| 1. |
- Correa, Fernando, et al.
(författare)
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Time-Dependent Effects of Systemic Lipopolysaccharide Injection on Regulators of Antioxidant Defence Nrf2 and PGC-1α in the Neonatal Rat Brain.
- 2013
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1423-0216 .- 1021-7401. ; 20:4, s. 185-193
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Both excitotoxicity and neuroinflammation are associated with oxidative stress. One transcription factor, nuclear factor E2-related factor 2 (Nrf2), and one transcription cofactor, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), increase the endogenous antioxidant defence and can thus modulate neuronal cell death. Here, we investigated the temporal effects (after 24 and 72 h) of systemic (i.p.) administration of lipopolysaccharide (LPS) on the cerebral Nrf2 and PGC-1α systems. Methods and Results: Seven-day-old rat pups were injected with LPS (0.3 mg/kg). After 24 h, the protein levels of γ-glutamylcysteine ligase modulatory subunit, γ-glutamylcysteine ligase catalytic subunit, Nrf2, PGC-1α and manganese superoxide dismutase (MnSOD) were increased in parallel with decreased levels of Keap1. These effects were correlated with an increased level of phosphorylated Akt and elevated acetylation of histone 4. In contrast, 72 h following LPS, a decrease in the components of the Nrf2 system in parallel with an increase in Keap1 was observed. The down-regulation after 72 h correlated with phosphorylation of p38 mitogen-activated protein kinase, while there were no changes in PGC-1α and MnSOD protein levels or the acetylation/methylation pattern of histones. Conclusion: Systemic LPS in neonatal rats induced time-dependent changes in brain Nrf2 and PGC-1α that correlated well with the protective effect observed after 24 h (pre-conditioning) and the deleterious effects observed after 72 h (sensitizing) of systemic LPS reported earlier. Collectively, the results point towards Nrf2 and PGC-1α as a possible mechanism behind these effects.
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| 2. |
- Georen, SK, et al.
(författare)
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Timing-dependent effects of restraint stress on eosinophilic airway inflammation in mice
- 2008
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1423-0216 .- 1021-7401. ; 15:3, s. 157-164
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Chronicstress has been proposed to aggravate allergic inflammation, whereas acute stress may have functional beneficial effects. The aim of this study was to investigate the influence of timing of single short restraint stress (RST) in a model of eosinophilic airway inflammation. <i>Methods:</i> The airways of ovalbumin (OVA)-sensitized mice were exposed to an intranasal OVA challenge. RST was applied in two different ways; either 2 h before (pre-stress) or after (post-stress) the OVA challenge, respectively, or as a combination of stress before and after (double-stress) the OVA challenge. One group of mice was also treated with metyrapone (ME) prior to a pre-stress challenge. The inflammatory cell response was evaluated in bronchoalveolar lavage fluid (BALF), lung and nasal tissue, as well as bone marrow. <i>Result:</i> RST applied prior to the OVA challenge (pre-stress) inhibited OVA-induced airway inflammation in BALF and lung tissue, and reduced nasal histopathology compared to unstressed mice. Given as post-stress or double-stress, RST did not affect the inflammation in BALF, lungs or nasal tissue. Pre-treatment with ME prevented the pre-challenge stress evoked decrease in inflammation in BALF and lungs. <i>Conclusion:</i> Effects of RST on eosinophilic airway inflammation appear to be strongly dependent on timing and, as could be judged from the ME inhibition pattern, also corticosterone dependent. Hypothalamic-pituitary-adrenal axis activation probably influences eosinophilic inflammation through specific sequences of compartmental activation and thereby timing effects are evident on cellular recruitment pattern during the allergic reaction.
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| 3. |
- Gruden, Marina A., et al.
(författare)
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Correlation between Protective Immunity to alpha-Synuclein Aggregates, Oxidative Stress and Inflammation
- 2012
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1021-7401 .- 1423-0216. ; 19:6, s. 334-342
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Protein aggregation leading to central amyloid deposition is implicated in Parkinson's disease (PD). During disease progression, inflammation and oxidative stress may well invoke humoral immunity against pathological aggregates of PD-associated alpha-synuclein. The aim was to investigate any possible concurrence between autoimnnune responses to alpha-synuclein monomers, oligomers or fibrils with oxidative stress and inflammation.Methods: The formation of alpha-synuclein amyloid species was assessed by thioflavin-T assay and atomic force microscopy was employed to confirm their morphology. Serum autoantibody titers to alpha-synuclein conformations were determined by ELISA. Enzyme activity and concentrations of oxidative stress/inflammatory indicators were evaluated by enzyme and ELISA protocols.Results: In PD patient sera, a differential increase in autoantibody titers to alpha-synuclein monomers, toxic oligomers or fibrils was associated with boosted levels of the pro-inflammatory cytokine interleukin-6 and tumour necrosis factor-alpha, but a decrease in interferon-gamma concentration. In addition, levels of malondialdehyde were elevated whilst those of glutathione were reduced along with decrements in the activity of the antioxidants: superoxide dismutase, catalase and glutathione transferase.Conclusions: It is hypothesized that the generation of alpha-synuclein amyloid aggregates allied with oxidative stress and inflammatory reactions may invoke humoral immunity protecting against dopaminergic neuronal death. Hence, humoral immunity is a common integrative factor throughout PD progression which is directed towards prevention of further neurodegeneration, so potential treatment strategies should attempt to maintain PD patient immune status. Copyright (c) 2012 S. Karger AG, Basel
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| 4. |
- Jurberg, AD, et al.
(författare)
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VLA-4 as a Central Target for Modulating Neuroinflammatory Disorders
- 2021
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1423-0216 .- 1021-7401. ; 28:4, s. 213-221
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Tidskriftsartikel (refereegranskat)abstract
- The complex steps leading to the central nervous system (CNS) inflammation and the progress to neuroinflammatory and neurodegenerative disorders have opened up new research and intervention avenues. This review focuses on the therapeutic targeting of the VLA-4 integrin to discuss the clear-cut effect on immune cell trafficking into brain tissues. Besides, we explore the possibility that blocking VLA-4 may have a relevant impact on nonmigratory activities of immune cells, such as antigen presentation and T-cell differentiation, during the neuroinflammatory process. Lastly, the recent refinement of computational techniques is highlighted as a way to increase specificity and to reduce the detrimental side effects of VLA-4 immunotherapies aiming at developing better clinical interventions.
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| 5. |
- Lekander, M, et al.
(författare)
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Cytokine inhibition after glucocorticoid exposure in healthy men with low versus high basal cortisol levels
- 2009
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1423-0216 .- 1021-7401. ; 16:4, s. 245-250
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Tidskriftsartikel (refereegranskat)abstract
- <i>Objective:</i> The balance between glucocorticoid (GC) release and GC sensitivity in target cells is believed to be important to maintain homeostasis in the neuroendocrine control of inflammation. We investigated the impact of in vivo exposure to adrenocorticotropic hormone (ACTH) and dexamethasone (DEX) on GC sensitivity measured in vitro in healthy individuals with high versus low baseline cortisol levels. <i>Methods:</i>136 healthy male volunteers were screened twice and sorted according to their 24-hour urinary free cortisol (UFC) excretion. The 10 individuals with the highest UFC (290 ± 87 nmol/24 h) and the 10 with the lowest UFC (168 ± 34 nmol/24 h) were further tested. Measurements were performed at baseline, after a low dose (0.5 μg/1.73 m<sup>2</sup>) of ACTH challenge and after 2 weeks’ exposure to DEX (0.1 mg twice daily). GC sensitivity was assessed in vitro as the ability of DEX to inhibit lipopolysaccharide-stimulated production of the cytokines interleukin 1-β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in a whole-blood assay. <i>Results:</i>After exposure to DEX in vivo<i>,</i> inhibition of IL-6 and TNF-α decreased. Also<i>, </i>after DEX in vivo, low-cortisol men showed lower inhibition of IL-1β and IL-6, both compared to the high-cortisol group and their own baseline levels. <i>Conclusion:</i> A downregulation of GC sensitivity in leukocytes after exposure to an exogenous GC seems to occur most strongly in men with low cortisol levels.
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| 6. |
- Liu, YJ, et al.
(författare)
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Modulation of early immune responses and suppression of Trypanosoma brucei brucei infections by surgical denervation of the spleen
- 2000
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1021-7401 .- 1423-0216. ; 8:1, s. 31-38
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Tidskriftsartikel (refereegranskat)abstract
- <i>Objective:</i> To examine critical interactions between the nervous system and the immune system during experimental African trypanosomiasis. <i>Methods and Results:</i> Inoculation of <i>Trypanosoma brucei brucei </i>resulted in early interferon (IFN)-γ production, elevated corticosterone and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) levels and increased splenocyte proliferation, as measured by enzyme-linked immunospot assay, radioimmunoassay and thymidine incorporation assay, respectively. Splenic denervation suppressed IFN-γ, corticosterone and PGE<sub>2</sub> production, enhanced splenocyte proliferation, and significantly reduced parasitemia and prolonged rat survival. <i>Conclusions:</i> Our data show substantial effects of the nervous system on early immune responses that may influence the outcome of this disease. These effects were not dependent on cytokine inhibitory mediators such as prostaglandins or stress hormones. More investigations are required to understand the evident neural control over the immune system during infectious challenges, which may assist in novel therapeutic approaches.
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| 7. |
- Liu, YJ, et al.
(författare)
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Splenic denervation suppresses mRNA gene expression and protein production of IL-1beta and IL-6 by peritoneal macrophages in both Trypanosoma brucei brucei-infected and non-infected rats
- 2004
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1021-7401 .- 1423-0216. ; 11:2, s. 113-118
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Tidskriftsartikel (refereegranskat)abstract
- <i>Objective:</i> To test the hypothesis that the nervous system participates in modulating the immune response during experimental African trypanosomiasis caused by <i>Trypanosoma brucei brucei</i>. <i>Methods and Results:</i> Using in situ hybridization and immunochemistry, we studied the effects of splenic sympathectomy on mRNA gene expression and protein production of IL-1β and IL-6 in splenic and peritoneal macrophages (PMΦ) of Sprague-Dawley rats infected with <i>T. brucei brucei</i> and non-infected rats. The enhancements of mRNA gene expression and production of IL-1β and IL-6 by peritoneal macrophages were significantly suppressed by the splenic sympathectomy in both infected and non-infected rats. <i>Conclusions:</i> Our data indicate a probably stimulatory role of the sympathetic nervous system during the host immune response in both normal and <i>T. brucei brucei</i>-infected rats.
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| 8. |
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| 9. |
- Patil, Jaspal, et al.
(författare)
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Sustained Effects of Neonatal Systemic Lipopolysaccharide on IL-1 beta and Nrf2 in Adult Rat Substantia Nigra Are Partly Normalized by a Spirulina-Enriched Diet
- 2016
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1021-7401 .- 1423-0216. ; 23:4, s. 250-259
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Neonatal infection can sensitize the adult substantia nigra (SN) to secondary insults, causing a decrease in antioxidant capacity which may lead to Parkinson's disease in adults. We studied the prolonged effect of systemic infection by (i.p.) administration of lipopolysaccharide (LPS) on interleukin (IL)-1 beta, the antioxidant regulator nuclear factor-erythroid 2-related factor 2 (Nrf2), and the peroxi-some proliferator-activated receptor gamma coactivator (PGC)-1 alpha in rat SN. Method and Results: Five-day-old rat pups were treated with LPS (i. p. 2 mg/kg). After 65 days, the mRNA level of IL-1 beta was significantly increased, in parallel with a decrease in that of the rate-limiting enzyme in glutathione synthesis, the gamma-glutamylcysteine ligase catalytic subunit (gamma GCLc), Nrf2, and brain-derived neurotrophic factor (BDNF). Protein levels of gamma GCLc and Nrf2 were decreased while IL-1 beta protein was significantly increased. These LPS-induced long-term changes correlated with a decrease in phosphorylated (active) AKT (pAKT) and phosphorylated (inactive) GSK-3 beta (pGSK-3 beta). In another set of experiments, a 0.1% Spirulina-containing diet was given to lactating mothers 24 h before the LPS treatment of the pups. The Spirulina-supplemented diet decreased IL-1 beta protein expression in SN and elevated the mRNA level of gamma GCLc, Nrf2 protein, PGC-1 alpha protein, and pAKT. Conclusion: Early-life infection can negatively affect Nrf2, pAKT, and pGSK-3 beta for a long time in SN. A diet en-riched with antioxidant and anti-inflammatory phytochemicals can partly restore some, but not all, of the effects on the antioxidant defense, possibly via normalizing effects on pAKT. (C) 2016 S. Karger AG, Basel
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| 10. |
- Rajda, Cecilia, et al.
(författare)
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Increased dopamine content in lymphocytes from high-dose L-Dopa-treated Parkinson's disease patients
- 2005
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Ingår i: Neuroimmunomodulation. - : S. Karger AG. - 1021-7401 .- 1423-0216. ; 12:2, s. 81-84:12, s. 81-84
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The intracellular (i.c.) content of dopamine and its metabolites was measured in the peripheral blood lymphocytes (PBLs) of Parkinson's disease (PD) patients and healthy controls. METHODS: Catecholamine levels of PBLs were measured using capillary electrophoresis in healthy controls and PD patients receiving different doses of L-dihydroxyphenylalanine (L-Dopa). RESULTS: Higher i.c. dopamine content was found in lymphocytes from PD patients receiving a high dose of L-Dopa (700 +/- 30 mg/day) as compared to lymphocytes from the healthy controls (p = 0.002) and from PD patients treated with a low dose of L-Dopa (400 +/- 30 mg/day) (p = 0.022). The dihydroxyphenylacetic acid to dopamine ratio was significantly lower in the high-dose L-Dopa-treated PD patients than in the controls (p = 0.013). CONCLUSIONS: These findings suggest that the dopamine content and metabolism in the peripheral lymphocytes of PD patients are influenced by L-Dopa administration. This is the first study in which a dose-related effect of L-Dopa treatment was found in lymphocytes from PD patients.
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