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Background: In the present work, we studied the modulatory effect of Leptin (Lep) against pro-inflammatory cytokines, tumour necrosis factor-alpha (TNFα), interleukin 1-beta (IL1β) and interferon-gamma (IFNγ), in primary glial cell cultures., Methods: Glial cultures were treated with pro-inflammatory cytokines (TNFα, 20ng/ml; IL1β, 20ng/ml; IFNγ 20ng/ml). Cells were pre-treated with Lep 500nM, 1h prior to cytokine treatment. NO released from glial cells was determined using the Griess reaction. Cell viability was determined by the MTT method. Protein expression was determined by western blot., Results: Pre-treatment with 500nM Lep produced an inhibitory effect on inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production after glial cells exposure to pro-inflammatory cytokines. Anti-inflammatory effect can be related to a decrease in P38 MAP Kinase (MAPK) pathway activity. Treatment of glial cell cultures with Lep also reduced the intrinsic apoptotic pathway (cytochrome c release and caspase-3 activation)., Conclusions: We suggest that Lep would act as an anti-inflammatory factor in glial cells exposed to pro-inflammatory cytokines, exerting its function on p38 MAPK pathway and reducing NO production., (Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies. The release of pro-inflammatory cytokines and chemokines by activated glial cells, astrocytes and microglia plays an important role in this process. However, the role of hypoxia-inducible factor-1α (HIF-1α), the key transcription factor regulating the expression of hypoxia-inducible genes, during glial activation is less known. Thus, we examined the significance of HIF-1α in three experimental models: first in an acute model of inflammation induced by pro-inflammatory cytokines TNF-α, IL-1β and IFN-γ; secondly, in a chronic model of inflammation using an APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease and thirdly via the inhibition of the PI3K/AKT pathway in a model of neuronal apoptosis. During acute glial inflammation induced by in vitro administration of TNF-α, IL-1β and IFN-γ, mRNA expression levels of HIF-1α were significantly upregulated; however, this effect was blocked by SP600126, a pharmacological inhibitor of mitogen-activated protein kinases (MAPKs). These data suggest that MAPKs could be involved in HIF-1α regulation. In addition, we observed that HIF-1α is not involved in the neuronal apoptotic process mediated by PI3-kinase inhibition, which is regulated by c-Jun. Finally, we did not detect significant differences in the expression of HIF-1α mRNA in APP/PS1 mice during the course of the study (3-12 months of age). Thus, we demonstrated that HIF-1α has a prominent role in acute but not in chronic inflammatory processes, such as the one which occurs in the APP/PS1 experimental model of AD. Moreover, HIF-1α is not involved in neuronal apoptosis after PI3K/AKT inhibition., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Tryptophan (TRP), which plays an important role in immune system regulation, protein synthesis, serotonin (5-HT) and melatonin production, is a potent endogenous free radical scavenger and antioxidant. The aim of this work was to determine the efficacy of TRP in neuro-inflammation induced by systemic administration of lipopolysacharide (LPS, 20mg/kg) which promotes the synthesis of free radical (LPO: MDA and 4-HDA), and pro-inflammatory cytokine Interferon-γ (IFN-γ) in different brain regions (cerebral cortex and hippocampus) of rats. Experiments were performed on adult female, pregnant and lactating rats fed with a diet of TRP content (0.5mg/100g protein), cerebral cortex and hippocampus were evaluated for lipid peroxidation (LPO) products, nitrites, nitrates and plasmatic concentration of IFN-γ. LPO levels in LPS+TRP groups were significantly decreased than that obtained in the LPS group. However, there were no observed differences in plasmatic levels of nitrites and nitrates as well as IFN-γ, neither in the cerebral cortex or hippocampus. The TRP has protective effect in the oxidative damage in a model of endotoxic shock in the breading nurslings induced by the systemic administration of LPS, acting as a scavenger of free radicals. So, it can be proposed as an innocuous protector agent in the endotoxic shock process., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Background: Experimental liver fibrosis induced by carbon tetrachloride (CCl(4)) is associated with oxidative stress, lipid peroxidation, and inflammation. This work was focused on elucidating the anti-inflammatory and antioxidant effects of ethylenediaminetetraacetic acid (EDTA) in this model of hepatotoxicity., Methods: Wistar male rats were treated with CCl(4) and EDTA (60, 120, or 240 mg/kg). Morphometric analyses were carried out in Masson's stained liver sections to determine fibrosis index. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) were also determined. Gene expression for transforming growth factor beta (TGF-beta1), alpha1(I) procollagen gene (alpha1 Col I), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and superoxide dismutase (SOD) was monitored by real-time PCR. Antioxidant effect of EDTA was measured by its effects on lipid peroxidation; biological activity of ceruloplasmin (Cp), SOD, and catalase (Cat) were analyzed by zymography assays., Results: Animals with CCl(4)-hepatic injury that received EDTA showed a decrement in fibrosis (20%) and lipid peroxidation (22%). The mRNA expression for TNF-alpha (55%), TGF-beta1 (50%), IL-6 (52%), and alpha1 Col I (60%) was also decreased. This group of animals showed increased Cp (62%) and SOD (25%) biological activities. Coagulation blood tests, Cat activity, and gene expression for SOD were not modified by EDTA treatment., Conclusion: This study demonstrates that EDTA treatment induces the activity of antioxidant enzymes, decreases lipid peroxidation, hepatic inflammation, and fibrosis in experimental liver fibrosis induced by CCl(4).