia to modulate inflammatory response. However, whether inhibition of H3R is responsible for the neurogenesis and cognition in chronic neuroinflammation induced injury and the mechanism remains unclear. In this study, we found that inhibition of H3R by thioperamide reduced the microglia activity and promoted a phenotypical switch from pro-inflammatory M1 to anti-inflammatory M2 in microglia, and ultimately attenuated lipopolysaccharide (LPS) induced neuroinflammation in mice. Additionally, thioperamide rescued the neuroinflammation induced impairments of neurogenesis and cognitive function. Mechanically, the neuroprotection of thioperamide was involved in histamine dependent H2 receptor (H2R) activation, because cimetidine, an H2R antagonist but not pyrilamine, an H1R antagonist reversed the above effects of thioperamide. Moreover, thioperamide activated the H2R downstream phosphorylated protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) pathway but inhibited nuclear factor kappa-B (NF-κB) signaling. Activation of CREB by thioperamide promoted interaction of CREB-CREB Binding Protein (CBP) to increase anti-inflammatory cytokines (Interleukin-4 and Interleukin-10) and brain-derived neurotrophic factor (BDNF) release but inhibited NF-κB-CBP interaction to decrease pro-inflammatory cytokines (Interleukin-1β, Interleukin-6 and Tumor necrosis factor α) release. H89, an inhibitor of PKA/CREB signaling, abolished effects of thioperamide on neuroinflammation and neurogenesis. Taken together, these results suggested under LPS induced neuroinflammation, the H3R antagonist thioperamide inhibited microglia activity and inflammatory response, and ameliorated impairment of neurogenesis and cognitive dysfunction via enhancing histamine release. Histamine activated H2R and reinforced CREB-CBP interaction but weakened NF-κB-CBP interaction to exert anti-inflammatory effects. This study uncovered a novel histamine dependent mechanism behind the therapeutic effect of thioperamide on neuroinflammation.

Cyclin-dependent kinase 5 inhibitor attenuates lipopolysaccharide-induced neuroinflammation through metabolic reprogramming

The atypical cyclin-dependent kinase 5 (CDK5) is considered a neuron-specific kinase that plays important roles in many cellular functions including neuronal migration, neuronal differentiation, synapse development, and synaptic functions. However, the role of CDK5 in microglia under physiological and pathological conditions remains unclear. This study showed that treatment with lipopolysaccharide (LPS) caused the release of pro-inflammatory mediators and increased expression of CDK5 in BV2 microglia in vitro. Moreover, lipopolysaccharide treatment-induced glycolysis by increasing the expression levels of HIF-1α, PFKFB3, and HK2. Application of CDK5 inhibitor roscovitine significantly decreased LPS-induced CDK5 expression and glycolysis, thus suppressing neuroinflammation in the cells. The roscovitine treatment of BV2 cells also significantly blocked the HIF-1 activator, CoCl2-mediated HIF-1α, HK2, and PFKFB3 expression. Finally, we demonstrated that roscovitine inhibited microglial activation, metabolic reprogramming, expression of pro-inflammatory markers, cell apoptosis, and alleviated memory impairment in LPS-injected mice. In summary, our results suggest that inhibition of CDK5 can reduce the neuroinflammation of microglia through modulation of metabolic reprogramming.

Neuroprotective Effect of Bcl-2 on Lipopolysaccharide-Induced Neuroinflammation in Cortical Neural Stem Cells.

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases due to increased levels of pro-inflammatory cytokines in the central nervous system (CNS). Chronic neuroinflammation induced by neurotoxic molecules accelerates neuronal damage. B-cell lymphoma 2 (Bcl-2) is generally accepted to be an important anti-apoptotic factor. However, the role of Bcl-2 in neuroprotection against neuroinflammation remains to be determined. The purpose of this study was to investigate the neuroprotective effect of Bcl-2 on lipopolysaccharide (LPS)-induced neuroinflammation in cortical neural stem cells (NSCs). LPS decreased mRNA and protein levels of Tuj-1, a neuron marker, and also suppressed neurite outgrowth, indicating that LPS results in inhibition of neuronal differentiation of NSCs. Furthermore, LPS treatment inhibited Bcl-2 expression during neuronal differentiation; inhibition of neuronal differentiation by LPS was rescued by Bcl-2 overexpression. LPS-induced pro-inflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α), were decreased by Bcl-2 overexpression. Conversely, Bcl-2 siRNA increased the LPS-induced levels of IL-6 and TNF-α, and decreased neuronal differentiation of NSCs, raising the possibility that Bcl-2 mediates neuronal differentiation by inhibiting the LPS-induced inflammatory response in NSC. These results suggest that Bcl-2 has a neuroprotective effect by inhibiting the LPS-induced inflammatory response in NSCs.

Neuropharmacological effects of honey in lipopolysaccharide-induced neuroinflammation, cognitive impairment, anxiety and motor impairment

ABSTRACT Objectives: Honey contains phenolic acids and flavonoids, which are significant in developing drugs against neuroinflammation. The study was designed to evaluate the ameliorative potential of honey in lipopolysaccharides-induced neuroinflammation. Methods: Thirty male Wistar rats were divided into six groups, namely: the control group (10 mL/kg vehicle), the LPS only group (250 µg/kg), the honey (0.26, 0.31 and 0.36 g/kg) and the ibuprofen (100 mg/kg). LPS (250 µg/kg i.p) was administered for 7days followed by the treatment with honey and Ibuprofen for another 7days. Animals were assessed for memory impairment and anxiety levels using a Novel object recognition test (NORT), elevated plus maze (EPM), and open field test (OFT). Brain levels of pro-inflammatory cytokine level, acetylcholinesterase activity, and oxidative stress were determined. The neuronal alteration was assessed histologically using cresyl fast violet staining of the hippocampus, prefrontal cortex, and striatum. Results: Honey (0.31 and 0.36 g/kg) significantly ameliorated LPS-induced memory impairment on NORT and increased time spent in the open arm and increased the locomotor activity in the OFT. Honey significantly (p < 0.05) reduced LPS-induced elevation of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). It significantly reduced malondialdehyde and nitrite levels in mice brains and reversed depletion of reduced glutathione levels. Honey attenuated LPS-induced elevation of acetylcholinesterase activity in rat brains. Cresyl violet staining showed the restoration of neuronal organization and Nissl body distribution in the hippocampus, prefrontal cortex and striatum compared to the LPS only group. Discussion: Honey effectively ameliorated LPS-induced poor cognitive performance, anxiety, motor coordination responses to neuroinflammation, and oxidative stress.

Ciproxifan Attenuates Lipopolysaccharide-Induced Neuroinflammation and Mitochondrial Dysfunctions in Mouse Brain

Ciproxifan Attenuates Lipopolysaccharide-Induced Neuroinflammation and Mitochondrial Dysfunctions in Mouse Brain

Protective effects of endotoxin tolerance on peripheral lipopolysaccharide-induced neuroinflammation and dopaminergic neuronal injury

Context Parkinson's disease is a common chronic neurodegenerative disease characterized by massive loss of dopaminergic neurons in the substantia nigra. Neuroinflammation has been shown to play an important role in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease. The role of immune tolerance in neuroinflammation and neurodegenerative diseases induced by peripheral factors is unclear. Objective This study established a model of endotoxin tolerance to explore the protective effect of endotoxin tolerance on Parkinson-like changes induced by repeated peripheral injections of high-dose LPS, and to explore its inflammatory mechanism. Materials and methods In this study, mice were injected intraperitoneally with low dose (0.5 mg/kg) LPS for 4 days to induce endotoxin tolerance (ET). Then, high-dose (1 mg/kg) LPS was injected continuously intraperitoneally for 4 days to induce Parkinson-like changes. Cytokines were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Activation of microglial cells was detected by protein expression of CD68 and ionized calcium binding adapter molecule 1(Iba-1) by Western blotting and immunofluorescence. Hematoxylin and eosin staining and expression of tyrosine hydroxylase (TH) and dopamine (DA) were used to assess dopaminergic neuronal injury. The open field test and muscle tension test were used to assess behavioral disorders. Results As expected, compared with non-ET animals, ET preconditioning significantly reduced the production of inflammatory cytokines in the substantia nigra, inhibited microglial activation, and alleviated the pathological changes of dopaminergic neurons. Conclusions ET may be a promising intervention method for neurodegenerative diseases. Highlights ET was successfully induced by continuous low-dose intraperitoneal LPS injection in mice. ET pretreatment inhibited neuroinflammation in the SN induced by continuous peripheral high doses of LPS. ET pretreatment inhibited continuous peripheral high-dose LPS injection-induced microglial activation in the SN. ET pretreatment decreased LPS-induced functional impairment of dopaminergic neurons. ET reversed the morphological changes of dopaminergic neurons induced by peripheral high-dose LPS. ET pretreatment improved continuous peripheral high-dose LPS injection-induced behavioral impairment.

Protective Effect of Portulaca oleracea Extract Against Lipopolysaccharide-Induced Neuroinflammation, Memory Decline, and Oxidative Stress in Mice: Potential Role of miR-146a and miR-let 7.

Neuroinflammation is an adaptive immune response to the central nervous system (CNS) injury induced by infection or toxins. MicroRNAs (miRs) showed critical roles in neuroinflammation as either proinflammatory or anti-inflammatory molecules. Interestingly, Portulaca oleracea (purslane) is an edible plant capable of ameliorating several diseases, including headache, burns, and diabetes; however, its effect on the neuroinflammation-associated miRs was not previously investigated. This study aimed to investigate the effect of aqueous purslane extract on the neuroinflammation induced by lipopolysaccharide (LPS) in mice and to identify its effect on animal cognition, oxidative stress, and expressions of miR-146a and miR-let 7. Adult mice were divided into the following groups: Normal group, LPS group, and Purslane+LPS group. Novel target recognition test, brain histopathology, and measurement of oxidative stress and inflammatory markers were performed. The results showed that LPS group exhibited significant decline in the cognitive memory, brain histopathological injury and a decrease in the number of intact neurons compared to the normal group. Furthermore, the LPS group showed a significant increase in malondialdehyde concentration, whereas superoxide dismutase and catalase activities were decreased. The LPS group also showed an increase in the inflammatory markers tumor necrosis factor-α and nuclear factor kappa B and downregulation of miR-146a and miR-let 7 expressions in the brain cells compared to the normal group, P value <.05. Interestingly, all these changes were reversed by administration of the aqueous purslane extract. In conclusion, the aqueous purslane extract protected from LPS-induced neuroinflammation and memory decline in mice through antioxidant and anti-inflammatory effect where upregulation of miR-146a and miR-1et 7 expressions was involved.

The therapeutic mechanism of Shenyuan Gan in lipopolysaccharide-induced neuroinflammation in BV2 microglial cells

ObjectiveTo study the therapeutic effects of Shenyuan Gan (参远苷, SYG) on the inflammatory response in BV2 microglial cells induced by lipopolysaccharide (LPS). MethodsThe cytotoxicity of SYG to BV2 microglial cells was evaluated using a Cell Counting Kit-8 (CCK-8) assay, and the effect of SYG concentrations on LPS-induced BV2 microglial cells was studied. The morphological changes were observed using an optical microscope. The nitric oxide (NO) concentration in cell culture supernatant was determined using Griess reagent. The expression of cytokines and inflammatory mediators were also measured by an enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to determine the levels of inducible NO synthase (iNOS), nuclear factor-kappa B (NF-κB) p65, alpha inhibitor of NF-κB (IκB-α), phosphorylation-IκB-α (p-IκB-α), NOD-like receptor 3 (NLRP3), and caspase-1 expression. Moreover, the expression of iNOS, NLRP3, and ionized calcium binding adapter molecule 1 (Iba1) was also observed using immunofluorescent staining. ResultsSYG had a low cytotoxic effect on BV2 microglial cells and could significantly decr-ease LPS-induced morphological changes of BV2 microglial cells (P < 0.05). ELISA results showed that SYG significantly inhibited the LPS-induced increase in interleukin (IL)-1β and IL-6 in BV2 microglia cells (P < 0.05), and Western blot analysis showed that the phosphorylation levels of iNOS, NF-κB p65, and IκB-α as well as NLRP3 and caspase-1 expression were also significantly decreased, and IκB-α expression was increased after SYG treatment (P < 0.05, compared with the LPS-treated group). The immunofluorescence results were consistent with the Western blot results, and Iba1 staining indicated that the cell morphology tended to be resting. These results indicate that SYG has a certain inhibitory effect on LPS-induced inflammation in BV2 microglial cells. ConclusionSYG can inhibit LPS-induced release of inflammatory factors in BV2 microglial cells by affecting the phosphorylation levels of NF-κB p65 and IκB-α. SYG is a valuable candidate for treating neuroinflammation-related diseases.

Omarigliptin/galangin combination mitigates lipopolysaccharide-induced neuroinflammation in rats: Involvement of glucagon-like peptide-1, toll-like receptor-4, apoptosis and Akt/GSK-3β signaling

AimsThe objectives of this work were to assess the possibility of administration of omarigliptin and/or galangin to combat lipopolysaccharide (LPS)-induced neuroinflammation in rats and to explore the possible mechanisms that might contribute to their actions. Materials and methodsIn a rat model of LPS-induced neuroinflammation, the changes in the behavioral tests, biochemical parameters, and the histopathological picture were assessed. Key findingsAdministration of either omarigliptin or galangin to LPS-injected rats was able to significantly improve the behavioral changes with restoration of the oxidant/antioxidant balance, decrement of toll-like receptor-4 levels, and amelioration of the neuroinflammation associated with inhibition of apoptosis and restoration of glucagon-like peptide-1 levels in the cerebral tissues. In addition, omarigliptin and/or galangin significantly reduced the levels of phospho-Akt and glycogen synthase kinase 3 beta (GSK-3β) and significantly increased the expression of beclin-1 in the cerebral tissues compared versus the group treated with LPS alone. As a result, these changes were positively reflected on the histopathological and the electron microscopic picture of the cerebral tissues. These beneficial effects were maximally evidenced in rats treated with omarigliptin/galangin combination relative to the use of either omarigliptin or galangin alone. Significance: Omarigliptin/galangin combination might be proposed as a promising therapeutic line for mitigation of the pathophysiologic events of LPS-induced neuroinflammation.

Quercetin ameliorates lipopolysaccharide-induced neuroinflammation and oxidative stress in adult zebrafish.

Quercetin is a natural flavonoid that is known to have numerous pharmacological activities such as antioxidative, anti-inflammatory, and neuroprotective effects against various neurological disorders. Lipopolysaccharide (LPS) is a potent endotoxin, reported causing several neurological disorders. The present study was designed to investigate the possibility that quercetin ameliorates LPS induced oxidative stress and neuroinflammation in adult zebrafish. Zebrafish (weighing 470-530mg) were treated with a single injection of LPS (1mg/kg) intraperitoneally (i.p.) followed by post-treatment with quercetin (50 and 100mg/kg; i.p.) for 7days. After sacrificing brain was harvested and subjected for biochemical, molecular, and histological analyses. Results revealed post-treatment with quercetin was able to ameliorate the behavioral abnormalities as in novel tank diving test- time spent in the top zone (TSTZ), and the number of entries in the top zone was significantly (p < 0.01) more as compared to time spent in the bottom zone (TSBZ). In the light-dark chamber test- time spent in the light zone (TSLZ), and the number of entries in the light zone were significantly (p < 0.01) more as compared to time spent in the dark compartment (TSDC). Additionally, results of histopathology (H & E stain) studies showed less disruption in neuronal cells as compared to the LPS treated group. Moreover, the results of the molecular analysis revealed that quercetin treatment significantly (p < 0.01) decrease TNF-α and IL-1β levels as compared to LPS treated animals. Further, results of the biochemical analysis reveal that quercetin significantly (p < 0.01) reduces the level of LPO, nitrite, AChEs and increases anti-oxidant GSH. Quercetin treatment helps to prevent oxidative damage and neuroinflammation in LPS treated adult zebrafish.

Minor terpenoids from the stems and twigs of Rhododendron ovatum

Four minor undescribed terpenoids, including a monoterpenoid (1) and three triterpenoids (3, 6 and 7), together with 26 known terpenoids were isolated from the stems and twigs of Rhododendron Ovatum. Their structures were identified by extensive spectroscopic analyses and electronic circular dichroism (ECD) techniques. Compound 10 showed excellent cytotoxicity against human colon cancer cell (HCT-116) with IC50 value of 2.56 μM. Compounds 9 and 19 exhibited partly inhibitory effects on nitric oxide production stimulated by lipopolysaccharide-induced neuroinflammation in microglia cells at 10 μM with inhibition ratios of 39.70% and 28.08%, respectively.

Apelin-13 Protects Against Lipopolysaccharide-Induced Neuroinflammation and Cognitive Decline by Restoring Glucocorticoid Receptor Function in Rats

Apelin-13 Protects Against Lipopolysaccharide-Induced Neuroinflammation and Cognitive Decline by Restoring Glucocorticoid Receptor Function in Rats

Minocycline Activates the Nucleus of the Solitary Tract-Associated Network to Alleviate Lipopolysaccharide-Induced Neuroinflammation

ObjectiveTo examine the neuroanatomical substrates underlying the effects of minocycline in alleviating lipopolysaccharide (LPS)-induced neuroinflammation. MethodsForty C57BL/6 male mice were randomly and equally divided into eight groups. Over three consecutive days, saline was administered to four groups of mice and minocycline to the other four groups. Immediately after the administration of saline or minocycline on the third day, two groups of mice were additionally injected with saline and the other two groups were injected with LPS. Six or 24 hours after the last injection, mice were sacrificed and the brains were removed. Immunohistochemical staining across the whole brain was performed to detect microglia activation via Iba1 and neuronal activation via c-Fos. Morphology of microglia and the number of c-Fo-positive neurons were analyzed by Image-Pro Premier 3D. One-way ANOVA and Fisher's least-significant differences were employed for statistical analyses. ResultsMinocycline alleviated LPS-induced neuroinflammation as evidenced by reduced activation of microglia in multiple brain regions, including the shell part of the nucleus accumbens (Acbs), paraventricular nucleus (PVN) of the hypothalamus, central nucleus of the amygdala (CeA), locus coeruleus (LC), and nucleus tractus solitarius (NTS). Minocycline significantly increased the number of c-Fo-positive neurons in NTS and area postrema (AP) after LPS treatment. Furthermore, in NTS-associated brain areas, including LC, lateral parabrachial nucleus (LPB), periaqueductal gray (PAG), dorsal raphe nucleus (DR), amygdala, PVN, and bed nucleus of the stria terminali (BNST), minocycline also significantly increased the number of c-Fo-positive neurons after LPS administration. ConclusionMinocycline alleviates LPS-induced neuroinflammation in multiple brain regions, possibly due to increased activation of neurons in the NTS-associated network.

Resistance-exercise training attenuates LPS-induced astrocyte remodeling and neuroinflammatory cytokine expression in female Wistar rats

Neuroinflammation is an early detectable marker of mild cognitive impairment, the transition state between normal cognition and dementia. Resistance-exercise training can attenuate the cognitive decline observed in patients with mild cognitive impairment. However, the underlying mechanisms of resistance training effects are largely unknown. To further elucidate mechanisms of the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training could ameliorate lipopolysaccharide-induced neuroinflammation. Five-week-old female Wistar rats received intracerebroventricular injections of lipopolysaccharides to induce neuroinflammation and cognitive impairment. Rats then underwent 3 wk of progressive ladder climbing to recapitulate resistance-exercise training in humans. Cognition was assessed toward the end of the training period by novelty object recognition testing. Neuroinflammation was measured one and 24 h after the last resistance-exercise training workout. Resistance-exercise training ameliorated cognitive impairment, diminished lipopolysaccharide-induced neuroinflammatory cytokine expression, and attenuated astrocyte remodeling in the dentate gyrus 24 h post exercise. Here, we provide evidence that the ladder-climbing model of resistance-exercise training in rats can improve cognition as early as 3 wk. In addition, these data support the hypothesis that resistance exercise can reduce lipopolysaccharide-induced neuroinflammation in the dentate gyrus.NEW & NOTEWORTHY To further elucidate the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training in rats would attenuate lipopolysaccharide-induced neuroinflammation. Our data demonstrated that resistance training had an anti-inflammatory effect in the brain as LPS-induced neuroinflammatory cytokine expression and reactive astrocytic remodeling were reduced in the dentate gyrus after 3 wk of progressive ladder climbing.