Journal articles on the topic 'Neuroinflammatory cytokine expression'
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Alasmari, Fawaz, Musaad A. Alshammari, Abdullah F. Alasmari, Wael A. Alanazi, and Khalid Alhazzani. "Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism." BioMed Research International 2018 (October 25, 2018): 1–8. http://dx.doi.org/10.1155/2018/3087475.
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Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer’s disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.
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Griffin, W. Sue T., and Steven W. Barger. "Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis." US Neurology 06, no. 02 (2010): 19. http://dx.doi.org/10.17925/usn.2010.06.02.19.
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This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer’s neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis was proposed. This states that in response to the negative impact on neurons of known and unknown risk factors—which include genetic inheritance, comorbid and environmental factors—microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each.
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Griffin, W. Sue T., and Steven W. Barger. "Neuroinflammatory Cytokines - The Common Thread in Alzheimer Pathogenesis." European Neurological Review 6, no. 2 (2011): 89. http://dx.doi.org/10.17925/enr.2011.06.02.89.
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This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer’s neuropathologies, whether they are the result of gene mutations, gene polymorphisms and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis was proposed. This states that in response to the negative impact on neurons of known and unknown risk factors – which include genetic inheritance, comorbid and environmental factors – microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in foetuses and neonates with Down’s syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid-β(Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favour the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions and the potential contribution of glial activation with excessive cytokine expression to each.
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Wu, Ling-Hsuan, Chingju Lin, Hsiao-Yun Lin, Yu-Shu Liu, Caren Yu-Ju Wu, Cheng-Fang Tsai, Pei-Chun Chang, Wei-Lan Yeh, and Dah-Yuu Lu. "Naringenin Suppresses Neuroinflammatory Responses Through Inducing Suppressor of Cytokine Signaling 3 Expression." Molecular Neurobiology 53, no. 2 (January 13, 2015): 1080–91. http://dx.doi.org/10.1007/s12035-014-9042-9.
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Cho, Jun Hwi, Dae Hyun Kim, Jong Suk Lee, Mi-Suk Seo, Mi Eun Kim, and Jun Sik Lee. "Sargassum horneri (Turner) C. Agardh Extract Regulates Neuroinflammation In Vitro and In Vivo." Current Issues in Molecular Biology 44, no. 11 (November 3, 2022): 5416–26. http://dx.doi.org/10.3390/cimb44110367.
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Previously, we reported that Sargassum horneri (Turner) C. Agardh (S. horneri) is a brown algae species that exerts anti-inflammatory activity toward murine macrophages. However, the anti-neuroinflammatory effects and the mechanism of S. horneri on microglia cells are still unknown. We investigated the anti-neuroinflammatory effects of S. horneri extract on microglia in vitro and in vivo. In the present study, we found that S. horneri was not cytotoxic to BV-2 microglia cells and it significantly decreased lipopolysaccharide (LPS)-induced NO production. Moreover, S. horneri also diminished the protein expression of iNOS, COX-2, and cytokine production, including IL-1β, TNF-α, and IL-6, on LPS-stimulated microglia activation. S. horneri elicited anti-neuroinflammatory effects by inhibiting phosphorylation of p38 MAPK and NF-κB. In addition, S. horneri inhibited astrocytes and microglia activation in LPS-challenged mice brain. Therefore, these results suggested that S. horneri exerted anti-neuroinflammatory effects on LPS-stimulated microglia cell activation by inhibiting neuroinflammatory factors and NF-κB signaling.
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Kelty, Taylor J., Xuansong Mao, Nathan R. Kerr, Thomas E. Childs, Gregory N. Ruegsegger, and Frank W. Booth. "Resistance-exercise training attenuates LPS-induced astrocyte remodeling and neuroinflammatory cytokine expression in female Wistar rats." Journal of Applied Physiology 132, no. 2 (February 1, 2022): 317–26. http://dx.doi.org/10.1152/japplphysiol.00571.2021.
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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.
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Yuhas, Yael, Shai Ashkenazi, Eva Berent, and Abraham Weizman. "Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells." Brain Sciences 12, no. 12 (December 12, 2022): 1703. http://dx.doi.org/10.3390/brainsci12121703.
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Schizophrenia (SCZ) is a chronic neurodevelopmental psychotic disorder. The immune system and neuroinflammation seem to play a central role in the pathophysiology of SCZ. Clozapine is an effective atypical antipsychotic used for treatment-resistant SCZ. Life-threatening side effects, such as myocarditis, limit its use. We investigated the immunomodulatory effects of clozapine in an astroglial model of neuroinflammation. We thus assessed the effect of clozapine on the production of inflammatory mediators in human-derived astroglial (A172) cells, stimulated with a cytokine mix (TNFα, IL-1β, IFNγ). RT-PCR and ELISA analyses demonstrated that clozapine suppressed gene expression and production of TNFα, IL-1β and IL-8 and increased COX2 mRNA 24 h after stimulation. Clozapine inhibited Akt phosphorylation induced by the cytokine mix at 10 min and 40 min, as assessed by Western blot analysis with anti-pT308Akt antibody. Pretreatment with the Akt inhibitor MK-2206 increased COX2 gene expression in cytokine-stimulated cells, suggesting that Akt inhibition may be involved in COX2 gene expression upregulation. Clozapine may possess dual beneficial effects: inhibiting astroglial production of proinflammatory cytokines, thus attenuating neuroinflammation, and upregulating COX2 expression that may be relevant to improvement of neural functioning while accounting for some of its detrimental effects. Patients with TRS and neuroinflammatory markers may benefit particularly from clozapine treatment.
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Han, Shu, Fan Zhang, Zhiying Hu, Yayi Sun, Jing Yang, Henry Davies, David T. W. Yew, and Marong Fang. "Dose-Dependent Anti-Inflammatory and Neuroprotective Effects of anανβ3 Integrin-Binding Peptide." Mediators of Inflammation 2013 (2013): 1–24. http://dx.doi.org/10.1155/2013/268486.
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Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, anανβ3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α(TNF-α) and interferon-γ(IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease.
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Muscat, Stephanie M., and Ruth M. Barrientos. "The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging." Brain Plasticity 7, no. 1 (August 23, 2021): 47–60. http://dx.doi.org/10.3233/bpl-210127.
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Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain’s innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF, AMPA and NMDA receptor-mediated long-term potentiation.
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Henry, Christopher J., Yan Huang, Robert Dantzer, Rodney W. Johnson, and Jonathan P. Godbout. "Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide (B13)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB3. http://dx.doi.org/10.4049/jimmunol.178.supp.b13.
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Abstract Age-associated changes in glial reactivity may predispose individuals to exacerbated neuroinflammatory cytokine responses that are permissive to cognitive and behavioral complications. The purpose of this study was to determine if aging is associated with an exaggerated sickness response to central innate immune activation. Our results show that intracerebroventricular (i.c.v) administration of lipopolysaccharide (LPS) caused a heightened proinflammatory cytokine response (IL-1β, IL-6, and TNFα) in the cerebellum 2 h post i.c.v. injection in aged mice compared to adults. This amplified inflammatory profile was consistent with a brain region-dependent increase in reactive glial markers (MHC class II, TLR2 and TLR4). Moreover, LPS caused a prolonged sickness behavior response in aged mice that was paralleled by a protracted expression of brain cytokines in the cerebellum and hippocampus. Finally, central LPS injection caused amplified and prolonged IL-6 levels in the periphery of aged mice. Collectively, these data establish that activation of the central innate immune system leads to exacerbated neuroinflammation and prolonged sickness behavior in aged as compared to adult mice.
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Rom, Slava, Holly Dykstra, Viviana Zuluaga-Ramirez, Nancy L. Reichenbach, and Yuri Persidsky. "miR-98 and let-7g* Protect the Blood-Brain Barrier Under Neuroinflammatory Conditions." Journal of Cerebral Blood Flow & Metabolism 35, no. 12 (July 1, 2015): 1957–65. http://dx.doi.org/10.1038/jcbfm.2015.154.
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Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier ‘leakiness’ in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.
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Bhusal, Anup, Youngpyo Nam, Donggun Seo, Won-Ha Lee, and Kyoungho Suk. "Cathelicidin-Related Antimicrobial Peptide Negatively Regulates Bacterial Endotoxin-Induced Glial Activation." Cells 11, no. 23 (December 1, 2022): 3886. http://dx.doi.org/10.3390/cells11233886.
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Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited LPS-mediated inflammatory activation of glial cells in culture. In the animal model of LPS-induced neuroinflammation, CRAMP expression was highly induced in multiple cell types, such as astrocytes, microglia, and neurons. Injection of exogenous CRAMP peptide significantly inhibited inflammatory cytokine expression and the reactivity of glial cells in the mouse brain following intraperitoneal or intracerebroventricular LPS administration. Altogether, results of the study suggest that CRAMP plays an important part in containment of LPS-induced neuroinflammatory responses, and that CRAMP can be exploited for the development of targeted therapies for neuroinflammatory conditions associated with bacterial infection.
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Jiang, Yanhua, Zhe Li, Hong Ma, Xuezhao Cao, Fang Liu, Ayong Tian, Xijia Sun, Xiaoqian Li, and Jun Wang. "Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice." Cellular Physiology and Biochemistry 46, no. 4 (2018): 1398–411. http://dx.doi.org/10.1159/000489155.
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Background/Aims: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. Methods: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer’s disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection. The behavioral changes were evaluated with an open-field test and Morris water maze test on postoperative days 3, 7, and 14. Hippocampal TREM2, DAP12, and interleukin (IL)-1β were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3β (GSK-3β) were also examined in the hippocampus. Results: Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1β expression in the transgenic mice on postoperative days 3 and 7. A corresponding decline in the levels of TREM2 was also found on postoperative days 3, 7, and 14. Overexpression of TREM2 downregulated the levels of IL-1β, ameliorated T396 expression, inhibited the activity of GSK-3β, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression. Conclusion: The downregulation of TREM2 exacerbated surgery-induced cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Overexpression of TREM2 potentially attenuated these effects by decreasing the associated production of proinflammatory cytokines, inhibiting tau hyperphosphorylation, and enhancing synaptophysin expression.
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Park, Jihyun, Kyung Mi Jang, and Kwan-Kyu Park. "Apamin Suppresses LPS-Induced Neuroinflammatory Responses by Regulating SK Channels and TLR4-Mediated Signaling Pathways." International Journal of Molecular Sciences 21, no. 12 (June 17, 2020): 4319. http://dx.doi.org/10.3390/ijms21124319.
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Neuroinflammation plays a vital role in neurodegenerative conditions. Microglia are a key component of the neuroinflammatory response. There is a growing interest in developing drugs to target microglia and thereby control neuroinflammatory processes. Apamin (APM) is a specifically selective antagonist of small conductance calcium-activated potassium (SK) channels. However, its effect on neuroinflammation is largely unknown. We examine the effects of APM on lipopolysaccharide (LPS)-stimulated BV2 and rat primary microglial cells. Regarding the molecular mechanism by which APM significantly inhibits proinflammatory cytokine production and microglial cell activation, we found that APM does so by reducing the expression of phosphorylated CaMKII and toll-like receptor (TLR4). In particular, APM potently suppressed the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription (STAT)3 and phosphorylated mitogen-activated protein kinases (MAPK)-extracellular signal-regulated kinase (ERK). In addition, the correlation of NF-κB/STAT3 and MAPK-ERK in the neuroinflammatory response was verified through inhibitors. The literature and our findings suggest that APM is a promising candidate for an anti-neuroinflammatory agent and can potentially be used for the prevention and treatment of various neurological disorders.
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Choo, Xin Yi, Lachlan E. McInnes, Alexandra Grubman, Joanna M. Wasielewska, Irina Belaya, Emma Burrows, Hazel Quek, et al. "Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone–Pyridylhydrazone Copper(II) Complex." International Journal of Molecular Sciences 23, no. 18 (September 14, 2022): 10722. http://dx.doi.org/10.3390/ijms231810722.
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Neuroinflammation has a major role in several brain disorders including Alzheimer’s disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone–pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer’s disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.
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Madiraju, Charitha, Jacob Alexander Karp, Martha Oppong, and Robert Matson. "A Unique Multiplex Assay to Identify Th1/Th2 Cytokine Profile in MS Patients." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 86.26. http://dx.doi.org/10.4049/jimmunol.204.supp.86.26.
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Abstract Multiple Sclerosis (MS) is a chronic neuroinflammatory, demyelinating autoimmune disease of the central nervous system (CNS). There are diverse views on the paradigm that disease pathogenesis of MS is due to an imbalance in the proinflammatory T helper 1 (Th1)-type cytokines and anti-inflammatory Th2-type cytokines. Several factors play a crucial role in Th1/Th2 polarization that contributes towards disease activation or progression and this is dependent on MS disease sub-type. The goal of our research study is to investigate a unique and robust multiplex assay for identification of Th1 versus Th2 cytokine expression pattern as applicable to samples derived from MS patients. Towards this end, a sandwich ELISA-based multiplex assay method in a 96-well plate format is designed for establishing Th1/Th2 cytokine profile. Cerebrospinal fluid (CSF) samples derived from MS patients diagnosed with either Relapsing-Remitting MS (RRMS, N = 10) or Secondary progressive MS (SPMS, N = 10) and two unaffected control CSF samples derived from the otherwise healthy human subjects are included in the study. Multiplex ELISA analysis in a 96-well format included TNF, IFN-gamma, IL-4, IL-13 and IL-17E cytokines. Each well is imprinted in a 3*3 format with a capture antibody against a given cytokine of interest. The colorimetric read-outs from multiplex assay are analyzed by ImageJ. Preliminary results identify the multiplex assay to be robust, unique and cost-effective for establishing Th1/Th2 cytokine profiles in two different sub-types of MS. Th1/Th2 cytokine pattern could help predict the course of MS disease progression and remission.
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Lainez, Nancy M., and Djurdjica Coss. "Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice." Neuroendocrinology 108, no. 4 (2019): 291–307. http://dx.doi.org/10.1159/000496754.
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Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.
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Lee, Sung-Gyu, and Hyun Kang. "Saussurea lappa Clarke extract exhibits potent antioxidant effect and attenuates neuroinflammatory responses in lipopolysaccharide-stimulated microglial cells." Tropical Journal of Pharmaceutical Research 19, no. 9 (November 24, 2020): 1911–17. http://dx.doi.org/10.4314/tjpr.v19i9.16.
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Purpose: To investigate the antioxidant and anti-neuroinflammatory potential of Saussurea lappa Clarke (SLC-EA) extract in LPS-stimulated BV-2 microglial cells.Methods: Cell viability was measured by using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay while antioxidant activity was evaluated by using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity. Lipopolysaccharide (LPS) was used to stimulate BV-2 microglia. Griess assay was employed to assess nitric oxide (NO) production. iNOS (inducible NO synthase) expression and TNF-α (tumor necrosis factor-alpha) cytokine production were measured by ELISA (enzyme-linked immunosorbent assay) and immuno blot analysis, respectively.Results: Pretreatment of 100 mg/ml of SLC-EA (p < 0.001) was inhibited Nitric Oxide (NO) by 1 ug/ml of LPS-treated murine BV-2 cells. The expression of iNOS and TNF-α were reduced by SLC-EA concentration dependent manner (p < 0.001 at 100 mg/ml). SLC-EA were scavenged 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals in a dose-dependent manner with an IC50 value of approximately 51.4 μg/ml.Conclusion: The results indicate that SLC-EA extract exhibits strong antioxidant properties and inhibits excessive pro-inflammatory cytokine due probably to the antioxidant phenolic compounds present in SLC-EA extract. Further work in exploring the in-depth mechanisms of SLC-EA extract in regulating inflammatory signaling pathways in treating neuroinflammatory diseases is necessary.
Keywords: Saussurea lappa, Antioxidant, Neuroinflammation, Microglia, TNF-α, iNOS
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Herman, Andrzej P., Dorota Tomaszewska-Zaremba, Marta Kowalewska, Aleksandra Szczepkowska, Małgorzata Oleszkiewicz, Agata Krawczyńska, Maciej Wójcik, Hanna Antushevich, and Janina Skipor. "Neostigmine Attenuates Proinflammatory Cytokine Expression in Preoptic Area but Not Choroid Plexus during Lipopolysaccharide-Induced Systemic Inflammation." Mediators of Inflammation 2018 (October 9, 2018): 1–9. http://dx.doi.org/10.1155/2018/9150207.
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The study was designed to examine whether the administration of neostigmine (0.5 mg/animal), a peripheral inhibitor of acetylcholinesterase (AChE), during an immune/inflammatory challenge provoked by intravenous injection of bacterial endotoxin—lipopolysaccharide (LPS; 400 ng/kg)—attenuates the synthesis of proinflammatory cytokines in the ovine preoptic area (POA), the hypothalamic structure playing an essential role in the control of the reproduction process, and in the choroid plexus (CP), a multifunctional organ sited at the interface between the blood and cerebrospinal fluid in the ewe. Neostigmine suppressed (p<0.05) LPS-stimulated synthesis of cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the POA, and this effect was similar to that induced by the treatment with systemic AChE inhibitor—donepezil (2.5 mg/animal). On the other hand, both AChE inhibitors did not influence the gene expression of these cytokines and their corresponding receptors in the CP. It was found that this structure seems to not express the neuronal acetylcholine (ACh) receptor subunit alpha-7, required for anti-inflammatory action of ACh. The mechanism of action involves inhibition of the proinflammatory cytokine synthesis on the periphery as well as inhibition of their de novo synthesis rather in brain microvessels and not in the CP. In conclusion, it is suggested that the AChE inhibitors incapable of reaching brain parenchyma might be used in the treatment of neuroinflammatory processes induced by peripheral inflammation.
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Mohamed, Mona Yasin, and Willias Masocha. "Indomethacin augments lipopolysaccharide-induced expression of inflammatory molecules in the mouse brain." PeerJ 8 (November 18, 2020): e10391. http://dx.doi.org/10.7717/peerj.10391.
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Indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and fever including during infections. However, some studies suggest that NSAIDs protect against neuroinflammation, while some find no effects or worsening of neuroinflammation. We evaluated the effect of indomethacin alone on in combination with minocycline, a drug that inhibits neuroinflammation, on the expression of transcripts of neuroinflammatory molecules-induced by lipopolysaccharide (LPS) in the brain of mice. Inoculation of male BALB/c mice with LPS induced the expression of the microglia marker ionized calcium binding adaptor molecule protein, mRNA expression of the genes for cytokines interleukin-1beta (Il1b) and tumor necrosis factor-alpha (Tnf) and inducible nitric oxide synthase gene (Nos2), but not Il10, in the brain. Treatment with indomethacin had no significant effect on the cytokines or Nos2 mRNA expression in naïve animals. However, pretreatment with indomethacin increased LPS-induced Nos2 mRNA and inducible nitric oxide (iNOS) protein expression, but had no significant effect on LPS-induced mRNA expression of the cytokines. Minocycline reduced LPS-induced Il1b and Tnf, but not Nos2, mRNA expression. Treatment with indomethacin plus minocycline had no effect on LPS-induced Il1b, Tnf and Nos2 mRNA expression. In conclusion these results show that indomethacin significantly augments LPS-induced Nos2 mRNA and iNOS protein expression in the brain. In the presence of indomethacin, minocycline could not inhibit LPS-induced pro-inflammatory cytokine expression. Thus, indomethacin could exacerbate neuroinflammation by increasing the expression of iNOS and also block the anti-inflammatory effects of minocycline.
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Cui, Yan Ji, Sung-Cherl Jung, and Su Yong Eun. "Anti-neuroinflammatory and anti-oxidative activities of the ethanol extract from Citrus unshiu MARC." Journal of Medicine and Life Science 7, no. 1 (June 1, 2010): 88–93. http://dx.doi.org/10.22730/jmls.2010.7.1.88.
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Citrus peel extract has shown anti-inflammatory and anti-oxidative effects in several tissues. Therefore ，we investigated whether the ethanol extract from Fruit peel of Citrus unshiu MARC. suppresses brain insult-induced excessive microglial activation and neuronal oxidative stress. Releases of NO，the major inflammatory mediator in microglia，and iNOS mRNA expressions were markedly inhibited in a dose-dependent manner following treatment of the ethanol extract from Citrus unshiu MARC. in LPS-stimulated BV-2 microglia cells. In addition, the extract significantly suppressed LPS-induced mRNA expression of pro-inflammatory cytokine TNF-α IL-lβ and IL-6. On the other hand, the thanol extract exerted intracellular ROS scavenging activities in HT-22 neurons in a dose dependent manner (50-400 ug/ml)， suggesting the potent anti-oxidative stress effects in neurons. Taken together，these results suggest that Citrus unshiu MARC. peel extract has therapeutic potential against neuroinflammation and neurodegeneration via suppression of brain insult-induced microglial activation and neuronal oxidative stresses.
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Jiwrajka, Manasi, Alexandra Phillips, Matt Butler, Miriam Rossi, and Jennifer M. Pocock. "The Plant-Derived Chalcone 2,2′,5′-Trihydroxychalcone Provides Neuroprotection against Toll-Like Receptor 4 Triggered Inflammation in Microglia." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/6301712.
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Chalcones are plant metabolites with potential for therapeutic exploitation as antioxidant, anti-inflammatory, and antiproliferative agents. Here we explored the neuroprotective effects of 2,2′,5′-trihydroxychalcone (225THC), a potent antioxidant with radical-scavenging properties. 225THC was found to be a potent inhibitor of apoptosis in stimulated primary rat neuronal cultures. This was likely mediated by an anti-inflammatory effect on microglial cells since 225THC inhibited LPS-stimulated TNF-αand IL-6 secretion from primary rat microglia and modulated the cytokine/chemokine profile of BV2 microglial cells. Additionally, 225THC inhibited LPS-evoked inducible nitric oxide synthase expression but did not influence endogenous superoxide generation. Microglial flow cytometric analyses indicated the 225THC treatment induced a shift from an M1-like phenotype to a more downregulated microglial profile. Taken together these data suggest that the chalcone 2,2′,5′-trihydroxychalcone can modulate neuroinflammatory activation in brain-derived microglia and holds promise as a therapeutic in neuroinflammatory conditions.
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Gutiérrez, Irene L., Fabiana Novellino, Javier R. Caso, Borja García-Bueno, Juan C. Leza, and José L. M. Madrigal. "CCL2 Inhibition of Pro-Resolving Mediators Potentiates Neuroinflammation in Astrocytes." International Journal of Molecular Sciences 23, no. 6 (March 18, 2022): 3307. http://dx.doi.org/10.3390/ijms23063307.
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The chemokine CCL2 participates in multiple neuroinflammatory processes, mainly through the recruitment of glial cells. However, CCL2 has also been proven to exert different types of actions on these cells, including the modification of their response to inflammatory stimuli. In the present study we analyzed the effect of CCL2 on the resolution of inflammation in astrocytes. We observed that genetic removal of CCL2 increases the expression of the enzymes responsible for the synthesis of specialized pro-resolving mediators arachidonate 15-lipoxygenase and arachidonate 5-lipoxygenase in the brain cortex of 5xFAD mice. The expression of FPR2 receptor, known to mediate the activity of pro-resolving mediators was also increased in mice lacking CCL2.The downregulation of these proteins by CCL2 was also observed in cultured astrocytes. This suggests that CCL2 inhibition of the resolution of inflammation could facilitate the progression of neuroinflammatory processes. The production of the pro-inflammatory cytokine IL-1beta by astrocytes was analyzed, and allowed us to confirm that CCL2 potentiates the activation of astrocytes trough the inhibition of pro-resolving pathways mediated by Resolvin D1. In addition, the analysis of the expression of TNFalpha, MIP1alpha and NOS2 further confirmed CCL2 inhibition of inflammation resolution in astrocytes.
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Castany, Sílvia, Anna Bagó-Mas, José Miguel Vela, Enrique Verdú, Karolina Bretová, Viktorie Svobodová, Petr Dubový, and Pere Boadas-Vaello. "Transient Reflexive Pain Responses and Chronic Affective Nonreflexive Pain Responses Associated with Neuroinflammation Processes in Both Spinal and Supraspinal Structures in Spinal Cord-Injured Female Mice." International Journal of Molecular Sciences 24, no. 2 (January 16, 2023): 1761. http://dx.doi.org/10.3390/ijms24021761.
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Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.
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Porro, Chiara, Antonia Cianciulli, Teresa Trotta, Dario Domenico Lofrumento, and Maria Antonietta Panaro. "Curcumin Regulates Anti-Inflammatory Responses by JAK/STAT/SOCS Signaling Pathway in BV-2 Microglial Cells." Biology 8, no. 3 (June 27, 2019): 51. http://dx.doi.org/10.3390/biology8030051.
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Microglia play important physiological roles in central nervous system (CNS) homeostasis and in the pathogenesis of inflammatory brain diseases. Inflammation stimulates microglia to secrete cytokines and chemokines that guide immune cells to sites of injury/inflammation. Neuroinflammation is also strongly implicated in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, for which nutritional intervention could represent a benefit due to a lack of clinically efficacious drugs. To this end, the anti-inflammatory mechanisms of several phytochemicals, including curcumin, have been extensively studied. The present experiments show that the administration of curcumin is able to increase the production of the anti-inflammatory cytokines, IL-4 and IL-10, in murine BV-2 microglial cells treated with lipopolysaccharide (LPS). Consistent with these data, curcumin stimulation upregulates the expression of Suppressors of cytokine signaling (SOCS)-1, whereas phosphorylation of the JAK2 and STAT3 was reduced. Taken together, these results provide evidence that curcumin is able to regulate neuroinflammatory reactions by eliciting anti-inflammatory responses in microglia through JAK/STAT/SOCS signaling pathway modulation.
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Park, Bo-Kyung, Young Hwa Kim, Yu Ri Kim, Jeong June Choi, Changsop Yang, Ik-Soon Jang, and Mi Young Lee. "Antineuroinflammatory and Neuroprotective Effects of Gyejibokryeong-Hwan in Lipopolysaccharide-Stimulated BV2 Microglia." Evidence-Based Complementary and Alternative Medicine 2019 (April 1, 2019): 1–14. http://dx.doi.org/10.1155/2019/7585896.
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Microglia, the central nervous system’s innate immune cells, mediate neuroinflammation and are implicated in a variety of neuropathologies. The present study investigated the antineuroinflammatory and neuroprotective effects of Gyejibokryeong-hwan (GBH), a traditional Korean medicine, in lipopolysaccharide- (LPS-) stimulated murine BV2 microglia. BV2 cells were pretreated with GBH, fluoxetine (FXT), or amitriptyline (AMT) for 1 h and then stimulated with LPS (100 ng/mL). The expression levels of nitric oxide (NO), cytokines, and chemokines were determined by the Griess method, ELISA, or real-time PCR. Western blotting was used to measure various transcription factors and mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt activity. GBH significantly reduced the levels of NO, inducible nitric oxide synthase (iNOS), cyclooxygenase- (COX-) 2, tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, macrophage inhibitory protein- (MIP-) 1α, macrophage chemoattractant protein- (MCP-) 1, and IFN-γ inducible protein- (IP-) 10, regulated upon activation normal T cell expressed sequence (RANTES) in a dose-dependent manner. Expression of nuclear factor- (NF-) κB p65 was significantly decreased and phosphorylation of extracellular signal-regulated kinase (Erk), c-Jun NH2-terminal kinase (JNK), and PI3K/Akt by GBH, but not p38 MAPK, was decreased. Furthermore, production of anti-inflammatory cytokine IL-10 was increased and Heme oxygenase-1 (HO-1) was upregulated via the nuclear factor-E2-related factor 2 (NRF2)/cAMP response element-binding protein (CREB) pathway, collectively indicating the neuroprotective effects of GBH. We concluded that GBH may suppress neuroinflammatory responses by inhibiting NF-κB activation and upregulating the neuroprotective factor, HO-1. These results suggest that GBH has potential as anti-inflammatory and neuroprotective agents against microglia-mediated neuroinflammatory disorders.
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Yu, Huaxu, Bin He, Xu Han, and Ting Yan. "Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage." Open Life Sciences 16, no. 1 (January 1, 2021): 845–55. http://dx.doi.org/10.1515/biol-2021-0090.
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Abstract Rufinamide (RUF) is a structurally unique anti-epileptic drug, but its protective mechanism against brain injury remains unclear. In the present study, we validated how the RUF protected mice with kainic acid (KA)-induced neuronal damage. To achieve that, a mouse epilepsy model was established by KA intraperitoneal injection. After Nissl staining, although there was a significant reduction in Nissl bodies in mice treated with KA, 40, 80, and 120 mg/kg, RUF significantly reduced KA-induced neuronal damage, in a dose-dependent manner. Among them, 120 mg/kg RUF was most pronounced. Immunohistochemistry (IHC) and western blot analysis showed that RUF inhibited the IBA-1 overexpression caused by KA to block microglia cell overactivation. Further, RUF treatment partially reversed neuroinflammatory cytokine (IL-1β, TNFα, HMGB1, and NLRP3) overexpression in mRNA and protein levels in KA mice. Moreover, although KA stimulation inhibited the expression of tight junctions, RUF treatment significantly upregulated expression of tight junction proteins (occludin and claudin 5) in both mRNA and protein levels in the brain tissues of KA mice. RUF inhibited the overactivation of microglia, suppressed the neuroinflammatory response, and reduced the destruction of blood–brain barrier, thereby alleviating the excitatory nerve damage of the KA-mice.
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Ren, Zhili, Hui Ding, Ming Zhou, and Piu Chan. "Ganoderma lucidum Modulates Inflammatory Responses following 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Administration in Mice." Nutrients 14, no. 18 (September 19, 2022): 3872. http://dx.doi.org/10.3390/nu14183872.
Full textAbstract:
Ganoderma lucidum, one of the most valued medicinal mushrooms, has been used for health supplements and medicine in China. Our previous studies have proved that Ganoderma lucidum extract (GLE) could inhibit activation of microglia and protect dopaminergic neurons in vitro. In the present study, we investigated the anti-neuroinflammatory potential of GLE in vivo on Parkinsonian-like pathological dysfunction. Male C57BL/6J mice were subjected to acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion, and a treatment group was administered intragastrically with GLE at a dose of 400 mg/kg. Immunohistochemistry staining showed that GLE efficiently repressed MPTP-induced microglia activation in nigrostriatal region. Accordingly, Bio-plex multiple cytokine assay indicated that GLE treatment modulates abnormal cytokine expression levels. In microglia BV-2 cells incubated with LPS, increased expression of iNOS and NLRP3 were effectively inhibited by 800 μg/mL GLE. Furthermore, GLE treatment decreased the expression of LC3II/I, and further enhanced the expression of P62. These results indicated that the neuroprotection of GLE in an experimental model of PD was partially related to inhibition of microglia activation in vivo and vitro, possibly through downregulating the iNOS/NLRP3 pathway, inhibiting abnormal microglial autophagy and lysosomal degradation, which provides new evidence for Ganoderma lucidum in PD treatment.
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Shahbazi, Sajad, and Tara Zakerali. "Methylenedioxy Piperamide-Derived Compound D5 Regulates Inflammatory Cytokine Secretion in a Culture of Human Glial Cells." Molecules 27, no. 11 (May 30, 2022): 3527. http://dx.doi.org/10.3390/molecules27113527.
Full textAbstract:
Neuroinflammation is the cornerstone of most neuronal disorders, particularly neurodegenerative diseases. During the inflammatory process, various pro-inflammatory cytokines, chemokines, and enzymes—such as interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthases (iNOS), inhibitory kappa kinase (IKK), and inducible nitric oxide (NO)—are over-expressed in response to every stimulus. Methods: In the present study, we focused on the anti-neuroinflammatory efficacy of (2E,4E)-N,5-bis(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamide, encoded D5. We investigated the efficacy of D5 on the upstream and downstream products of inflammatory pathways in CHME3 and SVG cell lines corresponding to human microglia and astrocytes, respectively, using various in silico, in vitro, and in situ techniques. Results: The results showed that D5 significantly reduced the level of pro-inflammatory cytokines byup-regulating PPAR-γ expression and suppressing IKK-β, iNOS, NO production, and NF-κB activation in inflamed astrocytes (SVG) and microglia (CHME3) after 24 h of incubation. The data demonstrated remarkably higher efficacy of D5 compared to ASA (Aspirin) in reducing NF-κB-dependent neuroinflammation. Conclusions: We observed that the functional-group alteration had an extreme influence on the levels of druggability and the immunomodulatory properties of two analogs of piperamide, D5, and D4 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-(hydroxymethyl)phenyl)penta-2,4-dienamide)). The present study suggested D5 as a potential anti-neuroinflammatory agent for further in vitro, in vivo, and clinical investigations.
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Chakrabarti, Sudipta, Malabendu Jana, Avik Roy, and Kalipada Pahan. "Upregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic Acid." Current Alzheimer Research 15, no. 10 (August 15, 2018): 894–904. http://dx.doi.org/10.2174/1567205015666180507104755.
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Background: Neuroinflammation plays an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer’s disease (AD). Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory molecule that suppresses cytokine signaling and inflammatory gene expression in different cells including microglia. Objective: The pathways through which SOCS3 could be upregulated are poorly described. Cinnamic acid is a metabolite of cinnamon, a natural compound that is being widely used all over the world as a spice or flavoring agent. Here, we examined if cinnamic acid could upregulate SOCS3 in microglia. Method: Microglia and astroglia isolated from mouse brain as well as BV-2 microglial cells were treated with cinnamic acid followed by monitoring the level of SOCS3 and different proinflammatory molecules by RT-PCR and real-time PCR. To nail down the mechanism, we also performed ChIP analysis to monitore the recruitment of cAMP response element binding (CREB) to the socs3 gene promoter and carried out siRNA knockdown of CREB. Results: Cinnamic acid upregulated the expression of SOCS3 mRNA and protein in mouse BV-2 microglial cells in dose- and time-dependent manner. Accordingly, cinnamic acid also increased the level of SOCS3 and suppressed the expression of inducible nitric oxide synthase and proinflammatory cytokines (TNFα, IL-1β and IL-6) in LPSstimulated BV-2 microglial cells. Similar to BV-2 microglial cells, cinnamic acid also increased the expression of SOCS3 in primary mouse microglia and astrocytes. We have seen that cAMP response element is present in the promoter of socs3 gene, that cinnamic acid induces the activation of CREB, that siRNA knockdown of CREB abrogates cinnamic acid-mediated upregulation of SOCS3, and that cinnamic acid treatment leads to the recruitment of CREB to the socs3 gene. Conclusions: These studies suggest that cinnamic acid upregulates the expression of SOCS3 in glial cells via CREB pathway, which may be of importance in neuroinflammatory and neurodegenerative disorders.
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Gombodorj, Jargalsaikhan, Enkhjargal Bayarsaikhan, Chimedragchaa Chimedtseren, Uuganbayar Baatartsogt, Baigali Gansukh, and Seesregdorj Surenjid. "An Analysis of Khurtsiin Deed-6 Compound’s Effect on IL-1β Expression in Nitroglycerin Induced Migraine and Alcohol Exposed Neurodegeneration Model in Rat." Biomedical and Pharmacology Journal 15, no. 3 (September 29, 2022): 1687–93. http://dx.doi.org/10.13005/bpj/2507.
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Objectives: To investigate the anti-inflammatory activity of Khurtsiin deed-6 in migraine and neurodegeneration rat models. Methods: This study uses nitroglycerin induced migraine was model and alcohol exposed neurodegeneration model in Wistar rats to evaluate anti-inflammatory effect of Khurtsiin deed-6 at the 3 different doses of 50, 100and 150 mg/kg, orally. After anesthesia, the brains were removed, then trigeminal nucleus caudal is and hippocampus region isolated from fresh brain. And followed by protein and RNA extraction. Interleukin-1β expression was analyzed by real time polymerase chain reaction. Results: Nitroglycerin induced rat migraine model had increased Interleukin-1β expression in brain TNC area (p<0.001). It has been decreased dramatically after treatment of Khurtsiin deed-6 by doses of 50mg/kg, 100mg/kg and 150mg/kg treatment in brain trigeminal nucleus caudal is region (p<0.01) comparing ibuprofen treated group. Moreover alcohol exposed neurodegeneration rat model had observed increased Interleukin-1β expression in brain Hp area (p<0.001). But Khurtsiin deed-6 doses of 50mg/kg, 100mg/kg and 150mg/kg treatment reduced neuroinflammatory cytokines IL1β expression in hippocampus region (p<0.01, p<0.001) of alcoholic rat models comparing pyridoxamine administrated animals. Conclusion: The present finding indicates that Khurtsiin deed-6shows anti-inflammatory activity decreasing the level of Interleukin -1β cytokine in nitroglycerin induced migraine and alcohol exposed neurodegeneration rat models
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Olmos, Gabriel, and Jerònia Lladó. "Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity." Mediators of Inflammation 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/861231.
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Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-α; thisde novoproduction of TNF-αis an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-αcan potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca+2permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAAreceptors on neurons. Thus, the net effect of TNF-αis to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-αlinks the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS). As microglial activation and upregulation of TNF-αexpression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-αsignaling may represent a valuable target for intervention.
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Airapetov, M. I., S. O. Eresko, E. R. Bychkov, A. A. Lebedev, and P. D. Shabanov. "Expression of Toll-like receptors in emotiogenic structures of rat brain is changed under longterm alcohol consumption and ethanol withdrawal." Medical Immunology (Russia) 22, no. 1 (January 31, 2020): 77–86. http://dx.doi.org/10.15789/1563-0625-eot-1836.
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Recent studies have provided strong evidence that long-term ethanol consumption leads to activation the mechanisms of neuroimmune signaling. Recently, much attention has been focused on the study of toll-like receptors (Toll-like receptors, TLRs), which play one of the key roles in the mechanisms of activation of the innate immune system in brain structures subsequently ethanol consumption. It is known that the activation of TLRs leads to the release of many proinflammatory cytokines with the resulting neuroinflammatory process. There are suggestions that TLRs may also be involved in the modulation of neurotransmitter systems of the brain, thereby contributing to the formation of pathological dependence on ethanol. The goal of our work was to study the level of expression the genes of TLRs (TLR3, TLR4, TLR7) and pro-inflammatory cytokine genes (IL-1β, CCL2) in the rat brain (amygdala, hippocampus, medial entorhinal cortex, striatum) under conditions of prolonged alcoholization and on different periods of alcohol withdrawal, which was previously not studied by researchers. Prolonged alcoholization of rats with ethanol did not lead to changes in levels mRNA of TLRs in the studied structures of the rat brain, with the exception of a small increase in the level of TLR3 mRNA in the hippocampus of prolonged alcoholized rats and a slight increase in the level of TLR3 mRNA in mEC. However, gene expression of TLRs undergoes changes in all the structures of the rat brain studied by us at different periods of alcohol withdrawal. The increased level of expression of both TLRs and proinflammatory genes in the period of alcohol withdrawal in the rat brain hippocampus deserves special attention, which indicates the presence of a persistent neuroinflammatory process in this brain structure in the period of alcohol withdrawal, which is probably supported with the participation of TLR-dependent signaling. The study of the mechanisms of inflammatory process activation by TLR-dependent signaling in different brain structures can open new targets for drug exposure. Such drugs can be used in the treatment of alcoholism.
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Rubio-Casillas, Alberto, Elrashdy M. Redwan, and Vladimir N. Uversky. "On the Potential Therapeutic Roles of Taurine in Autism Spectrum Disorder." Neuroglia 4, no. 1 (December 23, 2022): 1–14. http://dx.doi.org/10.3390/neuroglia4010001.
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Contemporary research has found that people with autism spectrum disorder (ASD) exhibit aberrant immunological function, with a shift toward increased cytokine production and unusual cell function. Microglia and astroglia were found to be significantly activated in immuno-cytochemical studies, and cytokine analysis revealed that the macrophage chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and transforming growth factor β-1 (TGFB-1), all generated in the neuroglia, constituted the most predominant cytokines in the brain. Taurine (2-aminoethanesulfonic acid) is a promising therapeutic molecule able to increase the activity of antioxidant enzymes and ATPase, which may be protective against aluminum-induced neurotoxicity. It can also stimulate neurogenesis, synaptogenesis, and reprogramming of proinflammatory M1 macrophage polarization by decreasing mitophagy (mitochondrial autophagy) and raising the expression of the markers of the anti-inflammatory and pro-healing M2 macrophages, such as macrophage mannose receptor (MMR, CD206) and interleukin 10 (IL-10), while lowering the expression of the M1 inflammatory factor genes. Taurine also induces autophagy, which is a mechanism that is impaired in microglia cells and is critically associated with the pathophysiology of ASD. We hypothesize here that taurine could reprogram the metabolism of M1 macrophages that are overstimulated in the nervous system of people suffering from ASD, thereby decreasing the neuroinflammatory process characterized by autophagy impairment (due to excessive microglia activation), neuronal death, and improving cognitive functions. Therefore, we suggest that taurine can serve as an important lead for the development of novel drugs for ASD treatment.
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Akassoglou, K., L. Probert, G. Kontogeorgos, and G. Kollias. "Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice." Journal of Immunology 158, no. 1 (January 1, 1997): 438–45. http://dx.doi.org/10.4049/jimmunol.158.1.438.
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Abstract To study the involvement of TNF in cerebral pathology in vivo and to define cellular interactions within the central nervous system (CNS) that promote TNF signaling, we have expressed this cytokine either as a wild-type or a mutant transmembrane form in astrocytes or neurons of transgenic mice. Mice expressing wild-type human TNF in either of these cell types spontaneously develop a neurologic disorder manifested by ataxia, seizures, and paralysis and bear histologic evidence of chronic CNS inflammation and degeneration. Moreover, astrocyte-specific expression of transmembrane TNF triggers a similar neurologic phenotype. Interestingly, transgenic mice producing a high level of transmembrane TNF in their neurons develop no apparent phenotypic abnormalities, suggesting that appropriate cellular interactions should form to allow for contact-dependent TNF signals to induce CNS pathology. These results demonstrate that target cells mediating the neuroinflammatory activities of TNF localize in the vicinity of astrocytes rather than neurons.
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Montaner, Joan, Alex Rovira, Carlos A. Molina, Juan F. Arenillas, Marc Ribó, Pilar Chacón, Jasone Monasterio, and José Alvarez-Sabín. "Plasmatic Level of Neuroinflammatory Markers Predict the Extent of Diffusion-Weighted Image Lesions in Hyperacute Stroke." Journal of Cerebral Blood Flow & Metabolism 23, no. 12 (December 2003): 1403–7. http://dx.doi.org/10.1097/01.wcb.0000100044.07481.97.
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Sixteen patients with acute middle cerebral artery stroke were studied to correlate neuroinflammatory markers with perfusion- and diffusion-weighted magnetic resonance imaging (MRI) lesion volumes (PWI and DWI). At arrival (less than 6 hours), plasmatic matrix metalloproteinase (MMP)-9, MMP-2, interleukin (IL)-6, IL-8, intercellular adhesion molecule (ICAM)-1, and tumor necrosis factor (TNF)-α were serially measured (by ELISA), and MRI was performed. In cerebral ischemia, tissue destruction seems related to matrix metalloproteinases expression because baseline MMP-9 was the only predictor of the infarct volume measured as a DWI lesion (lineal regression: b = 0.50, 0.25–0.74; P < 0.001). Moreover, the extent of hypoperfused brain area (PWI) was associated with a proinflammatory cytokine release in the next hours (TNF-α and IL-6).
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Zhou, Xueling, Wenhao Lu, You Wang, Jiani Li, and Yong Luo. "A20-Binding Inhibitor of NF-κB 1 Ameliorates Neuroinflammation and Mediates Antineuroinflammatory Effect of Electroacupuncture in Cerebral Ischemia/Reperfusion Rats." Evidence-Based Complementary and Alternative Medicine 2020 (October 13, 2020): 1–14. http://dx.doi.org/10.1155/2020/6980398.
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A20-binding inhibitor of NF-κB 1 (ABIN1) is an inhibitor of NF-κB and exerts anti-inflammatory effect. Electroacupuncture (EA) is considered as a neuroprotective strategy by inhibiting neuroinflammatory damage after cerebral ischemia. This study was performed to explore the role of ABIN1 and investigate whether the ABIN1 is involved in the mechanism of EA in cerebral ischemia/reperfusion (I/R) rats. Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and received EA after reperfusion once a day. Lentivirus-mediated ABIN1 gene knockdown was used to detect the role of ABIN1 in neuroinflammation after I/R. ABIN1 expression, proinflammatory cytokine levels, microglial activation, neurological function, infarct volumes, and NF-κB activation were assessed. ABIN1 expression was elevated in the peri-infarct cortex and was further upregulated by EA. ABIN1 knockdown increased the levels of proinflammatory cytokines and activation of microglia, worsened neurological deficits, and enlarged the infarct volume. Moreover, ABIN1 was blocked to partially reverse the neuroprotective effect of EA, and this treatment weakened the ability of EA to suppress NF-κB activity. Based on these findings, ABIN1 is a potential suppressor of neuroinflammation and ABIN1 mediates the antineuroinflammatory effect of EA in cerebral I/R rats.
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Habas, Agata, Srinivasa Reddy Natala, Jon K. Bowden-Verhoek, Emily M. Stocking, Diana L. Price, Wolfgang Wrasidlo, Douglas W. Bonhaus, and Martin B. Gill. "NPT1220-312, a TLR2/TLR9 Small Molecule Antagonist, Inhibits Pro-Inflammatory Signaling, Cytokine Release, and NLRP3 Inflammasome Activation." International Journal of Inflammation 2022 (February 27, 2022): 1–12. http://dx.doi.org/10.1155/2022/2337363.
Full textAbstract:
Toll-like receptors (TLRs) play a critical role in innate immune system responses to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). A growing body of evidence suggests that excessive TLR-mediated innate immune system activation can lead to neuronal damage and precipitate or perpetuate neurodegenerative diseases. Among TLR subtypes, both TLR2 and TLR9 have been implicated in neurodegenerative disorders with increased expression of these receptors in the central nervous system being associated with pro-inflammatory signaling and increased burdens of pathologic aggregated proteins. In the current study, we characterized the actions of a combined TLR2/TLR9 antagonist, NPT1220-312, on pro-inflammatory signaling and cytokine release in monocyte/macrophage-derived heterologous cells, human microglia, and murine and human whole blood. NPT1220-312 potently blocked TLR2- and TLR9-mediated release of inflammatory cytokines in monocyte/macrophage cells and in human microglia. NPT1220-312 also blocked TLR2-mediated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome including IL-1β, IL-18, and apoptosis-associated speck-like protein containing a CARD (ASC) release to the culture medium of human differentiated macrophages. The ability of NPT1220-312 to inhibit TLR2 mediated pro-inflammatory release of chemokines and cytokines in situ was demonstrated using murine and human whole blood. Together, these findings suggest that blockade of TLR2 and TLR9 may reduce inappropriate production of pro-inflammatory cytokines and chemokines from peripheral and central immune cells and thus potentially provide therapeutic benefit in neuroinflammatory/neurodegenerative disorders.
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Ansel, J. C., J. R. Brown, D. G. Payan, and M. A. Brown. "Substance P selectively activates TNF-alpha gene expression in murine mast cells." Journal of Immunology 150, no. 10 (May 15, 1993): 4478–85. http://dx.doi.org/10.4049/jimmunol.150.10.4478.
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Abstract There is increasing evidence that the neurologic system is capable of modulating a wide range of immunologic responses, including certain inflammatory processes in the lung, gastrointestinal tract, and skin. It has been proposed that secreted neuropeptides such as substance P (SP) may mediate these neuroinflammatory interactions by binding to and stimulating immune cells such as mast cells and lymphoid cells. SP is secreted in a variety of tissues by an extensive network of neurosensory C and A5 fibers in response to a wide range of noxious stimuli and injury. Previous studies to examine the effect of SP on mast cells have focused on its role in triggering histamine release and mediating immediate hypersensitivity responses. Recently it was demonstrated that mast cells are also capable of secreting multiple cytokines including TNF-alpha, IL-1, IL-3, IL-4, IL-6, and GM-CSF. In this study we tested the possibility that SP may also influence mast cell-mediated late inflammatory events by modulating the production of one or several of these cytokines. Our results indicate that SP induces TNF-alpha mRNA expression and TNF-alpha secretion in a dose-dependent manner in a murine mast cell line, CFTL12. Likewise, SP stimulates TNF-alpha secretion in freshly isolated murine peritoneal mast cells. The induction of mast cell TNF-alpha is selective, since SP does not stimulate the production of IL-1, IL-3, IL-4, IL-6, or GM-CSF in these cells. The CFTL 12 mast cell line constitutively expresses high levels of SP receptor mRNA which is not modulated by PMA/cycloheximide treatment or SP. These results further support the concept that the neurologic system modulates inflammatory events by neuropeptide-mediated mast cell cytokine release.
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Cole, Katherine E., Christine A. Strick, Timothy J. Paradis, Kevin T. Ogborne, Marcel Loetscher, Ronald P. Gladue, Wen Lin, et al. "Interferon–inducible T Cell Alpha Chemoattractant (I-TAC): A Novel Non-ELR CXC Chemokine with Potent Activity on Activated T Cells through Selective High Affinity Binding to CXCR3." Journal of Experimental Medicine 187, no. 12 (June 15, 1998): 2009–21. http://dx.doi.org/10.1084/jem.187.12.2009.
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Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2–activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-γ–inducible 10-kD protein (IP-10) and IFN-γ– induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN-γ and IL-1 together results in an ∼400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1–stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.
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Szczepkowska, Aleksandra, Maciej Wójcik, Dorota Tomaszewska-Zaremba, Hanna Antushevich, Agata Krawczyńska, Wiktoria Wiechetek, Janina Skipor, and Andrzej Przemysław Herman. "Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model." International Journal of Molecular Sciences 22, no. 24 (December 8, 2021): 13237. http://dx.doi.org/10.3390/ijms222413237.
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This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin—lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1β) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.
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Shu, Shiyu, Zhi Zhang, Dawn Spicer, Ewa Kulikowicz, Ke Hu, Savalan Babapoor-Farrokhran, Sujatha Kannan, Raymond C. Koehler, and Courtney L. Robertson. "Administration of a 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor Improves Outcome in a Rat Model of Pediatric Traumatic Brain Injury." Developmental Neuroscience 41, no. 3-4 (2019): 166–76. http://dx.doi.org/10.1159/000500895.
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The arachidonic acid pathway metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia/reperfusion brain injury. Inhibition of 20-HETE formation can protect the developing brain from global ischemia. Here, we examined whether treatment with the 20-HETE synthesis inhibitor N-hydroxy-N-4-butyl-2-methylphenylformamidine (HET0016) can protect the immature brain from traumatic brain injury (TBI). Male rats at postnatal day 9–10 underwent controlled cortical impact followed by intraperitoneal injection with vehicle or HET0016 (1 mg/kg, 5 min and 3 h post-injury). HET0016 decreased the lesion volume by over 50% at 3 days of recovery, and this effect persisted at 30 days as the brain matured. HET0016 decreased peri-lesion gene expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β]) at 1 day and increased reparative cytokine (IL-4, IL-10) expression at 3 days. It also partially preserved microglial ramified processes, consistent with less activation. HET0016 decreased contralateral hindlimb foot faults and improved outcome on the novel object recognition memory task 30 days after TBI. In cultured BV2 microglia, HET0016 attenuated the lipopolysaccharide-evoked increase in release of TNF-α. Our data show that HET0016 improves acute and long-term histologic and functional outcomes, in association with an attenuated neuroinflammatory response after contusion of an immature rat brain.
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Jüttler, Eric, Eckhard Bonmann, Matthias Spranger, Victoria Kolb-Bachofen, and Christoph V. Suschek. "A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory diseases." Molecular and Cellular Neuroscience 34, no. 4 (April 2007): 612–20. http://dx.doi.org/10.1016/j.mcn.2007.01.004.
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Guidotti, Giulia, Chiara Scarlata, Liliana Brambilla, and Daniela Rossi. "Tumor Necrosis Factor Alpha in Amyotrophic Lateral Sclerosis: Friend or Foe?" Cells 10, no. 3 (March 1, 2021): 518. http://dx.doi.org/10.3390/cells10030518.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a massive neuroinflammatory reaction, which plays a key role in the progression of the disease. One of the major mediators of the inflammatory response is the pleiotropic cytokine tumor necrosis factor α (TNFα), mainly released within the central nervous system (CNS) by reactive astrocytes and microglia. Increased levels of TNFα and its receptors (TNFR1 and TNFR2) have been described in plasma, serum, cerebrospinal fluid and CNS tissue from both ALS patients and transgenic animal models of disease. However, the precise role exerted by TNFα in the context of ALS is still highly controversial, since both protective and detrimental functions have been reported. These opposing actions depend on multiple factors, among which includes the type of TNFα receptor activated. In fact, TNFR2 seems to mediate a harmful role being involved in motor neuron cell death, whereas TNFR1 signaling mediates neuroprotective effects, promoting the expression and secretion of trophic factors. This suggests that a better understanding of the cytokine impact on ALS progression may enable the development of effective therapies aimed at strengthening the protective roles of TNFα and at suppressing the detrimental ones.
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Wu, Dongsheng, Camilla Cerutti, Miguel A. Lopez-Ramirez, Gareth Pryce, Josh King-Robson, Julie E. Simpson, Susanne MA van der Pol, et al. "Brain Endothelial miR-146a Negatively Modulates T-Cell Adhesion through Repressing Multiple Targets to Inhibit NF-κB Activation." Journal of Cerebral Blood Flow & Metabolism 35, no. 3 (March 2015): 412–23. http://dx.doi.org/10.1038/jcbfm.2014.207.
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Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation.
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Goudarzi, Salman, Shannon E. Gilchrist, and Sassan Hafizi. "Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia." Cells 9, no. 8 (July 26, 2020): 1779. http://dx.doi.org/10.3390/cells9081779.
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The Gas6–TAM (Tyro3, Axl, Mer) ligand–receptor system is believed to promote central nervous system (CNS) (re)myelination and glial cell development. An additional important function of Gas6–TAM signalling appears to be the regulation of immunity and inflammation, which remains to be fully elucidated in the CNS. Here, we characterised the expression of TAM receptors and ligands in individual CNS glial cell types, observing high expression of Gas6 and the TAM receptors, Mer and Axl, in microglia, and high expression of Tyro3 in astrocytes. We also investigated the effect of Gas6 on the inflammatory cytokine response in the optic nerve and in mixed glial cell cultures from wildtype and single TAM receptor knockout mice. In wildtype and Mer-deficient cultures, Gas6 significantly stimulated the expression of the anti-inflammatory/pro-repair cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β), whereas this effect was absent in either Tyro3 or Axl knockout cultures. Furthermore, Gas6 caused upregulation of myelin basic protein (MBP) expression in optic nerves, which was blocked by a neutralising antibody against IL-10. In conclusion, our data show that microglia are both a major source of Gas6 as well as an effector of Gas6 action in the CNS through the upregulation of anti-inflammatory and pro-repair mediators. Furthermore, the presence of both Axl and Tyro3 receptors appears to be necessary for these effects of Gas6. In addition, IL-10, alongside suppressing inflammation and immunity, mediates the pro-myelinating mechanism of Gas6 action in the optic nerve. Therefore, Gas6 may present an attractive target for novel therapeutic interventions for demyelinating as well as neuroinflammatory disorders of the CNS.
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Ogurcov, Sergei, Iliya Shulman, Ekaterina Garanina, Davran Sabirov, Irina Baichurina, Maxim Kuznetcov, Galina Masgutova, et al. "Blood Serum Cytokines in Patients with Subacute Spinal Cord Injury: A Pilot Study to Search for Biomarkers of Injury Severity." Brain Sciences 11, no. 3 (March 4, 2021): 322. http://dx.doi.org/10.3390/brainsci11030322.
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Background. Despite considerable interest in the search for a spinal cord injury (SCI) therapy, there is a critical need to develop a panel of diagnostic biomarkers to determine injury severity. In this regard, there is a requirement for continuing research into the fundamental processes of neuroinflammatory and autoimmune reactions in SCI, identifying changes in the expression of cytokines. Methods. In this pilot study, an extended multiplex analysis of the cytokine profiles in the serum of patients at 2 weeks post-SCI (n = 28) was carried out, together with an additional assessment of neuron-specific enolase (NSE) and vascular endothelial growth factor (VEGF) levels by enzyme-linked immunosorbent assay. A total of 16 uninjured subjects were enrolled as controls. Results. The data obtained showed a large elevation of IFNγ (>52 fold), CCL27 (>13 fold), and CCL26 (>8 fold) 2 weeks after SCI. The levels of cytokines CXCL5, CCL11, CXCL11, IL10, TNFα, and MIF were different between patients with baseline American Spinal Injury Association Impairment Scale (AIS) grades of A or B, whilst IL2 (>2 fold) and MIP-3a (>6 fold) were significantly expressed in the cervical and thoracic regions. There was a trend towards increasing levels of NSE. However, the difference in NSE was lost when the patient set was segregated based on AIS group. Conclusions. Our pilot research demonstrates that serum concentrations of cytokines can be used as an affordable and rapid detection tool to accurately stratify SCI severity in patients.
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Ko, Wonmin, Chi-Su Yoon, Kwan-Woo Kim, Hwan Lee, Nayeon Kim, Eun-Rhan Woo, Youn-Chul Kim, et al. "Neuroprotective and Anti-Inflammatory Effects of Kuwanon C from Cudrania tricuspidata Are Mediated by Heme Oxygenase-1 in HT22 Hippocampal Cells, RAW264.7 Macrophage, and BV2 Microglia." International Journal of Molecular Sciences 21, no. 14 (July 8, 2020): 4839. http://dx.doi.org/10.3390/ijms21144839.
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Heme oxygenase (HO)-1 is a detoxifying phase II enzyme that plays a role in both inflammatory and oxidative stress responses. Curdrania tricuspidata is widespread throughout East Asia and is used as a therapeutic agent in traditional medicine. We investigated whether treatment with sixteen flavonoid or xanthone compounds from C. tricuspidata could induce HO-1 expression in HT22 hippocampal cells, RAW264.7 macrophage, and BV2 microglia. In these compounds, kuwanon C showed the most remarkable HO-1 expression effects. In addition, treatment with kuwanon C reduced cytoplasmic nuclear erythroid 2-related factor (Nrf2) expression and increased Nrf2 expression in the nucleus. Significant inhibition of glutamate-induced oxidative injury and induction of reactive oxygen species (ROS) occurred when HT22 hippocampal cells were pretreated with kuwanon C. The levels of inflammatory mediator and cytokine, which increased following lipopolysaccharide (LPS) stimulation, were suppressed in RAW264.7 macrophage and BV2 microglia after kuwanon C pretreatment. Kuwanon C also attenuated p65 DNA binding and translocation into the nucleus in LPS-induced RAW264.7 and BV2 cells. The anti-inflammatory, anti-neuroinflammatory, and neuroprotective effects of kuwanon C were reversed when co-treatment with HO-1 inhibitor of tin protoporphyrin-IX (SnPP). These results suggest that the neuroprotective and anti-inflammatory effects of kuwanon C are regulated by HO-1 expression.
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Kaneko, Yuji, Colleen Pappas, Teresita Malapira, Fernando Ĺ. Vale, Naoki Tajiri, and Cesar V. Borlongan. "Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells." Cellular Physiology and Biochemistry 41, no. 3 (2017): 947–59. http://dx.doi.org/10.1159/000460513.
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Background/Aims: Neuroinflammatory processes have been implicated in the pathophysiology of seizure/epilepsy. High mobility group box 1 (HMGB1), a non-histone DNA binding protein, behaves like an inflammatory cytokine in response to epileptogenic insults. Kainic acid (KA) is an excitotoxic reagent commonly used to induce epilepsy in rodents. However, the molecular mechanism by which KA-induced HMGB1 affords the initiation of epilepsy, especially the role of extracellular HMGB1 in neurotransmitter expression, remains to be elucidated. Methods: Experimental early stage of epilepsy-related hyperexcitability was induced in primary rat neural cells (PRNCs) by KA administration. We measured the localization of HMGB1, cell viability, mitochondrial activity, and expression level of glutamate metabolism-associated enzymes. Results: KA induced the translocation of HMGB1 from nucleus to cytosol, and its release from the neural cells. The translocation is associated with post-translational modifications. An increase in extracellular HMGB1 decreased PRNC cell viability and mitochondrial activity, downregulated expression of glutamate decarboxylase67 (GAD67) and glutamate dehydrogenase (GLUD1/2), and increased intracellular glutamate concentration and major histocompatibility complex II (MHC II) level. Conclusions: That a surge in extracellular HMGB1 approximated seizure initiation suggests a key pathophysiological contribution of HMGB1 to the onset of epilepsy-related hyperexcitability.
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Stevens, Andrea M., Lu Liu, Dylan Bertovich, Jelena M. Janjic, and John A. Pollock. "Differential Expression of Neuroinflammatory mRNAs in the Rat Sciatic Nerve Following Chronic Constriction Injury and Pain-Relieving Nanoemulsion NSAID Delivery to Infiltrating Macrophages." International Journal of Molecular Sciences 20, no. 21 (October 24, 2019): 5269. http://dx.doi.org/10.3390/ijms20215269.
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The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Cav2.2, Itgam/Cd11b, Scn9a/Nav1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE2 at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.