Academic literature on the topic 'Astrocytes Neuroinflammation'
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Journal articles on the topic "Astrocytes Neuroinflammation"
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Michinaga, Shotaro, and Yutaka Koyama. "Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury." International Journal of Molecular Sciences 22, no. 12 (June 15, 2021): 6418. http://dx.doi.org/10.3390/ijms22126418.
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Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood–brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases. Although several candidate drugs exerted beneficial effects in TBI animal models, most of them failed to show significant effects in clinical trials. Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI. Increased reactive astrocytes and astrocyte-derived factors are commonly observed in both TBI patients and experimental animal models. Astrocytes have beneficial and detrimental effects on TBI, including promotion and restriction of neurogenesis and synaptogenesis, acceleration and suppression of neuroinflammation, and disruption and repair of the BBB via multiple bioactive factors. Additionally, astrocytic aquaporin-4 is involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI, although astrocyte-targeting drugs have not yet been developed. This article reviews recent observations of the roles of astrocytes and expected astrocyte-targeting drugs in TBI.
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Lindman, Marissa, Juan Angel, Kimberly Newman, Colm Atkins, and Brian Daniels. "Astrocytic RIPK3 confers protection against deleterious neuroinflammation during Zika virus infection." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 163.27. http://dx.doi.org/10.4049/jimmunol.208.supp.163.27.
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Abstract This study aims to identify the function(s) of RIPK3 signaling in astrocytes following Zika virus infection. Previous work found that RIPK3 signaling in Zika virus-infected neurons activates inflammatory transcription factors such as NFκB and IRF1, leading to the upregulation of inflammation-associated transcripts. We were thus interested in determining the role of RIPK3 signaling in astrocytes, which are critical regulators of neuroinflammation. Using mice with an astrocyte-specific conditional Ripk3 deletion, we found that intracranial Zika virus infection was significantly more lethal in mice deficient in astrocytic Ripk3 than in littermate controls. To identify mechanisms underlying this difference, we isolated and infected primary fore- and hind-brain astrocytes with Zika virus to determine the transcriptional consequences of genetic Ripk3 ablation. Surprisingly, we found increased expression of several chemokines, cytokines and ISGs in Ripk3−/− hindbrain astrocytes, in contrast to our previous findings in neurons. Subsequent leukocyte profiling from the brains of Zika virus-infected mice revealed increased numbers of CD4+ and CD8+ T cells, natural killer cells, and monocytes in mice deficient in astrocytic Ripk3 compared to those found in littermate controls. As previous work has demonstrated that astrocytic type I interferon signaling in the hindbrain is responsible for downregulating proinflammatory molecules to prevent lethal neuroinflammation, our data suggest that synergistic signaling between type I IFN and RIPK3 in hindbrain astrocytes suppresses deleterious neuroinflammation and promotes host survival in the setting of Zika virus encephalitis. Supported by a grant from NIH (R01 NS120895).
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Zulfiqar, Shadaan, Pretty Garg, and Katja Nieweg. "Contribution of astrocytes to metabolic dysfunction in the Alzheimer’s disease brain." Biological Chemistry 400, no. 9 (August 27, 2019): 1113–27. http://dx.doi.org/10.1515/hsz-2019-0140.
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AbstractHistorically considered as accessory cells to neurons, there is an increasing interest in the role of astrocytes in normal and pathological conditions. Astrocytes are involved in neurotransmitter recycling, antioxidant supply, ion buffering and neuroinflammation, i.e. a lot of the same pathways that go astray in Alzheimer’s disease (AD). AD remains the leading cause of dementia in the elderly, one for which there is still no cure. Efforts in AD drug development have largely focused on treating neuronal pathologies that appear relatively late in the disease. The neuroenergetic hypothesis, however, focuses on the early event of glucose hypometabolism in AD, where astrocytes play a key role, caused by an imbalanced neuron-astrocyte lactate shuttle. This further results in a state of oxidative stress and neuroinflammation, thereby compromising the integrity of astrocyte-neuron interaction. Compromised astrocytic energetics also enhance amyloid generation, further increasing the severity of the disease. Additionally, apolipoprotein E (APOE), the major genetic risk factor for AD, is predominantly secreted by astrocytes and plays a critical role in amyloid clearance and regulates glucose metabolism in an amyloid-independent manner. Thus, boosting the neuroprotective properties of astrocytes has potential applications in delaying the onset and progression of AD. This review explores how the metabolic dysfunction arising from astrocytes acts as a trigger for the development of AD.
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Karpuk, Nikolay, Maria Burkovetskaya, and Tammy Kielian. "Neuroinflammation alters voltage-dependent conductance in striatal astrocytes." Journal of Neurophysiology 108, no. 1 (July 1, 2012): 112–23. http://dx.doi.org/10.1152/jn.01182.2011.
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Neuroinflammation has the capacity to alter normal central nervous system (CNS) homeostasis and function. The objective of the present study was to examine the effects of an inflammatory milieu on the electrophysiological properties of striatal astrocyte subpopulations with a mouse bacterial brain abscess model. Whole cell patch-clamp recordings were performed in striatal glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP)+ astrocytes neighboring abscesses at postinfection days 3 or 7 in adult mice. Cell input conductance ( Gi) measurements spanning a membrane potential ( Vm) surrounding resting membrane potential (RMP) revealed two prevalent astrocyte subsets. A1 and A2 astrocytes were identified by negative and positive Gi increments vs. Vm, respectively. A1 and A2 astrocytes displayed significantly different RMP, Gi, and cell membrane capacitance that were influenced by both time after bacterial exposure and astrocyte proximity to the inflammatory site. Specifically, the percentage of A1 astrocytes was decreased immediately surrounding the inflammatory lesion, whereas A2 cells were increased. These changes were particularly evident at postinfection day 7, revealing increased cell numbers with an outward current component. Furthermore, RMP was inversely modified in A1 and A2 astrocytes during neuroinflammation, and resting Gi was increased from 21 to 30 nS in the latter. In contrast, gap junction communication was significantly decreased in all astrocyte populations associated with inflamed tissues. Collectively, these findings demonstrate the heterogeneity of striatal astrocyte populations, which experience distinct electrophysiological modifications in response to CNS inflammation.
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Phillips, Emma C., Cara L. Croft, Ksenia Kurbatskaya, Michael J. O’Neill, Michael L. Hutton, Diane P. Hanger, Claire J. Garwood, and Wendy Noble. "Astrocytes and neuroinflammation in Alzheimer's disease." Biochemical Society Transactions 42, no. 5 (September 18, 2014): 1321–25. http://dx.doi.org/10.1042/bst20140155.
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Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.
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Zhang, Xiang, Hao Yao, Qingqing Qian, Nana Li, Wenjie Jin, and Yanning Qian. "Cerebral Mast Cells Participate In Postoperative Cognitive Dysfunction by Promoting Astrocyte Activation." Cellular Physiology and Biochemistry 40, no. 1-2 (2016): 104–16. http://dx.doi.org/10.1159/000452528.
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Background: Astrocytes, the major glial cell type that has been increasingly recognized as contributing to neuroinflammation, are critical in the occurrence and development of postoperative cognitive dysfunction (POCD). Although emerging evidence showed that brain mast cells (MCs) are the "first responders” in neuroinflammation, little is known about the functional communication between MCs and astrocytes. Methods: In this study, we investigated the potential regulation of astrocyte activation by MCs. Rats received an intracerebroventricular injection of Cromolyn (an MC stabilizer) or sterile saline 30 min before undergoing open tibial fracture surgery, and the levels of neuroinflammation and the degree of memory dysfunction were evaluated at 1 day and 3 days after surgery. In the in vitro study, the effect of activated MCs on astrocytes were further clarified. Results: Surgery increased the number of MCs, the astrocyte activation and the production of inflammatory factors, and resulted in cognitive deficits. Site-directed pre-injection of Cromolyn can inhibit this effect. In the vitro study, the conditioned medium from C48/80-stimulated mast cells (P815) could induce primary astrocyte activation and subsequent production of inflammatory cytokines, which could be inhibited by Cromolyn. Conclusion: These findings indicate that activated MCs could trigger astrocyte activation, be involved in neuroinflammation and possibly contribute to POCD. Interactions between MCs and astrocytes could provide potential therapeutic targets for POCD.
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Hansson, Elisabeth. "Long-term pain, neuroinflammation and glial activation." Scandinavian Journal of Pain 1, no. 2 (April 1, 2010): 67–72. http://dx.doi.org/10.1016/j.sjpain.2010.01.002.
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AbstractNociceptive and neuropathic pain signals are known to result from noxious stimuli, which are converted into electrical impulses within tissue nociceptors. There is a complex equilibrium of pain-signalling and pain-relieving pathways connecting PNS and CNS. Drugs against long-term pain are today directed against increased neuronal excitability, mostly with less success.An injury often starts with acute physiological pain, which becomes inflammatory, nociceptive, or neuropathic, and may be transferred into long-term pain. Recently a low-grade inflammation was identified in the spinal cord and along the pain pathways to thalamus and the parietal cortex. This neuroinflammation is due to activation of glial cells, especially microglia, with production of cytokines and other inflammatory mediators within the CNS. Additionally, substances released to the blood from the injured region influence the blood–brain barrier, and give rise to an increased permeability of the tight junctions of the capillary endothelial cells, leading to passage of blood cells into the CNS. These cells are transformed into reactive microglia. If the inflammation turns into a pathological state the astrocytes will be activated. They are coupled into networks and respond to substances released by the capillary endothelial cells, to cytokines released from microglia, and to neurotransmitters and peptides released from neurons. As the astrocytes occupy a strategic position between the vasculature and synapses, they monitor the neuronal activity and transmitter release. Increased release of glutamate and ATP leads to disturbances in Ca2+ signalling, increased production of cytokines and free radicals, attenuation of the astrocyte glutamate transport capacity, and conformational changes in the astrocytic cytoskeleton, the actin filaments, which can lead to formation and rebuilding of new synapses. New neuronal contacts are established for maintaining and spreading pain sensation with the astrocytic networks as bridges. Thereby the glial cells can maintain the pain sensation even after the original injury has healed, and convert the pain into long-term by altering neuronal excitability. It can even be experienced from other parts of the body. As astrocytes are intimate co-players with neurons in the CNS, more knowledge on astrocyte responses to inflammatory activators may give new insight in our understanding of mechanisms of low-grade inflammation underlying long-term pain states and pain spreading. Novel treatment strategies would be to restore glial cell function and thereby attenuate the neuroinflammation.
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Gayen, Manoshi, Manish Bhomia, Nagaraja Balakathiresan, and Barbara Knollmann-Ritschel. "Exosomal MicroRNAs Released by Activated Astrocytes as Potential Neuroinflammatory Biomarkers." International Journal of Molecular Sciences 21, no. 7 (March 27, 2020): 2312. http://dx.doi.org/10.3390/ijms21072312.
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Neuroinflammation is a hallmark of several neurodegenerative diseases and disorders, including traumatic brain injury (TBI). Neuroinflammation results in the activation of glial cells which exacerbates the neuroinflammatory process by secretion of pro-inflammatory cytokines and results in disruption of glial transmission networks. The glial cells, including astrocytes, play a critical role in the maintenance of homeostasis in the brain. Activated astrocytes release several factors as part of the inflammatory process including cytokines, proteins, and microRNAs (miRNAs). MiRNAs are noncoding RNA molecules involved in normal physiological processes and disease pathogenesis. MiRNAs have been implicated as important cell signaling molecules, and they are potential diagnostic biomarkers and therapeutic targets for various diseases, including neurological disorders. Exosomal miRNAs released by astrocytic response to neuroinflammation is not yet studied. In this study, primary human astrocytes were activated by IL-1β stimulation and we examined astrocytic exosomal miRNA cargo released in a neuroinflammatory stress model. Results indicate that acute neuroinflammation and oxidative stress induced by IL-1β generates the release of a specific subset of miRNAs via exosomes, which may have a potential role in regulating the inflammatory response. Additionally, these miRNAs may serve as potential biomarkers of neuroinflammation associated with neurological disorders and injuries.
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He, Tingting, Guo-Yuan Yang, and Zhijun Zhang. "Crosstalk of Astrocytes and Other Cells during Ischemic Stroke." Life 12, no. 6 (June 17, 2022): 910. http://dx.doi.org/10.3390/life12060910.
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Stroke is a leading cause of death and long-term disability worldwide. Astrocytes structurally compose tripartite synapses, blood–brain barrier, and the neurovascular unit and perform multiple functions through cell-to-cell signaling of neurons, glial cells, and vasculature. The crosstalk of astrocytes and other cells is complicated and incompletely understood. Here we review the role of astrocytes in response to ischemic stroke, both beneficial and detrimental, from a cell–cell interaction perspective. Reactive astrocytes provide neuroprotection through antioxidation and antiexcitatory effects and metabolic support; they also contribute to neurorestoration involving neurogenesis, synaptogenesis, angiogenesis, and oligodendrogenesis by crosstalk with stem cells and cell lineage. In the meantime, reactive astrocytes also play a vital role in neuroinflammation and brain edema. Glial scar formation in the chronic phase hinders functional recovery. We further discuss astrocyte enriched microRNAs and exosomes in the regulation of ischemic stroke. In addition, the latest notion of reactive astrocyte subsets and astrocytic activity revealed by optogenetics is mentioned. This review discusses the current understanding of the intimate molecular conversation between astrocytes and other cells and outlines its potential implications after ischemic stroke. “Neurocentric” strategies may not be sufficient for neurological protection and recovery; future therapeutic strategies could target reactive astrocytes.
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Takahashi, Shinichi, and Kyoko Mashima. "Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease." Antioxidants 11, no. 1 (January 17, 2022): 170. http://dx.doi.org/10.3390/antiox11010170.
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Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.
Dissertations / Theses on the topic "Astrocytes Neuroinflammation"
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Brothers, Holly M. "Neuroinflammation, Glutamate Regulation and Memory." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1363603410.
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Wu, Celina. "Dual agonist-antagonist functions of FTY720 influence neuroinflammation-relevant responses in human astrocytes." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110720.
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Astrocytes are the most abundant glia in the central nervous system (CNS), classically identified by their high expression of the intermediate filament, glial fibrillary acidic protein (GFAP). Astrocytes participate in a number of biochemical events important for CNS functions and play a dynamic role in regulating CNS injury/repair processes. In chronic inflammatory conditions such as multiple sclerosis (MS), astrocytes undergo pathophysiological changes that lead to a feature termed astrogliosis (Liberto, Albrecht et al. 2004; Sidoryk-Wegrzynowicz, Wegrzynowicz et al. 2011). Astrogliosis is common to MS lesions, and a novel therapeutic agent for MS, FTY720 (fingolimod, Gilenya™) demonstrates neuroprotective potential by inhibiting astrogliosis development (Choi, Gardell et al. 2011). FTY720 is an oral therapy recently approved for the treatment of MS, and is shown to readily access the CNS. There, it binds directly to sphingosine-1-phosphate receptors (S1PR) on astrocytes and the dynamics of S1PR signaling is shown to modulate astrocytic cellular responses that closely relate to MS pathology. This thesis examines the signaling and functional effects of FTY720 on primary human astrocytes. We used astrocytes derived from the human fetal CNS to explore neuroinflammation-relevant responses mediated by chronic (repeated daily) FTY720 administrations. FTY720 is known to initially acts as an agonist, activating S1PRs but also functions as an antagonist by promoting S1PR internalization and degradation; we examined whether these effects occurred in tandem. We report that receptors internalized by FTY720 can persist and continue to signal for an extended time period (hours). A single addition of FTY720 desensitizes the extracellular receptor-regulated phosphorylation (pERK) signaling response for >24 hours. Such refractory period for pERK signal transduction was maintained in astrocytes treated repeatedly (daily) with FTY720, otherwise the return of pERK activation was achieved by 72 hours following initial treatment. Moreover, receptor desensitization patterns correlated with the loss of proliferative responses induced by the natural ligand sphingosine-1-phosphate (S1P). We show that even under the condition of receptor desensitization (repeated daily administrations) FTY720 attenuated the capacity of the pro-inflammatory cytokine IL-1β, to activate calcium sensitive pathways. Repeated FTY720 treatments did not inhibit serum-induced pERK responses or the secretions of IL-6 and IP-10 in response to IL-1β activation. Our results indicate that daily FTY720 exposures can be a relevant regulator of neuro-inflammation by acting as a functional antagonist for external stimuli (natural ligand S1P) while sustaining internalized receptor-dependent agonist functions (inhibit IL-1β induced calcium mobilization).Les astrocytes sont les cellules gliales les plus abondantes du système nerveux central (SNC). Leur grande expression en filaments intermédiaires, la protéine acide fibrillaire gliale (GFAP), est une caractéristique permettant leur identification. Les astrocytes sont d'importants contributeurs aux événements biochimiques du SNC et jouent un rôle clé dans le processus de régulation des dommages et de la guérison du SNC. Sous des conditions d'inflammation chronique, tel la Sclérose en Plaques (SP), les astrocytes subissent des changements pathophysiologiques causant l'astrogliose (Liberto, Albrecht et al. 2004; Sidoryk-Wegrzynowicz, Wegrzynowicz et al. 2011). Ce mécanisme de cicatrisation est commun dans la SP et un nouvel agent thérapeutique, FTY720 (fingolimod, Gilenya™) démontre des effets protecteurs du SNC en prévenant l'évolution de l'astrogliose. (Choi, Gardell et al. 2011). FTY720 est un agent thérapeutique récemment approuvé pour traiter la SP. Il est administré oralement et a la capacité d'accéder au SNC. Une fois en place dans ce système, cet agent entre en contact direct avec le récepteur sphingosine-1-phosphate (S1PR) sur les astrocytes. Les réponses des astrocytes en réaction aux signaux générés par ce récepteur sont reliées à la pathologie de la SP. Cette thèse examine les signaux engendrés par FTY720 ainsi que ses fonctions sur les astrocytes humains primaires. Nous avons utilisé des astrocytes isolés à partir de SNC humains fœtaux pour examiner les réponses neuro-inflammatoires générées par l'administration quotidienne de FTY720. FTY720 agit initialement comme un agoniste en activant le récepteur S1P, mais il agit également comme un antagoniste en causant l'internalisation et la dégradation de ce récepteur. Nous avons examiné ces deux phénomènes de façon à savoir s'ils agissent en concert. Nous affirmons qu'un récepteur internalisé par FTY720 continue de générer des signaux pour une période de temps prolongée (heures). Une addition simple de FTY720 désensibilise l'astrocyte, pour une période de >24h, au signal de phosphorylation de ERK (pERK) qui est généré par le récepteur extracellulaire. Cette période réfractaire du signal de transduction de pERK fût maintenue dans les astrocytes traités quotidiennement avec FTY720, sinon le signal pERK reparaît 72 heures après le traitement initial. De plus, la désensibilisation du récepteur fût reliée à l'absence de réponse proliférative induite par le ligand naturel sphingosine-1-phosphate (S1P). Nous avons aussi démontré que le traitement quotidien des astrocytes avec FTY720 atténue la capacité de IL-1β à activer les voies moléculaires sensibles au calcium. Le traitement quotidien avec FTY720 n'inhibe pas les signaux de pERK lorsque les astrocytes sont stimulés à l'aide de sérum, ni la sécrétion de IL-6 ou de IP-10 lorsqu'ils sont stimulés avec IL-1β. Nos résultats suggèrent que l'exposition quotidienne à FTY720 agit comme un antagoniste aux stimuli extérieur (tel le ligand naturel S1P) ainsi qu'un agoniste lorsque le récepteur est internalisé (inhibe la mobilisation du calcium lorsqu'exposé à IL-1β).
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Hoskins, Andrew. "The Role of IRF1 in the Brain and in Adaptive Responses of Astrocytes." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5757.
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In neurodegenerative diseases, the CNS becomes inflamed through activation of pathways, including the NF-B pathway. Some of the therapies for those diseases target neuroinflammatory pathways. Here, we explore the mechanisms for the upregulation of a subset of genes following a restimulation of the NF-B pathway. We discover that this upregulation occurs independent of IRF1 expression and type 1 interferon signaling. A knockdown of IRF1 using siRNA and an inhibition of JAK proteins using inhibitor AG490 both had no effect on priming. A secreted factor was found to upregulate the expression of both this subset of genes and genes encoding pro-inflammatory cytokines induced by NF-B activation. We also explored the role of IRF1 in a mouse model of multiple sclerosis. We found that the deletion of IRF1 from oligodendrocytes diminished EAE severity. A deletion of IRF1 from myeloid cells within mice did not diminish EAE severity, however showed a promising decrease in the expression of certain inflammatory genes. Thus, IRF1 plays a critical role in fine-tuning inflammatory responses in the brain.
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Clement, Tifenn. "Contribution of astrocytes in brain vulnerability after juvenile mild traumatic brain injury." Thesis, Bordeaux, 2020. http://www.theses.fr/2020BORD0141.
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Les astrocytes sont des cellules cruciales pour une variété de fonctions physiologiques cérébrales telles que l’homéostasie, le métabolisme, le couplage neurovasculaire ou la régulation de la neurotransmission. Lors de lésions cérébrales, les astrocytes deviennent réactifs et tiennent un rôle prépondérant dans la réponse neuroinflammatoire. Cette réactivité astrocytaire est hétérogène et dépend de nombreux paramètres tels que le type et la sévérité de la lésion, la proximité de l’astrocyte à la lésion, ou encore l’état de maturité du cerveau. Cependant, la réponse spécifique des astrocytes au traumatisme crânien (TC) léger dans un contexte développemental n’a encore jamais été explorée. Le TC léger est pourtant la première cause de visite aux urgences pour la population pédiatrique. Il est maintenant établi qu’une proportion significative de ces patients pédiatriques souffrira de troubles cognitifs et émotionnels durables suite au TC léger, mais les mécanismes moléculaires et cellulaires sous-jacents sont encore peu connus. Il est possible que les astrocytes prennent part à cette vulnérabilité et soient en partie responsables des conséquences sur le long-terme.Nous avons investigué la réponse astrocytaire au TC juvénile léger et avons émis l’hypothèse que (1) les astrocytes déploient une réactivité spécifique évoluant au cours du temps et du développement cérébral, et que (2) cette réactivité diffère lorsque le TC est précédé d’une inflammation systémique précoce induisant un priming des astrocytes, avec une réponse neuroinflammatoire et vasculaire différente au TC juvénile léger, impactant la vulnérabilité cérébrale et les conséquences à long terme.Nous avons montré que :(1) Les astrocytes expriment une réactivité spatiotemporelle spécifique au TC, même à distance de la lésion, en termes d’expression de filaments intermédiaires et d’évolution morphologique, et que des altérations structurelles surviennent à l’imagerie cérébrale sur le long terme après un TC juvénile léger.(2) Lorsque le TC juvénile léger est précédé d’une inflammation systémique périnatale, les astrocytes ont un phénotype de réactivité différent, correspondant à un état de transition en direction des astrocytes formant la cicatrice gliale, avec une sur-régulation de gènes impliqués dans le métabolisme et la matrice extracellulaire, associés à des altérations morphologiques persistantes et une surexpression de VEGF retardée, modifiant les changements vasculaires survenant après un TC seul.Ce travail apporte de nouvelles connaissances sur les spécificités de la réactivité astrocytaire et sur la pathophysiologie de la vulnérabilité induite par un TC léger juvénile, ouvrant des possibilités en termes de cible thérapeutiqueAstrocytes are crucial for various physiological functions in the brain such as homeostasis, metabolism, neurovascular coupling or neurotransmission regulation. In injuries, astrocytes become reactive and have a crucial role in the neuroinflammatory response. This reactivity is heterogeneous and depends on many parameters such as the type and severity of insult, astrocyte proximity to insult, or state of brain maturity. However, the specific response of astrocytes to mild traumatic brain injury (TBI) in the developmental context has never been studied yet. Mild TBI is the leading cause of emergency department visits in the pediatric population. A significant proportion of mild TBI pediatric patients will suffer of long-lasting cognitive and emotional impairments but the underlying cellular and molecular mechanisms are still poorly understood. Astrocytes might take part to this vulnerability and be partly responsible for the long-term consequences.We investigated astrocyte response to juvenile mild TBI and hypothesized that: (1) astrocytes display a specific pattern of reactivity evolving over time and brain development; and that (2) astrocytes reactivity differs when the TBI is preceded by an early systemic inflammation inducing a priming of astrocytes, with a different neuroinflammatory and vascular response to juvenile mild TBI, impacting the brain vulnerability and long-term outcome.We have shown that:(1) Reactive astrocytes express a specific spatiotemporal reactivity pattern even at distance from the injury site, in terms of intermediate filaments expression and morphological evolution, and that structural alterations are observed in brain imaging on the long-term after juvenile mild TBI.(2) When the juvenile mild TBI is preceded by perinatal systemic inflammation, astrocytes express a different reactivity phenotype considered as a state of transition towards scar-forming astrocytes, with increased metabolism and extracellular matrix-related gene changes, associated to morphological alterations sustaining over time and delayed over-expression of VEGF, resulting in the absence of vascular alterations induced by TBI alone.This work brings new insights in the specificities of astrocyte reactivity and in the pathophysiology of vulnerability after juvenile mild TBI, opening possibilities for novel targets for therapeutics
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Phillips, Emma Claire. "Investigating the contribution of astrocytes and neuroinflammation to pathological tau changes in Alzheimer's disease." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/investigating-the-contribution-of-astrocytes-and-neuroinflammation-to-pathological-tau-changes-in-alzheimers-disease(d96f6fa6-6870-4461-82b2-0a19d5507eab).html.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterised by accumulation of ß-amyloid in extracellular plaques, intracellular neurofibrillary tangles composed of abnormally phosphorylated and aggregated tau, and widespread synaptic dysfunction and neuron loss that underlie the clinical symptoms of AD. Glial activation and a neuroinflammatory immune response is also a key aspect of the pathological progression of AD. The activation of astrocytes appears to be particularly associated with pathological changes in tau. This thesis aims to investigate the association between astrocyte activation and abnormal tau processing using primary cell culture and human post-mortem brain. Furthermore, it aims to explore possible regional differences in this role of astrocytes, and the molecular signalling pathways by which astrocytes exert their effects on tau. Experiments in primary astrocyte and neuron co-cultures demonstrated that astrocytes were involved in accelerating Aß-induced neurotoxicity in hippocampal cultures, but not cortical cultures although the differences were quite subtle. Interestingly, astrocytes were important for the neuronal release of tau from cortical neurons under basal conditions, suggesting that astrocytes may be important for pathological tau spread in AD. Analysis of human post-mortem brain showed differences in astrocytic changes in hippocampus and cortex as AD progresses. In addition, these experiments also suggested regional differences in mechanisms related to synaptic dysfunction and loss as disease progresses. These data suggest that different mechanisms may underlie the neurodegenerative effects of ß-amyloid and/or activated astrocytes in distinct brain regions; an important consideration when considering therapeutic strategies for AD. In addition, the potential benefits for tauopathy of repurposing an already licenced drug with anti-inflammatory action were investigated. Despite showing significant modulation of tau phosphorylation in primary cultures, dimethyl fumarate had little influence on disease-associated tau species when tested in vivo in a mouse model of tauopathy. Overall, the findings of this thesis suggest that there are regional differences in astrocyte activation during the development of AD, that are somewhat associated with AD-relevant changes in tau. This work also supports a role for astrocytes in physiological tau release. Further elucidating these differences will increase understanding of neurodegenerative mechanisms. Moreover, these data suggest that regional involvement at different disease stages could be an important consideration when targeting specific mechanisms for therapeutic development.
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Dorey, Evan J. "Apolipoprotein E Isoforms Differentially Regulate Amyloid-β Stimulated Inflammation in Rat and Mouse Astrocytes." Thesis, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23581.
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Neuroinflammation occurs in Alzheimer’s disease (AD) brain, and plays a role in neurodegeneration. The main aim of this study was to determine how treatments with exogenous apolipoprotein E (ApoE2, E3 and E4 isoforms), a genetic risk factor for AD, affects the amyloid-β (Aβ) induced inflammatory response in vitro in astrocytes. Recombinant, lipid-free ApoE4 was found not to affect Aβ-induced inflammation in rat astrocytes, while ApoE2 showed a protective effect. Mouse cells expressing human ApoE isoforms, which have similar lipidation and modification to native human ApoE, showed ApoE4 promoting inflammation, and no ApoE2 protective effect upon Aβ treatment. A Protein/DNA array was used to screen 345 transcription factors in rat astrocytes treated with Aβ and/or ApoE isoforms, in order to determine which contribute to the observed ApoE2 protection. Some candidates were validated by Western Blot or EMSA and/or by inhibition or activation. The findings suggest ApoE isoforms differentially regulate Aβ-induced inflammation, and multiple signalling pathways are involved in the process.
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Ceyzériat, Kelly. "Modulation de la réactivité astrocytaire par ciblage de la voie JAK2-STAT3 : conséquences dans des modèles murins de la maladie d’Alzheimer." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS556/document.
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Les astrocytes sont des éléments clés de la physiologie cérébrale. Dans les maladies neurodégénératives comme la maladie d’Alzheimer (MA), les astrocytes deviennent réactifs. Cette réactivité astrocytaire (RA) est essentiellement caractérisée par des changements morphologiques. En revanche, les effets de la réactivité sur les fonctions de support des astrocytes sont mal connus. De plus, les cascades de signalisation qui conduisent à la RA restent à déterminer. Les objectifs de ce projet étaient de : 1/ démontrer que la voie JAK2-STAT3 (Janus Kinase 2 - Signal Transducer and Activator of Transcription 3) joue un rôle central dans le contrôle de la RA au cours des maladies neurodégénératives ; 2/ comprendre quelle est l’implication de la RA dans les altérations moléculaires, cellulaires et fonctionnelles observées dans la MA. Nous avons montré que la voie JAK2-STAT3 est une cascade de signalisation centrale dans la RA (Ben Haim et al., 2015). Dans ce projet, nous démontrons en utilisant de nouveaux outils moléculaires basés sur des vecteurs viraux, que cette voie est nécessaire et suffisante à la RA. Nos résultats montrent également que la modulation de la RA dans deux modèles murins de la MA (souris APP/PS1dE9 et 3xTg-AD) influence certains index pathologiques, mais de façon contexte-dépendante. L’ensemble de ce travail a permis de valider de nouveaux outils pour étudier les astrocytes réactifs in situ et souligne l’importance et la complexité de leur fonctions au cours des maladies neurodégénérativesAstrocytes are emerging as key players in brain physiology. In Alzheimer’s disease (AD), astrocytes become reactive. Astrocyte reactivity (AR) is essentially characterized by morphological changes. But how the normal supportive functions of astrocytes are changed by their reactive state is unclear. Moreover, signaling cascades leading to AR are not yet determined. In this study, we aim to: 1/ demonstrate the JAK2-STAT3 pathway (Janus Kinase 2 - Signal Transducer and Activator of Transcription 3) is responsible for AR in neurodegenerative diseases ; 2/ understand the contribution of reactive astrocytes to molecular, cellular and functional alterations in AD. We already reported that the JAK2- STAT3 pathway is a central cascade for AR (Ben Haim et al., 2015). Here, we demonstrate, with new molecular tools based on viral vectors, that this pathway is necessary and sufficient to AR. Our results also show that the modulation of AR in two AD mouse models (APP/PS1dE9 and 3xTg-AD mice) influence several pathological hallmarks, but in a context-dependent manner. Overall, this work has generated new original tools to study reactive astrocytes in situ and it underlines the importance and complexity of their functions in neurodegenerative diseases
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Frakes, Ashley E. "The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417649954.
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Guillot, Flora. "Caractérisation de l'infiltrat lymphocytaire et de la réactivité astrocytaire dans un modèle de neuroinflammation autoimmune." Nantes, 2014. https://archive.bu.univ-nantes.fr/pollux/show/show?id=eba4b03e-07fe-4198-a88d-16cbb5f7f5eb.
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La sclérose en plaques (SEP) est une maladie autoimmune, démyélinisante et dégénérative du système nerveux central (SNC). La réponse T CD4 est impliquée dans le développement de la SEP et son modèle animal : l'encéphalomyélite autoimmune expérimentale (EAE). De récentes données montrent que les lymphocytes T CD8 anti-myéline peuvent être impliqués d'autant plus qu'ils sont présents abondamment dans les lésions SEP. Afin de mieux comprendre la contribution des T CD8 pathogéniques, deux récents modèles ont été évalués. Le premier consiste à immuniser des souris avec un épitope de la myéline T CD8 spécifique (MOG37-46). Les souris développent une EAE modéré avec une prépondérance de T CD4 dans le SNC. La réactivation périphérique des T CD8 augmente le rapport T CD8/T CD4 dans le SNC. Le second modèle est basé sur le transfert de T CD8 anti-hémagglutinine (HA) dans des souris DKI exprimant HA par les oligodendrocytes. L'irradiation (2Gy) des souris DKI permet une infiltration lymphocytaire sans symptôme apparent. Les résultats sont discutés au vu des données récentes de la littérature. En parallèle, nous avons caractérisé la réactivité astrocytaire dans le modèle classique EAE afin de mieux définir l'implication des astrocytes dans la maladie. Pour la première fois dans ce modèle, nous avons caractérisé le profil moléculaire des astrocytes de la substance blanche isolés par microdissection laser dans les lésions spinales mettant en évidence l'expression spécifique de médiateurs proinflammatoires et d'enzymes du métabolisme stéroïdien. Ces données ouvrent de nouvelles voies pour contrer la réactivité gliale dans les maladies neuroinflammatoires comme la SEPMultiple sclerosis (MS) is an autoimmune, demyelinating and degenerative disease of the central nervous system (CNS), in which astrocyte reactivity is considered an important player. The CD4 T cell response is strongly associated with development of MS and its animal models such as experimental autoimmune encephalomyelitis (EAE). Recent data suggest that anti-myelin CD8 T cells may be also implicated as CD8 T cells are abundant in MS lesions. To better understand the contribution of pathogenic CD8 T cells, two animal models that have been described were evaluated. The first one consists of mice immunized with a specific CD8 T cell myelin epitope (MOG37-46). Mice develop mild EAE with CD4 T overwhelming CD8 T cells in CNS. Boosting the CD8 immune response increased slightly the CD8/CD4 ratio in the CNS. The second model is based on the adoptive transfer of anti-HemAgglutinin (HA) CD8 T cells in DKI transgenic mice, which express HA by oligodendrocytes. Only irradiation (2Gy) of DKI mice allowed CNS infiltration of CD8 T cells but without apparent clinical signs. These results are discussed in light of recent literature. In parallel, we characterized the astrocyte reactivity in a classical EAE to better define the implication of astrocytes in the pathology. For this, we used for the first time in this model laser-capture microdissection to isolate white matter astrocytes in spinal cord lesion. Selected transcript profiling analysis revealed astrocytic expression of pro-inflammatory mediators and enzymes involved in oestrogen metabolism. These results give new clues for targeting glial reactivity in neuroinflammatory disorders such as MS
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Ben, Haim Lucile. "Modulation of the JAK2/STAT3 pathway in vivo : understanding reactive astrocyte functional features and contribution to neurodegenerative diseases." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066534/document.
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Les astrocytes deviennent réactifs dans les maladies neurodégénératives (MND) comme la maladie d’Alzheimer (MA) et de Huntington (MH) mais les conséquences fonctionnelles de cette réactivité sont peu connues. Dans cette étude, nous avons évalué 1) les voies de signalisation impliquées dans la réactivité astrocytaire, 2) la contribution des astrocyte réactifs (AR) à la dysfonction neuronale dans des modèles de MND et 3) les caractéristiques fonctionnelles des AR.Nous avons montré que la voie JAK2/STAT3 est responsable de la réactivité astrocytaire dans des modèles murins de la MA et la MH. Nous avons développé de nouveaux vecteurs viraux ciblant cette voie dans les astrocytes, in vivo. Grâce à ces outils, nous avons étudié la contribution des AR à la dysfonction neuronale dans deux modèles murins de la MH. Nos résultats suggèrent que les AR ne jouent pas un rôle central dans ces modèles de pathologie. En ciblant la voie JAK2/STAT3, nous avons induit la réactivité astrocytaire chez la souris sauvage et avons montré que cette voie régule la transcription de gènes impliqués dans des fonctions cellulaires importantes. De plus, nous avons observé que l’activation des astrocytes conduit à une diminution de la plasticité synaptique dans le cerveau de souris.En conclusion, nous avons montré que la voie JAK2/STAT3 est une voie centrale dans les AR. Nous avons développé des vecteurs viraux innovants pour évaluer 1) la contribution des AR à la dysfonction neuronale dans des modèles de MND et 2) les propriétés fonctionnelles des AR in vivo. L’étude des AR permettra d’identifier de nouvelles cibles moléculaires pour manipuler ces cellules pléiotropes à des fins thérapeutiquesAstrocyte reactivity is a hallmark of pathological conditions in the CNS including neurodegenerative diseases (ND) such as Alzheimer’s (AD) and Huntington’s (HD) diseases. Reactive astrocytes (RA) are identified by morphological changes but their functional features and influence on neurons are poorly understood, especially in ND. Therefore, we aimed at 1) identifying the signaling cascades involved in astrocyte reactivity in ND, 2) evaluating RA contribution to disease phenotype in ND models and 3) deciphering RA functional features. The JAK2/STAT3 pathway is a known trigger of astrocyte reactivity in CNS injuries. Here, we show that this pathway is a common inducer of astrocyte reactivity in AD and HD models. We developed new viral vectors to target this cascade in astrocytes and manipulate astrocyte reactivity in vivo. We used these vectors to determine the contribution of RA to neuronal dysfunction in HD mouse models. We found that RA do not primarily influence disease phenotype in HD. Last, we targeted the JAK2/STAT3 pathway in WT mice to characterize RA functional features in vivo. We show RA undergo transcriptional changes of numerous genes involved in metabolism, protein degradation pathways and immune response. Moreover, we show that astrocyte reactivity alters synaptic plasticity in the mouse hippocampus. Our results identify the JAK2/STAT3 pathway as a central cascade for astrocyte reactivity. The viral vectors developed in this project represent powerful tools to decipher the roles of RA in various ND models and to characterize RA functional features in vivo. Better understanding RA functions may lead to the identification of new therapeutic targets for ND
Book chapters on the topic "Astrocytes Neuroinflammation"
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Meares, Gordon P., and Etty N. Benveniste. "Inflammation and the Pathophysiology of Astrocytes in Neurodegenerative Diseases." In Neuroinflammation and Neurodegeneration, 61–80. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1071-7_4.
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Tewari, Manju, and Pankaj Seth. "Astrocytes in Neuroinflammation and Neuronal Disorders: Shifting the Focus from Neurons." In Inflammation: the Common Link in Brain Pathologies, 43–70. Singapore: Springer Singapore, 2016. http://dx.doi.org/10.1007/978-981-10-1711-7_3.
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Kriz, Jasna. "Neuron–Astrocyte Interactions in Neuroinflammation." In Advances in Neurobiology, 75–89. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-8313-7_5.
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Mishra, Pooja Shree, Anu Mary Varghese, K. Vijayalakshmi, Veeramani Preethish-Kumar, Kiran Polavarapu, Seena Vengalil, Atchayaram Nalini, Phalguni Anand Alladi, Talakad N. Sathyaprabha, and Trichur R. Raju. "Interplay Between Microglia and Astrocytes During Neuroinflammation: Lessons Learnt from In Vitro and In Vivo Models of Sporadic Amyotrophic Lateral Sclerosis." In The Biology of Glial Cells: Recent Advances, 439–57. Singapore: Springer Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-8313-8_16.
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Facci, Laura, Massimo Barbierato, and Stephen D. Skaper. "Astrocyte/Microglia Cocultures as a Model to Study Neuroinflammation." In Neurotrophic Factors, 127–37. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-7571-6_10.
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Bir, Shyamal C., Oleg Y. Chernyshev, and Alireza Minagar. "Roles of Macrophages and Astrocytes in Pathogenesis of Multiple Sclerosis." In Neuroinflammation, 517–28. Elsevier, 2018. http://dx.doi.org/10.1016/b978-0-12-811709-5.00028-4.
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Munir, Farwa, Nida Islam, Muhammad Hassan Nasir, Zainab Anis, Shahar Bano, Shahzaib Naeem, Atif Amin Baig, and Zaineb Sohail. "Impact of Hypoxia on Astrocyte Induced Pathogenesis." In Astrocytes in Brain Communication and Disease [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106263.
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Astrocytes are the most abundant cells of the central nervous system. These cells are of diverse types based on their function and structure. Astrocyte activation is linked mainly with microbial infections, but long-term activation can lead to neurological impairment. Astrocytes play a significant role in neuro-inflammation by activating pro-inflammatory pathways. Activation of interleukins and cytokines causes neuroinflammation resulting in many neurodegenerative disorders such as stroke, growth of tumours, and Alzheimer’s. Inflammation of the brain hinders neural circulation and compromises blood flow by affecting the blood–brain barrier. So the oxygen concentration is lowered, causing brain hypoxia. Hypoxia leads to the activation of nuclear factor kappa B (NFkB) and hypoxia-inducible factors (HIF), which aggravates the inflammatory state of the brain. Hypoxia evoked changes in the blood–brain barrier, further complicating astrocyte-induced pathogenesis.
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Benarroch, Eduardo E. "Microglia and Neuroinflammation." In Neuroscience for Clinicians, edited by Eduardo E. Benarroch, 402–15. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780190948894.003.0022.
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Microglia maintain cellular, synaptic, and myelin homeostasis during development and normal function and response to injury. Surveilling icroglia actively explore their environment by dynamically extending thin processes that respond to local signals. Activated (“reactive,” or “effector”) microglia constitute a heterogeneous population that dynamically change in phenotype depending on their environmental context and may mediate either injury or neuroprotection, repair, and circuit refinement. Any type of injury in the CNS elicits activation of microglia, astrocytes, and oligodendrocyte precursors, which together with infiltrating cells from the blood in the case of blood-brain barrier disruption interact via several signals to elicit elimination of pathogens, limit the spatial extent of the lesion, and eventually promote tissue remodeling, repair, and remyelination. Neuroinflammation is a feature of essentially all types of neurologic disorders, including traumatic, vascular, and inflammatory/demyelinating lesions; autoimmune encephalitis; and neurodegenerative disorders and has a major role in mechanisms of epilepsy and pain.
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Crespo-Castrillo, Andrea, Maria Angeles Arevalo, Luis M. Garcia-Segura, and Natalia Yanguas-Casás. "Estrogenic Regulation of Glia and Neuroinflammation." In Estrogens and Memory, 96–116. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780190645908.003.0008.
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This chapter on estrogenic regulation of glia and neuroinflammation reviews the role of glial cells in the modulation of synaptic function under physiological conditions and in the regulation of the neuroinflammatory response under pathological conditions. The anti-inflammatory actions of estradiol on astrocytes, oligodendrocytes, and microglia and the implication of these actions for the neuroprotective and tissue repair effects of the hormone are also discussed. Finally, the therapeutic potential of synthetic and natural estrogenic compounds for the control of neuroinflammation is examined. Because reducing neuroinflammation prevents the progressive loss of neural structure and function that leads to functional and mental impairments, regulation of glial cell activation via estradiol is a promising therapeutic approach.
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Vesce, Sabino, Daniela Rossi, Liliana Brambilla, and Andrea Volterra. "Glutamate Release from Astrocytes in Physiological Conditions and in Neurodegenerative Disorders Characterized by Neuroinflammation." In International Review of Neurobiology, 57–71. Elsevier, 2007. http://dx.doi.org/10.1016/s0074-7742(07)82003-4.
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