http://www.jneuroinflammation.com The most accessed research articles published by Journal of Neuroinflammation 2012-05-08T00:00:00Z Background: Inflammation caused by the Lyme disease spirochete B. burgdorferi is an important factor in the pathogenesis of Lyme neuroborreliosis. Our central hypothesis is that B. burgdorferi can cause disease via the induction of inflammatory mediators such as cytokines and chemokines in glial and neuronal cells. Earlier we demonstrated that interaction of B. burgdorferi with brain parenchyma induces inflammatory mediators in glial cells as well as glial (oligodendrocyte) and neuronal apoptosis using ex vivo and in vivo models of experimentation. Methods: In this study we evaluated the ability of live B. burgdorferi to elicit inflammation in vitro in differentiated human MO3.13 oligodendrocytes and in differentiated primary human oligodendrocytes, by measuring the concentration of immune mediators in culture supernatants using Multiplex ELISA assays. Concomitant apoptosis was quantified in these cultures by the in situ terminal deoxynucleotidyl transferase mediated UTP nick end labeling (TUNEL) assay and by quantifying active caspase-3 by flow cytometry. The above phenomena were also evaluated after 48 h of stimulation with B. burgdorferi in the presence and absence of various concentrations of the anti-inflammatory drug dexamethasone. Results: B. burgdorferi induced enhanced levels of the cytokine IL-6 and the chemokines IL-8 and CCL2 in MO3.13 cells as compared to basal levels, and IL-8 and CCL2 in primary human oligodendrocytes, in a dose-dependent manner. These cultures also showed significantly elevated levels of apoptosis when compared with medium controls. Dexamethasone reduced both the levels of immune mediators and apoptosis, also in a manner that was dose dependent. Conclusions: This finding supports our hypothesis that the inflammatory response elicited by the Lyme disease spirochete in glial cells contributes to neural cell damage. As oligodendrocytes are vital for the functioning and survival of neurons, the inflammation and subsequent apoptosis of oligodendrocytes induced by B. burgdorferi could contribute to the pathogenesis of Lyme neuroborreliosis. http://www.jneuroinflammation.com/content/9/1/72 Geeta Ramesh Shemi Benge Bapi Pahar Mario Philipp Journal of Neuroinflammation 2012, null:72 2012-04-23T00:00:00Z doi:10.1186/1742-2094-9-72 /content/figures/1742-2094-9-72-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 72 2012-04-23T00:00:00Z PDF Background: Histamine is commonly acknowledged as an inflammatory mediator in peripheral tissues, leaving its role in brain immune responses scarcely studied. Therefore, our aim was to uncover the cellular and molecular mechanisms elicited by this molecule and its receptors in microglia-induced inflammation by evaluating cell migration and inflammatory mediator release. Methods: Firstly, we detected the expression of all known histamine receptor subtypes (H1R, H2R, H3R and H4R), using a murine microglial cell line and primary microglia cell cultures from rat cortex, by real-time PCR analysis, immunocytochemistry and Western blotting. Then, we evaluated the role of histamine in microglial cell motility by performing scratch wound assays. Results were further confirmed using murine cortex explants. Finally, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels were evaluated by ELISA measurements to determine the role of histamine on the release of these inflammatory mediators. Results: After 12 h of treatment, 100 muM histamine and 10 mug/ml histamine-loaded poly (lactic-co-glycolic acid) microparticles significantly stimulated microglia motility via H4R activation. In addition, migration involves alpha5beta1 integrins, and p38 and Akt signaling pathways. Migration of microglial cells was also enhanced in the presence of lipopolysaccharide (LPS, 100 ng/ml), used as a positive control. Importantly, histamine inhibited LPS-stimulated migration via H4R activation. Histamine or H4R agonist also inhibited LPS-induced IL-1beta release in both N9 microglia cell line and hippocampal organotypic slice cultures. Conclusions: To our knowledge, we are the first to show a dual role of histamine in the modulation of microglial inflammatory responses. Altogether, our data suggest that histamine per se triggers microglia motility, whereas histamine impedes LPS-induced microglia migration and IL-1beta release. This last datum assigns a new putative anti-inflammatory role for histamine, acting via H4R to restrain exacerbated microglial responses under inflammatory challenge, which could have strong repercussions in the treatment of CNS disorders accompanied by microglia-derived inflammation. http://www.jneuroinflammation.com/content/9/1/90 Raquel Ferreira Tiago Santos Joana Gonçalves Graça Baltazar Lino Ferreira Fabienne Agasse Liliana Bernardino Journal of Neuroinflammation 2012, null:90 2012-05-08T00:00:00Z doi:10.1186/1742-2094-9-90 /content/figures/1742-2094-9-90-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 90 2012-05-08T00:00:00Z PDF Background: Stress during fetal life increases the risk of affective and immune disorders later in life. The altered peripheral immune response caused by prenatal stress may impact on brain function by the modification of local inflammation. In this study we have explored whether prenatal stress results in alterations in the immune response in the hippocampus of female mice during adult life. Methods: Pregnant C57BL/6 mice were subjected three times/day during 45 minutes to restraint stress from gestational Day 12 to delivery. Control non-stressed pregnant mice remained undisturbed. At four months of age, non-stressed and prenatally stressed females were ovariectomized. Fifteen days after surgery, mice received an i.p. injection of vehicle or of 5 mg/kg of lipopolysaccharide (LPS). Mice were sacrificed 20 hours later by decapitation and the brains were removed. Levels of interleukin-1beta (IL1beta), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interferon gamma-inducible protein 10 (IP10), and toll-like receptor 4 mRNA were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry. Statistical significance was determined by one-way or two-way analysis of variance. Results: Prenatal stress, per se, increased IL1beta mRNA levels in the hippocampus, increased the total number of Iba1-immunoreactive microglial cells and increased the proportion of microglial cells with large somas and retracted cellular processes. In addition, prenatally stressed and non-stressed animals showed different responses to peripheral inflammation induced by systemic administration of LPS. LPS induced a significant increase in mRNA levels of IL-6, TNF-alpha and IP10 in the hippocampus of prenatally stressed mice but not of non-stressed animals. In addition, after LPS treatment, prenatally stressed animals showed a higher proportion of Iba1-immunoreactive cells in the hippocampus with morphological characteristics of activated microglia compared to non-stressed animals. In contrast, LPS induced similar increases in expression of IL1beta and toll-like receptor 4 in both prenatally stressed and non-stressed animals. Conclusion: These findings indicate that prenatal stress induces long-lasting modifications in the inflammatory status of the hippocampus of female mice under basal conditions and alters the immune response of the hippocampus to peripheral inflammation. http://www.jneuroinflammation.com/content/9/1/71 Yolanda Diz-Chaves Olga Pernia Paloma Carrero Luis Garcia-Segura Journal of Neuroinflammation 2012, null:71 2012-04-20T00:00:00Z doi:10.1186/1742-2094-9-71 /content/figures/1742-2094-9-71-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 71 2012-04-20T00:00:00Z PDF It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia. http://www.jneuroinflammation.com/content/8/1/90 Judith Miklossy Journal of Neuroinflammation 2011, null:90 2011-08-04T00:00:00Z doi:10.1186/1742-2094-8-90 /content/figures/1742-2094-8-90-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 90 2011-08-04T00:00:00Z XML Background: Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R) injury. The P2X7 receptor (P2X7R) has been reported to be involved in the inflammatory response of many central nervous system diseases. However, the role of P2X7Rs in transient global cerebral I/R injury remains unclear. The purpose of this study is to determine the effects of inhibiting the P2X7R in a rat model of transient global cerebral I/R injury, and then to explore the association between the P2X7R and neuroinflammation after transient global cerebral I/R injury. Methods: Immediately after infusion with the P2X7R antagonists Brilliant blue G (BBG), adenosine 5' -triphosphate-2' ,3' -dialdehyde (OxATP) or A-438079, 20 minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. Survival rate was calculated, neuronal death in the hippocampal CA1 region was observed using H & E staining, and DNA cleavage was observed by deoxynucleotidyl transferase-mediated UTP nick end labeling TUNEL). In addition, behavioral deficits were measured using the Morris water maze, and RT-PCR and immunohistochemical staining were performed to measure the expression of IL-1beta, TNF-alpha and IL-6, and to identify activated microglia and astrocytes. Results: The P2X7R antagonists protected against transient global cerebral I/R injury in a dosage-dependent manner. A high dosage of BBG (10 ug) and A-0438079 (3 ug), and a low dosage of OxATP (1 ug) significantly increased survival rates, reduced I/R-induced learning memory deficit, and reduced I/R-induced neuronal death, DNA cleavage, and glial activation and inflammatory cytokine overexpression in the hippocampus. Conclusions: Our study indicates that inhibiting P2X7Rs protects against transient global cerebral I/R injury by reducing the I/R-induced inflammatory response, which suggests inhibition of P2X7Rs may be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury. http://www.jneuroinflammation.com/content/9/1/69 Ketan Chu Bo Yin Jingye Wang Guoping Peng Hui Liang Ziqi Xu Yue Du Marong Fang Qiang Xia Luo Benyan Journal of Neuroinflammation 2012, null:69 2012-04-18T00:00:00Z doi:10.1186/1742-2094-9-69 /content/figures/1742-2094-9-69-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 69 2012-04-18T00:00:00Z PDF Background: Experiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs). We investigated the roles and mechanisms of inducible nitric oxide synthase (iNOS) in stress-induced depression. Methods: We used a depressive-like state mouse model induced by unpredictable chronic mild stress (UCMS). Depressive-like behaviors were evaluated after 4 weeks of UCMS, in the presence and absence of the iNOS inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400W) compared with the control group. Immunohistochemistry was used to check the loss of Nissl bodies in cerebral cortex neurons. The levels of iNOS mRNA expression in the cortex and nitrites in the plasma were measured with real-time reverse transcription PCR (RT-PCR) and Griess reagent respectively. Results: Results showed that the 4-week UCMS significantly induced depressive-like behaviors, including decreased sucrose preference in a sucrose preference test, increased duration of immobility in a forced swim test, and decreased hole-searching time in a locomotor activity test. Meanwhile, in the locomotor activity test, UCMS had no effect on normal locomotor activities, such as resting time, active time and total travel distance. Furthermore, the levels of iNOS mRNA expression in the cortex and nitrites in the plasma of UCMS-exposed mice were significantly increased compared with that of the control group. Neurons of cerebral cortex in UCMS-exposed mice were shrunken with dark staining, together with loss of Nissl bodies. The above-mentioned stress-related depressive-like behaviors, increase of iNOS mRNA expression in the cortex and nitrites in the plasma, and neuron damage, could be abrogated remarkably by pretreating the mice with an iNOS inhibitor (1400W). Moreover, neurons with abundant Nissl bodies were significantly increased in the 1400W + UCMS group. Conclusions: These results support the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behaviors in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex. http://www.jneuroinflammation.com/content/9/1/75 Yun-Li Peng Yu-Ning Liu Lei Liu Xia Wang Chun-Lei Jiang Yun-Xia Wang Journal of Neuroinflammation 2012, null:75 2012-04-25T00:00:00Z doi:10.1186/1742-2094-9-75 /content/figures/1742-2094-9-75-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 75 2012-04-25T00:00:00Z PDF Background: Neuroinflammation and protein accumulation are characteristic hallmarks of both normal aging and age-related neurodegenerative diseases. However, the relationship between these factors in neurodegenerative processes is poorly understood. We have previously shown that proteasome inhibition produced higher neurodegeneration in aged than in young rats, suggesting that other additional age-related events could be involved in neurodegeneration. We evaluated the role of lipopolysaccharide (LPS)-induced neuroinflammation as a potential synergic risk factor for hippocampal neurodegeneration induced by proteasome inhibition. Methods: Young male Wistar rats were injected with 1 muL of saline or LPS (5 mg/mL) into the hippocampus to evaluate the effect of LPS-induced neuroinflammation on protein homeostasis. The synergic effect of LPS and proteasome inhibition was analyzed in young rats that first received 1 muL of LPS and 24 hours later 1 muL (5 mg/mL) of the proteasome inhibitor lactacystin. Animals were sacrificed at different times post-injection and hippocampi isolated and processed for gene expression analysis by real-time polymerase chain reaction; protein expression analysis by western blots; proteasome activity by fluorescence spectroscopy; immunofluorescence analysis by confocal microscopy; and degeneration assay by Fluoro-Jade B staining. Results: LPS injection produced the accumulation of ubiquitinated proteins in hippocampal neurons, increased expression of the E2 ubiquitin-conjugating enzyme UB2L6, decreased proteasome activity and increased immunoproteasome content. However, LPS injection was not sufficient to produce neurodegeneration. The combination of neuroinflammation and proteasome inhibition leads to higher neuronal accumulation of ubiquitinated proteins, predominant expression of pro-apoptotic markers and increased neurodegeneration, when compared with LPS or lactacystin (LT) injection alone. Conclusions: Our results identify neuroinflammation as a risk factor that increases susceptibility to neurodegeneration induced by proteasome inhibition. These results highlight the modulation of neuroinflammation as a mechanism for neuronal protection that could be relevant in situations where both factors are present, such as aging and neurodegenerative diseases. http://www.jneuroinflammation.com/content/9/1/87 Cristina Pintado María Gavilán Elena Gavilán Luisa García-Cuervo Antonia Gutiérrez Javier Vitorica Angélica Castaño Rosa Ríos Diego Ruano Journal of Neuroinflammation 2012, null:87 2012-05-04T00:00:00Z doi:10.1186/1742-2094-9-87 /content/figures/1742-2094-9-87-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 87 2012-05-04T00:00:00Z PDF Background: CD4+ CD25+ forkhead box P3 (FoxP3)+ regulatory T cells (T reg cells) are known to suppress adaptive immune responses, key control tolerance and autoimmunity. Methods: We challenged the role of CD4+ T reg cells in suppressing established CD8+ T effector cell responses by using the OT-I/II system in vitro and an OT-I-mediated, oligodendrocyte directed ex vivo model (ODC-OVA model). Results: CD4+ T reg cells dampened cytotoxicity of an ongoing CD8+ T effector cell attack in vitro and within intact central nervous system tissue ex vivo. However, their suppressive effect was limited by the strength of the antigen signal delivered to the CD8+ T effector cells and the ratio of regulatory to effector T cells. CD8+ T effector cell suppression required T cell receptor-mediated activation together with costimulation of CD4+ T reg cells, but following activation, suppression did not require restimulation and was antigen non-specific. Conclusions: Our results suggest that CD4+ T reg cells are capable of suppressing CD8+ T effector cell responses at the parenchymal site, that is, limiting parenchymal damage in autoimmune central nervous system inflammation. http://www.jneuroinflammation.com/content/9/1/41 Kerstin Gobel Stefan Bittner Nico Melzer Susann Pankratz Angela Dreykluft Michael Schuhmann Sven Meuth Heinz Wiendl Journal of Neuroinflammation 2012, null:41 2012-02-28T00:00:00Z doi:10.1186/1742-2094-9-41 /content/figures/1742-2094-9-41-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 41 2012-02-28T00:00:00Z XML Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal administration, for treatment of Alzheimer's disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer's disease and provides a promising area for additional investigation and therapeutic intervention. http://www.jneuroinflammation.com/content/5/1/2 Edward Tobinick Hyman Gross Journal of Neuroinflammation 2008, null:2 2008-01-09T00:00:00Z doi:10.1186/1742-2094-5-2 Therapeutic effect of etanercept in an Alzheimer's patient Report of rapid cognitive improvement in an Alzheimer's patient within minutes following delivery of an anti-tumor necrosis factor-alpha (TNF) therapeutic, etanercept. /content/figures/1742-2094-5-2-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 2 2008-01-09T00:00:00Z XML Background: Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. In prion-infected brains, activated microglia are often present in the vicinity of PrPSc aggregates, and microglial activation is thought to play a key role in the pathogenesis of prion diseases. Although interleukin (IL)-1beta release by prion-induced microglia has been widely reported, the mechanism by which primed microglia become activated and secrete IL-1beta in prion diseases has not yet been elucidated. In this study, we investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP)3 inflammasome in IL-1beta release from lipopolysaccharide (LPS)-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126). Methods: The inflammasome components NALP3 and apoptosis-associated speck-like protein (ASC) were knocked down by gene silencing. IL-1beta production was assessed using ELISA. The mRNA expression of NALP3, ASC, and pro-inflammatory factors was measured by quantitative PCR. Western blot analysis was used to detect the protein level of NALP3, ASC, caspase-1 and nuclear factor-kappaB. Results: We found that that PrP106-126-induced IL-1beta release depends on NALP3 inflammasome activation, that inflammasome activation is required for the synthesis of pro-inflammatory and chemotactic factors by PrP106-126-activated microglia, that inhibition of NF-kappaB activation abrogated PrP106-126-induced NALP3 upregulation, and that potassium efflux and production of reactive oxygen species were implicated in PrP106-126-induced NALP3 inflammasome activation in microglia. Conclusions: We conclude that the NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. To our knowledge, this is the first time that strong evidence for the involvement of NALP3 inflammasome in prion-associated inflammation has been found. http://www.jneuroinflammation.com/content/9/1/73 Fushan Shi Lifeng Yang Mohammed Kouadir Yang Yang Jihong Wang Xiangmei Zhou Xiaomin Yin Deming Zhao Journal of Neuroinflammation 2012, null:73 2012-04-24T00:00:00Z doi:10.1186/1742-2094-9-73 /content/figures/1742-2094-9-73-toc.gif Journal of Neuroinflammation 1742-2094 ${item.volume} 73 2012-04-24T00:00:00Z PDF