Single Administration Of Lipopolysaccharide Research Articles

Protective effects of Centella asiatica extract on spatial memory and learning deficits in animal model of systemic inflammation induced by lipopolysaccharide

Background and aim Centella asiatica (L.) Urb. (Apiaceae) is a renowned medicinal plant being used in the Ayurvedic system for its pharmacological effects on the central nervous system such as rejuvenating, sedative, anxiolytic and memory-enhancing properties. The present study was designed to investigate the effect of Centella asiatica (CA) extract on inflammatory responses induced by lipopolysaccharide (LPS) and resulting changes in cognitive behavior. Materials and methods Adult male Sprague-Dawley rats were divided into 4 groups as control, LPS, CA and LPS + CA. The treatments with LPS (5 mg/kg) were intraperitoneally (i.p) injected on day 4 and CA ethanol extract (200 mg/kg) were given orally for 14 days. Morris Water Maze (MWM) test was performed to assess spatial learning and memory performance. Acute oral toxicity of the extract at the highest dose of 5000 mg/kg was also conducted. Results Single administration of LPS was able to significantly elicit learning and memory impairment (p < .05) when compared to the control groups. Treatment with CA significantly improved the impaired learning ability in which the LPS + CA rats took the shortest time and route to find the hidden platform (15.85 ± 2.68 s (p < .001); 352.43 ± 88.10 cm (p < .001) on day 5) and induced differential cytokine responses in the blood. No mortality and no significant variation in the body and organ weights between the control and the treated group was observed after 14 days of acute toxicity study. Hematological analysis and biochemical parameters revealed no toxic effects of the extract. Pathologically, neither gross abnormalities nor histopathological changes were observed. Discussion and conclusion Centella asiatica extract exhibited significant learning and memory enhancement potential in animal model. Hence, indicating its putative preventive therapeutic effects in neuroinflammation related diseases. KEY MESSAGE A single dose of lipopolysaccharide (LPS) (5 mg/kg) administered systemically to mimic the consequences of LPS-induced inflammatory responses was able to affect some behavioral modification of spatial memory at the time point of study. The study showed that the learning capability during the training trial was restored or ameliorated with the pre-emptive treatment of Centella asiatica extract (200 mg/kg). Centella asiatica extract improves spatial memory, learning deficits and regulates proinflammatory responses in systemic LPS-treated rats.

CD14 is not required for carbon tetrachloride-induced hepatic inflammation and fibrosis with or without lipopolysaccharide challenge.

Binding of lipopolysaccharide (LPS) to CD14 is required for its cellular effects via TLR4. A role of LPS/TLR4-mediated signaling in activated hepatic stellate cells (aHSCs), the major fibrogenic cells, in liver fibrosis has been reported. We investigated effects of LPS on carbon tetrachloride (CCl4)-induced fibrosis in CD14-knockout (KO) mice in vivo, and culture-activated HSCs in vitro. CCl4(biweekly; 4 weeks)-treated wild type (WT) and CD14-KO mice were challenged with single LPS administration for 24 h. Liver injury, inflammation and fibrosis were determined. Culture-activated HSCs from WT or CD14-KO mice were stimulated with LPS. Parameters of fibrogenic activity (expression of collagen1a1 [Col1a1], α-smooth muscle actin [αSMA] and TGFβ1) and inflammatory cytokines/chemokines were measured. CCl4 treatment caused similar liver injury and fibrosis in WT and CD14-KO mice. LPS increased liver injury and inflammation similarly in CCl4-treated WT and CD14-KO mice, but downregulated Timp1 and upregulated Mmp13. LPS elicited similar NFκB activation and inflammatory response in WT and CD14-KO aHSCs. LPS similarly downregulated Acta2 (encodes αSMA), Pdgfrb, Col1a1 and Mmp13 expression but did not affect Timp1 expression in WT and CD14-KO aHSCs. LPS did not alter Tgfb1 but increased expression of decorin (Dcn) (inhibitor of TGFβ1) expression in WT and CD14-KO aHSCs. The results indicate that the effects of LPS on HSCs are CD14-independent, and CD14 is not required for hepatic fibrosis. LPS-induced down-modulation of fibrogenic markers in aHSCs is also CD14-independent.

Validation of the protective effects of Lonicera japonica polysaccharide on lipopolysaccharide-induced learning and memory impairments via regulation of autophagy based on network pharmacology.

Learning and memory impairments are important indexes in assessing Alzheimer's disease (AD). Lonicera japonica (L. japonica), a traditional Chinese herbal medicine, inhibits inflammation, but its role in neuroprotection is unclear. Polysaccharide is the main active ingredient in L. japonica. Here, we aimed to validate the effects of L. japonica polysaccharide (LJP) on lipopolysaccharide (LPS)-induced cognitive impairment and the underlying mechanism. The Chinese medicine system pharmacology database and analysis platform was used to predict the target of L. japonica; the GeneCards system was used to predict the AD target. We also performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Experiments were performed after bioinformatic analysis for verification. A chronic learning and memory impairment model was established by a single administration of LPS. Learning and memory abilities of Kunming mice were examined after 7 days of induction. The protective effects of LJP on LPS-induced impairment were investigated. Neuronal damage was observed by Nissl staining. Key proteins involved in the autophagy pathway were examined. Bioinformatic analysis showed that there were 151 genes in the intersection of the target and ADrelated genes, and KEGG analysis suggested that these genes may act via multiple pathways. LPS-induced changes in learning and memory in mice were significantly attenuated by LJP. Nissl staining revealed that the neurons in the control group were lost and cellular arrangement was disrupted. LJP alleviated the pathological changes in the neurons of mice. The autophagy pathway was selected to verify the mechanism. ATG5, Beclin 1, Vps34, and LC3 II expression in the LPS group was significantly increased, and it was further increased in the LJP group. LJP improved behavioral changes and neuronal loss associated with LPS-induced learning and memory impairments. The underlying mechanism may be related to the regulation of the autophagy pathways.

Estradiol Increases Microglial Response to Lipopolysaccharide in the Ventromedial Hypothalamus during the Peripubertal Sensitive Period in Female Mice.

Sensitive periods are times of development during which the effects of experience are unusually strong and long lasting. The peripubertal period has emerged as one such sensitive period, and a single administration of lipopolysaccharide (LPS) during this time reduces hormone-induced sexual behavior in adult female mice. During periods of high synaptic turnover, maturation, and elimination, as occurs during this sensitive period, microglia are particularly active. Estradiol also regulates microglial numbers, morphology, and activation. In addition, a good deal of evidence suggests that estradiol may confer this vulnerability to the effects of a stressor during the peripubertal period. Therefore, we investigated the effects of estradiol on microglial morphology, cytokine levels, and the sickness response to LPS. Estradiol levels were manipulated by implanting an estradiol-filled SILASTIC capsule (or oil-filled control) in ovariectomized mice or by administering the aromatase inhibitor, formestane (or oil control), to ovary-intact mice. We found that (1) estradiol elevates basal microglial Iba1 immunoreactivity in the ventromedial nucleus of the hypothalamus (VMH), (2) LPS induces higher levels of proinflammatory cytokines in the presence of estradiol, and (3) LPS causes hypothermia in the presence of estradiol. Taken together, these data suggest that estradiol enhances the effect of LPS during the pubertal sensitive period.

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson's Disease Model.

Systemic inflammation is a crucial factor for microglial activation and neuroinflammation in neurodegeneration. This work is aimed at assessing whether previous exposure to systemic inflammation potentiates neurotoxic damage by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and how chronic systemic inflammation participates in the physiopathological mechanisms of Parkinson's disease. Two different models of systemic inflammation were employed to explore this hypothesis: a single administration of lipopolysaccharide (sLPS; 5 mg/kg) and chronic exposure to low doses (mLPS; 100 μg/kg twice a week for three months). After three months, both groups were challenged with MPTP. With the sLPS administration, Iba1 staining increased in the striatum and substantia nigra, and the cell viability lowered in the striatum of these mice. mLPS alone had more impact on the proinflammatory profile of the brain, steadily increasing TNFα levels, activating microglia, reducing BDNF, cell viability, and dopamine levels, leading to a damage profile similar to the MPTP model per se. Interestingly, mLPS increased MAO-B activity possibly conferring susceptibility to MPTP damage. mLPS, along with MPTP administration, exacerbated the neurotoxic effect. This effect seemed to be coordinated by microglia since minocycline administration prevented brain TNFα increase. Coadministration of sLPS with MPTP only facilitated damage induced by MPTP without significant change in the inflammatory profile. These results indicate that chronic systemic inflammation increased susceptibility to MPTP toxic effect and is an adequate model for studying the impact of systemic inflammation in Parkinson's disease.

Combination of Geniposide and Eleutheroside B Exerts Antidepressant-like Effect on Lipopolysaccharide-Induced Depression Mice Model.

To study the antidepressant-like effect and action mechanism of geniposide and eleutheroside B combination treatment on the lipopolysaccharide (LPS)-induced depression mice model. Depression mice model was established by lipopolysaccharide (LPS) injection. Totally 48 mice were randomly divided into 6 groups (8 rats per group) according to a random number table, including normal, model, fluoxetine (20 mg/kg), geniposide (100 mg/kg) + eleutheroside B (100 mg/kg), geniposide + eleutheroside B + WAY 100635 (0.03 mg/kg), geniposide + eleutheroside B+ N-methyl-D-aspartic acid receptor (NMDA, 75 mg/kg) groups, respectively. After continuous administration for 10 days, autonomic activity tests after 30 min of administration were performed on the 10th day. On the 11th day, except for the normal group, the mice in the other groups were intraperitoneally injected with LPS (1 mg/kg), and the behavioral tests were performed 4 h later. Enzyme linked immunosorbent assay was used to detect tumor necrosis factor alpha (TNF- α) and interleukin-1 β (IL-1 β) levels in mice serum. The mRNA expression of indoleamine 2,3-dioxygenase (IDO) and nuclear transcription factor (NF- κB) were detected by real-time quantitative polymerase chain reaction. Western-blot analysis was used to detect IDO and NF- κB protein expressions in hippocampus tissue. Compared with the normal group, a single administration of LPS increased the immobility time in the forced swimming test (FST) and tail suspension test (TST, P<0.01), without affecting autonomous activity. Compared with the model group, fluoxetine and geniposide + eleutheroside B administration significantly improved the immobility time of depressed mice in the FST and TST, decreased serum IL-1 β content, inhibited the expression levels of NF- κ B gene and protein in hippocampus tissues (P<0.05 or P<0.01). Compared with the model group, geniposide + eleutheroside B treatment significantly reduced serum TNF-α content and inhibited IDO mRNA and protein expressions in hippocampus (P<0.05 or P<0.01). In addition, NMDA partly prevented the inhibition of IDO mRNA expression by geniposide + eleutheroside B; NMDA and WAY-100635 also partly prevented the reduction of IL-1 ß content induced by geniposide + eleutheroside B treatment (P<0.05 or P<0.01). The combination of geniposide and eleutheroside B showed a certain antidepression-like effect. Its main mechanism of action may be contributed to inhibiting the activation of NF- κB, decreasing the proinflammatory cytokines such as TNF-α, IL-1 β, and inhibiting in the neuroinflammatory reaction. Additionally, it also affects tryptophan metabolism, reduces the expression of a key enzyme of tryptophan metabolism, IDO. And this antidepressant-like effect may be mediated by 5-hydroxytryptamine and glutamate systems.

Protein arginine methyltransferase-1 deficiency restrains depression-like behavior of mice by inhibiting inflammation and oxidative stress via Nrf-2

Current evidence indicates that depression is accompanied by the activation of inflammatory response and oxidative stress. Protein arginine methyltransferase 1 (PRMT1) is a histone methyltransferase that methylates Arg3 on histone H4, playing crucial role in regulating various pathological processes. In the study, we attempted to explore the effects of PRMT1 on animal model with depression through a single administration of lipopolysaccharide (LPS). Our results indicated that PRMT1 knockout (PRMT1−/−) improved LPS-induced anxiety- and depressive-like behavior, along with up-regulated expression levels of brain-derived neurotrophic factor (BDNF) and PSD-95. Furthermore, PRMT1 deficiency significantly improved LPS-induced changes in dendritic spine density in the areas of prefrontal cortex (PFC), CA3 and dentate gyrus (DG), and nucleus accumbens (NAc). In addition, PRMT1 deletion ameliorated the neuroinflammatory responses, as evidenced by the reduced expression of interleukin 1β (IL-1β) and tumor necrosis factor (TNF)-α, which might be through repressing nuclear factor-κB (NF-κB) signaling. Moreover, oxidative stress induced by LPS was alleviated by PRMT1 knockout in hippocampus of mice at least partly via promoting Nrf-2 expressions. The anti-depressant effects of PRMT1 inhibition were verified in LPS-incubated astrocytes. Importantly, we found that PRMT1 knockout-alleviated inflammation and oxidative stress triggered by LPS were significantly recovered by the suppression of Nrf-2. Therefore, Nrf-2 was markedly involved in PRMT1-regulated depression-like behavior. Taken together, the results indicated that PRMT1 might be an important therapeutic target for developing effective treatment to prevent depressive-like behavior.

Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model

There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from Magnolia officinalis, which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.

Bone Marrow Mesenchymal Stem Cells Combat Lipopolysaccharide-Induced Sepsis in Rats via Amendment of P38-MAPK Signaling Cascade

Sepsis is a systemic inflammatory disorder which often occurs during extremely stressful conditions such as trauma, burn, shock, and infection. This study investigated the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) against hepatic, renal, and pulmonary responses caused by a single administration of lipopolysaccharide (LPS) (10mg/kg, i.p) in rats. Treatment with BM-MSCs (5 × 105 in 0.1ml PBS, i.p.) 3h after LPS antagonized the LPS-induced increment of the liver enzymes (ALT, AST) and kidney functions (BUN, sCr). BM-MSCs decreased tissue levels of P38-MAPK, NF-κB, STAT-3, TNF-α, IL-1β, iNOS, Bax together with elevation of the anti-inflammatory cytokine IL-10 and the anti-apoptotic biomarker Bcl-2. Meanwhile, rats exhibited marked reduction of the broncho-alveolar lavage fluid levels of TNF-α, IL-1β, and IFN-γ. Interestingly, BM-MSCs normalized both broncho-alveolar lavage fluid (BALF) neutrophils count and lung wet/dry ratios. Briefly, these findings may provide a preclinical platform for the management of LPS-induced sepsis using BM-MSCs via their ameliorative anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.

A Novel Role of a Chemotherapeutic Agent in a Rat Model of Endotoxemia: Modulation of the STAT-3 Signaling Pathway.

Sepsis caused by lipopolysaccharide (LPS) is a life-threatening disease accompanied by multiple organ failure. This study investigated the curative effects of imatinib (IMA) against hepatic, renal, and pulmonary responses caused by a single administration of LPS (10mg/kg, i.p.) in rats. Treatment with IMA (15mg/kg, i.p.) 30min after LPS antagonized the LPS-induced boost of liver enzymes (ALT, AST), kidney functions (BUN, sCr) as well as the elevated pulmonary vascular permeability and edema. IMA declined tissue contents of NF-κB, STAT-3, P38-MAPK, TNF-α, IL-1β, and iNOS. It also amplified the anti-inflammatory cytokine IL-10 as well as the Bcl-2/Bax ratio, a cardinal indicator of the anti-apoptotic effect. Meanwhile, the rats exhibited marked reduction of the broncho-alveolar lavage fluid (BALF) contents of TNF-α, IL-1β, IFN-γ, and neutrophil count; however, they revealed prominent augmentation of the BALF content IL-10. In conclusion, these findings suggest that IMA is endowed with anti-inflammatory, anti-oxidant, and anti-apoptotic properties and hence may provide a novel agent for the management of sepsis.

Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation

Inflammation plays a role in the pathophysiology of depression. Sulforaphane (SFN), an isothiocyanate compound derived from broccoli, is a potent activator of the NF-E2-related factor-2 (Nrf2), which plays a role in inflammation. In this study, we examined whether the prevention effects of SFN in lipopolysaccharide (LPS) induced depression-like behavior in mice. Pretreatment with SFN significantly blocked an increase in the serum tumor necrosis factor-α (TNF-α) level and an increase in microglial activation of brain regions after a single administration of LPS (0.5 mg/kg). Furthermore, SFN significantly potentiated increased serum levels of IL-10 after LPS administration. In the tail-suspension test and forced swimming test, SFN significantly attenuated an increase of the immobility time after LPS administration. In addition, SFN significantly recovered to control levels for LPS-induced alterations in the proteins such as brain-derived neurotrophic factor, postsynaptic density protein 95 and AMPA receptor 1 (GluA1) and dendritic spine density in the brain regions. Finally, dietary intake of 0.1% glucoraphanin (a glucosinolate precursor of SFN) food during the juvenile and adolescence could prevent the onset of LPS-induced depression-like behaviors and dendritic spine changes in the brain regions at adulthood. In conclusion, these findings suggest that dietary intake of SFN-rich broccoli sprout has prophylactic effects on inflammation-related depressive symptoms. Therefore, supplementation of SFN-rich broccoli sprout could be prophylactic vegetable to prevent or minimize the relapse by inflammation in the remission state of depressed patients.

Effects of escitalopram, R-citalopram, and reboxetine on serum levels of tumor necrosis factor-α, interleukin-10, and depression-like behavior in mice after lipopolysaccharide administration

Inflammation plays a role in the pathophysiology of depression. The purpose of this study is to examine whether the selective serotonin reuptake inhibitor (SSRI) escitalopram, its inactive enantiomer R-citalopram, and selective noradrenaline reuptake inhibitor (NRI) reboxetine, show anti-inflammatory and antidepressant effects in an inflammation-induced model of depression. Pretreatment with escitalopram (1, 3, or 10mg/kg, i.p.) markedly blocked an increase in the serum levels of pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), after a single administration of lipopolysaccharide (LPS; 0.5mg/kg). Furthermore, escitalopram (3 or 10mg/kg) significantly increased the serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) by a single administration of LPS. In contrast, pretreatment with R-citalopram (10mg/kg, i.p.) or reboxetine (10mg/kg, i.p.) did not affect the alterations in serum levels of TNF-α and IL-10 after LPS administration. Co-administration of reboxetine with escitalopram did not show anti-inflammatory effects. Pretreatment with escitalopram (10mg/kg) significantly attenuated LPS-induced increase of the immobility time in the tail-suspension test (TST) and forced swimming test (FST). In contrast, pretreatment with R-citalopram (10mg/kg), or reboxetine (10mg/kg) did not alter LPS-induced increase of immobility time of TST and FST. Interestingly, co-administration of reboxetine with escitalopram did not show antidepressant effect in this model. These findings suggest that escitalopram, but not R-citalopram and reboxetine, has anti-inflammatory and antidepressant effects in LPS-treated model of depression, and that reboxetine can antagonize the effects of escitalopram in the inflammation model. Therefore, it is likely that serotonergic system plays a key role in the pathophysiology of inflammation-induced depression.

Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB/BDNF signaling in mice

Current evidence supports that depression is accompanied by the activation of the inflammatory-response system, and overproduction of pro-inflammatory cytokines may play a role in the pathophysiology of depressive disorders. Resveratrol has anti-inflammatory, antioxidant and anti-depressant-like properties. Using an animal model of depression induced by a single administration of lipopolysaccharide (LPS), the present study investigated the effects of resveratrol on LPS-induced depressive-like behavior and inflammatory-response in adult mice. Our results showed that pretreatment with resveratrol (80mg/kg, i.p.) for 7 consecutive days reversed LPS-increased the immobility time in the forced swimming test and tail suspension test, and LPS-reduced sucrose preference test. Moreover, the antidepressant action of resveratrol was paralleled by significantly reducing the expression levels of pro-inflammatory cytokines, and up-regulating phosphorylated cAMP response-element-binding protein (pCREB)/brain-derived neurotrophic factor (BDNF) expression in prefrontal cortex (PFC) and hippocampus. In addition, resveratrol ameliorated LPS-induced NF-κB activation in the PFC and hippocampus. The results demonstrate that resveratrol may be an effective therapeutic agent for LPS-induced depressive-like behavior, partially due to its anti-inflammatory aptitude and by modulating pCREB and BDNF expression in the brain region of mice.

Oligodendrogenesis in the fornix of adult mouse brain; the effect of LPS-induced inflammatory stimulation

Evidence have been accumulated that continuous oligodendrogenesis occurs in the adult mammalian brain. The fornix, projection and commissure pathway of hippocampal neurons, carries signals from the hippocampus to other parts of the brain and has critical role in memory and learning. However, basic characterization of adult oligodendrogenesis in this brain region is not well understood. In the present study, therefore, we aimed to examine the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) and the effect of acute inflammatory stimulation on oligodendrogenesis in the fornix of adult mouse. We demonstrated the proliferation of OPCs and a new generation of mature oligodendrocytes by using bromodeoxyuridine and Ki67 immunohistochemistry. Oligodendrogenesis of adult fornix was also demonstrated by using oligodendrocyte transcription factor 2 transgenic mouse. A single systemic administration of lipopolysaccharide (LPS) attenuated proliferation of OPCs in the fornix together with reduced proliferation of hippocampal neural stem/progenitor cells. Time course analysis showed that a single administration of LPS attenuated the proliferation of OPCs during 24–48h. On the other hand, consecutive administration of LPS did not suppress proliferation of OPCs. The treatment of LPS did not affect differentiation of OPCs into mature oligodendrocytes. Treatment of a microglia inhibitor minocycline significantly attenuated basal proliferation of OPCs under normal condition. In conclusion, the present study indicates that continuous oligodendrogenesis occurs and a single administration of LPS transiently attenuates proliferation of OPCs without changing differentiation in the fornix of the adult mouse brains.

Effects of amycenone on serum levels of tumor necrosis factor-α, interleukin-10, and depression-like behavior in mice after lipopolysaccharide administration

Accumulating evidence suggests that inflammation plays a role in the pathophysiology of depression and that anti-inflammatory substances have antidepressant effects. Amycenone is obtained from extracts of the Yamabushitake (Hericium erinaceum). The purpose of this study is to examine whether amycenone shows anti-inflammatory and antidepressant effects in an inflammation-induced mouse model of depression. First, we examined the effects of amycenone on the serum levels of the pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokine, interleukin-10 (IL-10), after intraperitoneal administration of the bacterial endotoxin lipopolysaccharide (LPS). Oral administration of amycenone (50, 100, or 200mg/kg) markedly blocked an increase in the serum TNF-α levels after a single administration of LPS (0.5mg/kg). Furthermore, amycenone (200mg/kg) markedly increased the serum IL-10 levels by a single administration of LPS (0.5mg/kg). Next, we examined the effects of amycenone on depression-like behaviors in the tail-suspension test (TST) and forced swimming test (FST). Pretreatment with amycenone (200mg/kg) significantly attenuated LPS (0.5mg/kg)-induced increase of the immobility time by the TST and FST, indicating antidepressant effects of amycenone. In addition, oral administration of paroxetine (30mg/kg) showed anti-inflammatory and antidepressant effects in the same model. These findings suggest that amycenone has antidepressant effects in LPS-induced inflammation model of depression. Therefore, amycenone could represent a potential supplement to prevent inflammation-related depression.

Robust increase of microglia proliferation in the fornix of hippocampal axonal pathway after a single LPS stimulation.

Microglia are resident immunocompetent cells having important roles in innate immunity in the brains. In the present study, we found that a single lipopolysaccharide (LPS) administration significantly increased microglial proliferation in the fornix and dentate gyrus (DG) but not the cerebral cortex and corpus callosum of adult mice. LPS-induced microglial proliferation was especially robust at the white matter of the fornix. The density of microglia increased in the fornix and DG for roughly one week and returned to basal levels at least 20days after a single LPS administration. Consecutive LPS administration did not induce such dramatic increase of microglial proliferation in the fornix. The inhibition of vascular endothelial growth factor signaling by AZD2171 largely suppressed LPS-induced increase of microglial proliferation in the fornix. In conclusion, the present study indicates that the hippocampal neuronal system has a higher proliferative microglial capability against LPS-induced inflammatory administration compared with other brain regions.

The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice

Increasing evidence shows that inflammation may contribute to the pathophysiology of depression. Apigenin, one type of natural flavone, has a number of biological actions including anti-inflammatory effects. Although it has potential antidepressant activity in a chronic mild stress model, the mechanisms of antidepressant effect for apigenin remain unclear. Here, we examined the effects of apigenin on lipopolysaccharide (LPS)-induced depressive-like behavior in male mice. A single administration of LPS (0.5mg/kg, i.p.) increased the immobility time in the tail suspension test (TST) and reduced sucrose preference without changing spontaneous locomotor activity in open field test (OFT). Pre-treatment with apigenin (25, 50mg/kg, i.p.) or fluoxetine (positive control drug, 20mg/kg, i.p.) once daily for 7 consecutive days prevented the abnormal behavior induced by LPS. Apigenin or fluoxetine also effectively attenuated LPS-induced production of pro-inflammatory cytokines IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α). Moreover, apigenin or fluoxetine significantly suppressed the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at both the mRNA and protein level via the modulation of nuclear factor-κB (NF-κB) activation in the prefrontal cortex. Additionally, apigenin (50mg/kg, i.p.) or fluoxetine (20mg/kg, i.p.) effectively reversed the depressive-like behavior induced by TNF-α (0.1fg/site, i.c.v.) without altering the locomotor activity. These results demonstrate that apigenin exhibits antidepressant-like effects in LPS treated mice, partially due to its anti-inflammatory properties.

The effects of curcumin on depressive-like behavior in mice after lipopolysaccharide administration

Current evidence supports that inflammation and increased cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. Curcumin has anti-inflammatory, antioxidant and anti-depressant-like properties. Here, we examined the effects of curcumin on lipopolysaccharide (LPS)-induced depressive-like behavior and inflammation in male mice. A single administration of LPS (0.83mg/kg, i.p.) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), reduced sucrose consumption without affecting spontaneous locomotor activity. Pretreatment with curcumin (50mg/kg, i.p.) for 7 consecutive days reversed LPS-induced alterations in the FST, TST, and sucrose preference test. Moreover, pre-treatment with curcumin attenuated LPS-induced microglial activation and overproduction of pro-inflammatory cytokine (interleukin-1β and tumor necrosis factor-α), as well as the levels of inducible nitric oxide synthase and cyclooxygenase-2 mRNA in the hippocampus and prefrontal cortex (PFC). In addition, curcumin ameliorated LPS-induced NF-κB activation in the hippocampus and PFC. The results demonstrate that curcumin may be an effective therapeutic agent for LPS-induced depressive-like behavior, partially due to its anti-inflammatory aptitude.

Effect of Lipopolysaccharide (LPS) on Mouse Model of Steroid-Induced Avascular Necrosis in the Femoral Head (ANFH)

Avascular necrosis of the femoral head (ANFH) is commonly observed in patients treated with excessive glucocorticoid (GC). Single administration of lipopolysaccharide (LPS) has shown to induce immune stimulatory factors. However, the effect of repeated administration of LPS on GC-induced ANFH has not been studied. Thus, the purpose of this study was (i) to examine the cytokine profile induced by repeated LPS administrations and (ii) to test the effect of repeated LPS treatments on GC-induced ANFH. A mouse necrosis model of ANFH was designed by chronic GC administration with co-treatment of LPS. Mice body weights in the LPS/prednisolone (PDN) co-treated group were lower than that of the untreated control group, but spleen weights were greater than the control group. The levels of IL-6, TNFα, and IL-33 in the liver and spleen of the LPS/PDN group were lower than the untreated control group, whereas TNFα level in the femoral head of the LPS/PDN group increased. Collectively, the effect of repeated LPS on the pathogenesis of GC-induced ANFH was associated with the TNFα level in the femoral head, but the pathogenesis did not correspond to cytokine levels in immune tissues.

Effects of perillaldehyde on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration

Perillaldehyde (PAH), a major component of essential oil of Perilla Frutescens, has antidepressant-like effects and anti-inflammatory effects. The present study was designed to determine whether PAH is effective in treating lipopolysaccharide (LPS)-induced depression-like behavior in mice and to explore the possible mechanism between its antidepressant-like effect and anti-inflammatory activity. PAH (60 and 120mg/kg) and fluoxetine (20mg/kg) were administered intragastrically once daily for 7 consecutive days. In the 7th day, LPS (0.5mg/kg) was injected intraperitoneally 30min after drug administration. Blood samples were collected 90min after LPS injection to evaluate serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels by enzyme-linked immunosorbent assay (ELISA). Behavioral tests were measured 24h after LPS injection. After the behavioral tests the prefrontal cortex was rapidly dissected from the brain of the sacrificed mice, then the 5-hydroxytryptamine (5-HT) and norepinephrine (NE) levels in prefrontal cortex were determined by HPLC–MS, and IL-6 and TNF-α mRNA expression was measured using quantitative real-time PCR. Our results showed that a single administration of LPS significantly increased the levels of TNF-α and IL-6 in both the serum and the prefrontal cortex and decreased 5-HT and NE levels in the prefrontal cortex in mice. Pretreatment with fluoxetine (20mg/kg) or PAH (60 and 120mg/kg) could effectively reverse the alterations in the concentrations of 5-HT and NE, and attenuate LPS-induced increases in TNF-α and IL-6 levels. Besides, LPS administration increased the immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting spontaneous locomotor activity. Fluoxetine (20mg/kg) or PAH (60 and 120mg/kg) significantly shortened LPS-induced increases of immobility time in both TST and FST. In conclusion, PAH exhibited significant antidepressant-like effects in mice with LPS-induced depression. The antidepressant activity of PAH might be related to the alteration of monoaminergic responses and the anti-inflammatory effects.