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    Divergent transcriptional regulation of astrocyte reactivity across disorders. Nature Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions. 10.1038/s41586-022-04739-5
    Targetability of the neurovascular unit in inflammatory diseases of the central nervous system. Immunological reviews The blood-brain barrier (BBB) is a selectively permeable barrier separating the periphery from the central nervous system (CNS). The BBB restricts the flow of most material into and out of the CNS, including many drugs that could be used as potent therapies. BBB permeability is modulated by several cells that are collectively called the neurovascular unit (NVU). The NVU consists of specialized CNS endothelial cells (ECs), pericytes, astrocytes, microglia, and neurons. CNS ECs maintain a complex "seal" via tight junctions, forming the BBB; breakdown of these tight junctions leads to BBB disruption. Pericytes control the vascular flow within capillaries and help maintain the basal lamina. Astrocytes control much of the flow of material that has moved beyond the CNS EC layer and can form a secondary barrier under inflammatory conditions. Microglia survey the border of the NVU for noxious material. Neuronal activity also plays a role in the maintenance of the BBB. Since astrocytes, pericytes, microglia, and neurons are all able to modulate the permeability of the BBB, understating the complex contributions of each member of the NVU will potentially uncover novel and effective methods for delivery of neurotherapies to the CNS. 10.1111/imr.13121
    Astrocytic calcium release mediates peri-infarct depolarizations in a rodent stroke model. Rakers Cordula,Petzold Gabor C The Journal of clinical investigation Stroke is one of the most common diseases and a leading cause of death and disability. Cessation of cerebral blood flow (CBF) leads to cell death in the infarct core, but tissue surrounding the core has the potential to recover if local reductions in CBF are restored. In these areas, detrimental peri-infarct depolarizations (PIDs) contribute to secondary infarct growth and negatively affect stroke outcome. However, the cellular pathways underlying PIDs have remained unclear. Here, we have used in vivo multiphoton microscopy, laser speckle imaging of CBF, and electrophysiological recordings in a mouse model of focal ischemia to demonstrate that PIDs are associated with a strong increase of intracellular calcium in astrocytes and neurons. We found that astroglial calcium elevations during PIDs are mediated by inositol triphosphate receptor type 2-dependent (IP3R2-dependent) release from internal stores. Importantly, Ip3r2-deficient mice displayed a reduction of PID frequency and overall PID burden and showed increased neuronal survival after stroke. These effects were not related to local CBF changes in response to PIDs. However, we showed that the release and extracellular accumulation of glutamate during PIDs is strongly curtailed in Ip3r2-deficient mice, resulting in ameliorated calcium overload in neurons and astrocytes. Together, these data implicate astroglial calcium pathways as potential targets for stroke therapy. 10.1172/JCI89354
    Upregulation of RCAN1.4 by HIF1α alleviates OGD-induced inflammatory response in astrocytes. Annals of clinical and translational neurology OBJECTIVE:Ischemic stroke is a leading cause of human mortality and long-term disability worldwide. As one of the main forms of regulator of calcineurin 1 (RCAN1), the contribution of RCAN1.4 in diverse biological and pathological conditions has been implicated. But the role of RCAN1.4 in ischemic stroke progression remains elusive. This study is to explore the expression changes and roles of RCAN1.4 in ischemic stroke as well as the underlying mechanisms for these changes and effects of RCAN1.4 in ischemic stroke. METHODS:Middle cerebral artery occlusion model in C57BL/6J mice and oxygen-glucose deprivation (OGD) model in primary astrocytes were performed to induce the cerebral ischemic stroke. The expression pattern of RCAN1.4 was assessed using real-time quantitative PCR and western blotting in vivo and in vitro. Mechanistically, the underlying mechanism for the elevation of RCAN1.4 in the upstream was investigated. Lentiviruses were administrated, and the effect of RCAN1.4 in postischemic inflammation was clearly clarified. RESULTS:Here we uncovered that RCAN1.4 was dramatically increased in mouse ischemic brains and OGD-induced primary astrocytes. HIF1α, activated upon OGD, significantly upregulated RCAN1.4 gene expression through specifically binding to the RCAN1.4 promoter region and activating its promoter activity. The functional hypoxia-responsive element (HRE) was located between -254 and -245 bp in the RCAN1.4 promoter region. Moreover, elevated RCAN1.4 alleviated the release of pro-inflammatory cytokines TNFα, IL1β, IL6 and reduced expression of iNOS, COX2 in primary astrocytes upon OGD, whereas RCAN1.4 silencing has the opposite effect. Of note, RCAN1.4 overexpression inhibited OGD-induced NF-κB activation in primary astrocytes, leading to decreased degradation of IκBα and reduced nuclear translocation of NF-κB/p65. INTERPRETATION:Our results reveal a novel mechanism underscoring the upregulation of RCAN1.4 by HIF1α and the protective effect of RCAN1.4 against postischemic inflammation, suggesting its significance as a promising therapeutic target for ischemic stroke treatment. 10.1002/acn3.51624
    Reactive astrocytes and therapeutic potential in focal ischemic stroke. Choudhury Gourav Roy,Ding Shinghua Neurobiology of disease Astrocytes are specialized and the most abundant cell type in the central nervous system (CNS). They play important roles in the physiology of the brain. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke, the leading cause of brain injury and death in patients. One of the prominent pathological features of a focal ischemic stroke is reactive astrogliosis and glial scar formation. Reactive astrogliosis is accompanied with changes in morphology, proliferation, and gene expression in the reactive astrocytes. This study provides an overview of the most recent advances in astrocytic Ca(2+) signaling, spatial, and temporal dynamics of the morphology and proliferation of reactive astrocytes as well as signaling pathways involved in the reactive astrogliosis after ischemic stroke based on results from experimental studies performed in various animal models. This review also discusses the therapeutic potential of reactive astrocytes in focal ischemic stroke. As reactive astrocytes exhibit high plasticity, we suggest that modulation of local reactive astrocytes is a promising strategy for cell-based stroke therapy. 10.1016/j.nbd.2015.05.003
    Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Liu Zhongwu,Chopp Michael Progress in neurobiology Astrocytes are the most abundant cell type within the central nervous system. They play essential roles in maintaining normal brain function, as they are a critical structural and functional part of the tripartite synapses and the neurovascular unit, and communicate with neurons, oligodendrocytes and endothelial cells. After an ischemic stroke, astrocytes perform multiple functions both detrimental and beneficial, for neuronal survival during the acute phase. Aspects of the astrocytic inflammatory response to stroke may aggravate the ischemic lesion, but astrocytes also provide benefit for neuroprotection, by limiting lesion extension via anti-excitotoxicity effects and releasing neurotrophins. Similarly, during the late recovery phase after stroke, the glial scar may obstruct axonal regeneration and subsequently reduce the functional outcome; however, astrocytes also contribute to angiogenesis, neurogenesis, synaptogenesis, and axonal remodeling, and thereby promote neurological recovery. Thus, the pivotal involvement of astrocytes in normal brain function and responses to an ischemic lesion designates them as excellent therapeutic targets to improve functional outcome following stroke. In this review, we will focus on functions of astrocytes and astrocyte-mediated events during stroke and recovery. We will provide an overview of approaches on how to reduce the detrimental effects and amplify the beneficial effects of astrocytes on neuroprotection and on neurorestoration post stroke, which may lead to novel and clinically relevant therapies for stroke. 10.1016/j.pneurobio.2015.09.008
    Reactive astrogliosis in stroke: Contributions of astrocytes to recovery of neurological function. Sims Neil R,Yew Wai Ping Neurochemistry international Alterations in neuronal connectivity, particularly in the "peri-infarct" tissue adjacent to the region of ischemic damage, are important contributors to the spontaneous recovery of function that commonly follows stroke. Peri-infarct astrocytes undergo reactive astrogliosis and play key roles in modulating the adaptive responses in neurons. This reactive astrogliosis shares many features with that induced by other forms of damage to the central nervous system but also differs in details that potentially influence neurological recovery. A subpopulation of astrocytes within a few hundred micrometers of the infarct proliferate and are centrally involved in the development of the glial scar that separates the damaged tissue in the infarct from surrounding normal brain. The intertwined processes of astrocytes adjacent to the infarct provide the core structural component of the mature scar. Interventions that cause early disruption of glial scar formation typically impede restoration of neurological function. Marked reactive astrogliosis also develops in cells more distant from the infarct but these cells largely remain in the spatial territories they occupied prior to stroke. These cells play important roles in controlling the extracellular environment and release proteins and other molecules that are able to promote neuronal plasticity and improve functional recovery. Treatments manipulating aspects of reactive astrogliosis can enhance neuronal plasticity following stroke. Optimising these treatments for use in human stroke would benefit from a more complete characterization of the specific responses of peri-infarct astrocytes to stroke as well as a better understanding of the influence of other factors including age, sex, comorbidities and reperfusion of the ischemic tissue. 10.1016/j.neuint.2016.12.016
    Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases. Takahashi Shinichi International journal of molecular sciences Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression. 10.3390/ijms22126568
    Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke. Song Shanshan,Huang Huachen,Guan Xiudong,Fiesler Victoria,Bhuiyan Mohammad Iqbal H,Liu Ruijia,Jalali Shayan,Hasan Md Nabiul,Tai Albert K,Chattopadhyay Ansuman,Chaparala Srilakshmi,Sun Ming,Stolz Donna B,He Pingnian,Agalliu Dritan,Sun Dandan,Begum Gulnaz Progress in neurobiology The role of astrocytes in dysregulation of blood-brain barrier (BBB) function following ischemic stroke is not well understood. Here, we investigate the effects of restoring the repair properties of astrocytes on the BBB after ischemic stroke. Mice deficient for NHE1, a pH-sensitive Na/H exchanger 1, in astrocytes have reduced BBB permeability after ischemic stroke, increased angiogenesis and cerebral blood flow perfusion, in contrast to wild-type mice. Bulk RNA-sequencing transcriptome analysis of purified astrocytes revealed that ∼177 genes were differentially upregulated in mutant astrocytes, with Wnt7a mRNA among the top genes. Using a Wnt reporter line, we confirmed that the pathway was upregulated in cerebral vessels of mutant mice after ischemic stroke. However, administration of the Wnt/β-catenin inhibitor, XAV-939, blocked the reparative effects of Nhe1-deficient astrocytes. Thus, astrocytes lacking pH-sensitive NHE1 protein are transformed from injurious to "protective" by inducing Wnt production to promote BBB repair after ischemic stroke. 10.1016/j.pneurobio.2020.101963
    Reactive astrocytes prevent maladaptive plasticity after ischemic stroke. Aswendt Markus,Wilhelmsson Ulrika,Wieters Frederique,Stokowska Anna,Schmitt Felix Johannes,Pallast Niklas,de Pablo Yolanda,Mohammed Lava,Hoehn Mathias,Pekna Marcela,Pekny Milos Progress in neurobiology Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAPVim). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAPVim mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes modulate recovery-promoting plasticity responses after ischemic stroke. 10.1016/j.pneurobio.2021.102199
    Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. Yew Wai Ping,Djukic Natalia D,Jayaseelan Jaya S P,Walker Frederick R,Roos Karl A A,Chataway Timothy K,Muyderman Hakan,Sims Neil R Journal of neuroinflammation BACKGROUND:Altered neuronal connectivity in peri-infarct tissue is an important contributor to both the spontaneous recovery of neurological function that commonly develops after stroke and improvements in recovery that have been induced by experimental treatments in animal models. Microglia and astrocytes are primary determinants of the environment in peri-infarct tissue and hence strongly influence the potential for neuronal plasticity. However, the specific roles of these cells and the timing of critical changes in their function are not well understood. Minocycline can protect against ischemic damage and promote recovery. These effects are usually attributed, at least partially, to the ability of this drug to suppress microglial activation. This study tested the ability of minocycline treatment early after stroke to modify reactive responses in microglia and astrocytes and improve recovery. METHODS:Stroke was induced by photothrombosis in the forelimb sensorimotor cortex of Sprague-Dawley rats. Minocycline was administered for 2 days after stroke induction and the effects on forelimb function assessed up to 28 days. The responses of peri-infarct Iba1-positive cells and astrocytes were evaluated using immunohistochemistry and Western blots. RESULTS:Initial characterization showed that the numbers of Iba1-positive microglia and macrophages decreased in peri-infarct tissue at 24 h then increased markedly over the next few days. Morphological changes characteristic of activation were readily apparent by 3 h and increased by 24 h. Minocycline treatment improved the rate of recovery of motor function as measured by a forelimb placing test but did not alter infarct volume. At 3 days, there were only minor effects on core features of peri-infarct microglial reactivity including the morphological changes and increased density of Iba1-positive cells. The treatment caused a decrease of 57% in the small subpopulation of cells that expressed CD68, a marker of phagocytosis. At 7 days, the expression of glial fibrillary acidic protein and vimentin was markedly increased by minocycline treatment, indicating enhanced reactive astrogliosis. CONCLUSIONS:Early post-stroke treatment with minocycline improved recovery but had little effect on key features of microglial activation. Both the decrease in CD68-positive cells and the increased activation of astrogliosis could influence neuronal plasticity and contribute to the improved recovery. 10.1186/s12974-018-1379-y
    Ischemic stroke in neonatal and adult astrocytes. Revuelta Miren,Elicegui Amaia,Moreno-Cugnon Leire,Bührer Christoph,Matheu Ander,Schmitz Thomas Mechanisms of ageing and development The objective of this paper is to review current information regarding astrocytes function after a stroke in neonatal and adult brain. Based on the current literature, there are some molecular differences related to blood brain barrier (BBB) homeostasis disruption, inflammation and reactive oxygen species (ROS) mediated injury between the immature and mature brain after an ischemic event. In particular, astrocytes, the main glial cells in brain, play a different role in neonatal and adult brain after stroke, as time course of glial activation is strongly age dependent. Moreover, the present review provides further insight into the therapeutic approaches of using neonatal and adult astrocytes after stroke. More research will be needed in order to translate them into an effective treatment against stroke, the second main cause of death and disability worldwide. 10.1016/j.mad.2019.111147
    Single-Cell RNA-Sequencing Analyses Revealed Heterogeneity and Dynamic Changes of Metabolic Pathways in Astrocytes at the Acute Phase of Ischemic Stroke. Oxidative medicine and cellular longevity Astrocyte plays important roles in the pathogenesis of ischemic stroke and reperfusion injury. They intensively participate in the energy metabolism of the brain, while their heterogeneity and function after ischemic stroke remain controversial. By employing single-cell sequencing of mice cortex at 12 h after transient middle cerebral artery occlusion (tMCAO) and comparing with the similar published datasets of 24h after tMCAO, we uncover the cellular phenotypes and dynamic change of astrocytes at the acute phase of ischemic stroke. In this study, we separately identified 3 major subtypes of astrocytes at the 12 h-tMCAO-system and 24 h-tMCAO-system, indicated the significant differences in the expression of genes and metabolic pathways in the astrocytes between the two time nodes after ischemic stroke, and detected the major change in the energy metabolism. These results provided a comprehensive understanding of the characteristic changes of astrocytes after ischemic stroke and explored the potential astrocytic targets for neuroprotection. 10.1155/2022/1817721
    Pinin protects astrocytes from cell death after acute ischemic stroke via maintenance of mitochondrial anti-apoptotic and bioenergetics functions. Mukda Sujira,Tsai Ching-Yi,Leu Steve,Yang Jenq-Lin,Chan Samuel H H Journal of biomedical science BACKGROUND:Stroke is the second most common cause of deaths worldwide. After an ischemic stroke, the proliferated reactive astrocytes in the peri-infarct areas play a beneficial role in neuronal survival. As such, astrocytes have gradually become a target for neuroprotection in stroke. The present study assessed the hypothesis that Pinin (Pnn), originally identified as a nuclear and desmosome-associated protein and is now known to possess anti-apoptotic capacity, protects astrocytes from cell death after ischemic stroke and delineated the underlying mechanisms. METHODS:In in vivo experiments, adult male Sprague-Dawley rats (12-week old) were used to induce acute focal cerebral ischemia employing the middle cerebral artery occlusion (MCAO) method. In in vitro experiments, postnatal day 1 (P1) Sprague-Dawley rat pups were used to prepare cultures of primary astrocytes. Oxygen-glucose deprivation (OGD) and re-oxygenation (OGD/R) procedures were employed to mimic the hypoxic-ischemic condition of stroke in those astrocytes. RESULTS:We found in the peri-infarct area of the ipsilateral cortex and striatum in Sprague-Dawley rats after transient MCAO an increase in Pnn expression that correlated positively with the time-course of infarction as detected by T2-weighted imaging and triphenyltetrazolium chloride staining, augmented number of reactive astrocytes that double-labelled with Pnn as determined by immunofluorescence, and enhanced cytotoxic edema as revealed by diffusion weighted imaging; but mirrored the decreased cleaved caspase-3 as measured by western blot. In an OGD and OGD/R model using primary cultured astrocytes, treatment with Pnn siRNA doubled the chance of surviving astrocytes to manifest cell death as revealed by flow cytometry, and blunted activated ERK signaling, reduced Bcl-2 expression and augmented cleaved caspase 3 detected by western blot in the normoxia, OGD or OGD/R group. Gene-knockdown of Pnn also impeded the reversal from decline in cell viability, elevation in lactate dehydrogenase leakage and decrease in ATP production in the OGD/R group. CONCLUSION:We conclude that the endogenous Pnn participates in neuroprotection after acute ischemic stroke by preserving the viability of astrocytes that survived the ischemic challenge via maintenance of mitochondrial anti-apoptotic and bioenergetics functions. 10.1186/s12929-019-0538-5
    Inhibition of Reactive Astrocytes with Fluorocitrate Ameliorates Learning and Memory Impairment Through Upregulating CRTC1 and Synaptophysin in Ischemic Stroke Rats. Zhang Xinyu,Shen Xianzhi,Dong Jiali,Liu Wen-Cao,Song Min,Sun Yanyun,Shu Hui,Towse Clare-Louise,Liu Wenlan,Liu Chun-Feng,Jin Xinchun Cellular and molecular neurobiology Ischemic stroke often causes motor and cognitive deficits. Deregulated glia gap junction communication, which is reflected by increased protein levels of glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43), has been observed in ischemic hippocampus and has been associated with cognitive impairment in animal stroke models. Here, we tested the hypothesis that reactive astrocytes-mediated loss of synaptophysin (SYP) and CREB-regulated transcription coactivator 1 (CRTC1) contribute to dysfunction in glia gap junction communication and memory impairment after ischemic stroke. Male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) with 7-day reperfusion. Fluorocitrate (1 nmol), the reversible inhibitor of the astrocytic tricarboxylic acid cycle, was injected into the right lateral ventricle of MCAO rats once every 2 days starting immediately before reperfusion. The Morris water maze was used to assess memory in conjunction with western blotting and immunostaining to detect protein expression and distribution in the hippocampus. Our results showed that ischemic stroke caused significant memory impairment accompanied by increased protein levels of GFAP and Cx43 in hippocampal tissue. In addition, the levels of several key memory-related important proteins including SYP, CRTC1, myelin basic protein and high-mobility group-box-1 were significantly reduced in the hippocampal tissue. Of note, inhibition of reactive astrocytes with fluorocitrate was shown to significantly reverse the above noted changes induced by ischemic stroke. Taken together, our findings demonstrate that inhibiting reactive astrocytes with fluorocitrate immediately before reperfusion may protect against ischemic stroke-induced memory impairment through the upregulation of CRTC1 and SYP. 10.1007/s10571-019-00709-0
    Lactate Supply from Astrocytes to Neurons and its Role in Ischemic Stroke-induced Neurodegeneration. Yamagata Kazuo Neuroscience Glucose transported to the brain is metabolized to lactate in astrocytes and supplied to neuronal cells via a monocarboxylic acid transporter (MCT). Lactate is used in neuronal cells for various functions, including learning and memory formation. Furthermore, lactate can block stroke-induced neurodegeneration. We aimed to clarify the effect of astrocyte-produced lactate on stroke-induced neurodegeneration. Previously published in vivo and in vitro animal and cell studies, respectively, were searched in PubMed, ScienceDirect, and Web of Science. Under physiological conditions, lactate production and release by astrocytes are regulated by changes in lactate dehydrogenase (LDH) and MCT expression. Moreover, considering stroke, lactate production and supply are regulated through hypoxia-inducible factor (HIF)-1α expression, especially with hypoxic stimulation, which may promote neuronal apoptosis; contrastingly, neuronal survival may be promoted via HIF-1α. Stroke stimulation could prevent neurodegeneration through the strong enhancement of lactate production, as well as upregulation of MCT4 expression to accelerate lactate supply. However, studies using astrocytes derived from animal stroke models revealed significantly reduced lactate production and MCT expression. These findings suggest that the lack of lactate supply may strongly contribute to hypoxia-induced neurodegeneration. Furthermore, diminished lactate supply from astrocytes could facilitate stroke-induced neurodegeneration. Therefore, astrocyte-derived lactate may contribute to stroke prevention. 10.1016/j.neuroscience.2021.11.035
    Glucagon-like peptide-1 cleavage product GLP-1(9-36) reduces neuroinflammation from stroke via the activation of insulin-like growth factor 1 receptor in astrocytes. Huang Jing,Liu Yunhan,Cheng Liusiyuan,Li Jihong,Zhang Tangrui,Zhao Gang,Zhang Huinan European journal of pharmacology Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a "bio-inactive" metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Little is known about the effects and mechanisms of GLP-1 (9-36) in cerebral ischemia and reperfusion injury. Here, we report that systemic application of GLP-1 (9-36) in adult mice facilitated functional recovery and reduced infarct volume, astrogliosis, and neuronal apoptosis following middle cerebral artery occlusion and reperfusion. Interestingly, these effects were still observed in GLP-1 receptor knockout (Glp-1r) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1r) mice. Primary astrocytes were cultured and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and enzyme-linked immunosorbent assay indicated that GLP-1 (9-36) pretreatment reduces tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels. This effect was not diminished in Glp-1r astrocytes but was reversed in Igf-1r astrocytes, emphasizing that the anti-inflammatory effect of GLP-1 (9-36) in astrocytes is independent of GLP-1 receptor signaling and is instead mediated by IGF-1 receptor. Immunoprecipitation experiments showed that GLP-1 (9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-1 (9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD/R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. Thus, our findings suggest that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor. 10.1016/j.ejphar.2020.173581
    Reactive astrocytes facilitate vascular repair and remodeling after stroke. Williamson Michael R,Fuertes Cathleen Joy A,Dunn Andrew K,Drew Michael R,Jones Theresa A Cell reports Brain injury causes astrocytes to assume a reactive state that is essential for early tissue protection, but how reactive astrocytes affect later reparative processes is incompletely understood. In this study, we show that reactive astrocytes are crucial for vascular repair and remodeling after ischemic stroke in mice. Analysis of astrocytic gene expression data reveals substantial activation of transcriptional programs related to vascular remodeling after stroke. In vivo two-photon imaging provides evidence of astrocytes contacting newly formed vessels in cortex surrounding photothrombotic infarcts. Chemogenetic ablation of a subset of reactive astrocytes after stroke dramatically impairs vascular and extracellular matrix remodeling. This disruption of vascular repair is accompanied by prolonged blood flow deficits, exacerbated vascular permeability, ongoing cell death, and worsened motor recovery. In contrast, vascular structure in the non-ischemic brain is unaffected by focal astrocyte ablation. These findings position reactive astrocytes as critical cellular mediators of functionally important vascular remodeling during neural repair. 10.1016/j.celrep.2021.109048
    Function of Astrocytes in Neuroprotection and Repair after Ischemic Stroke. Zhang Shufen,Shang Deshu,Shi Han,Teng Weiyu,Tian Li European neurology BACKGROUND:Astrocytes are the most numerous cell types within the central nervous system, and many efforts have been put into determining the exact role of astrocytes in neuroprotection and repair after ischemic stroke. Although numerous studies have been done in recent years, there is still no thorough understanding of the exact function of astrocytes in the whole course of the stroke. SUMMARY:According to the recent literature, there are many structures and factors that play important roles in the process of ischemic stroke, among which blood-brain barrier, various growth factors, gap junctions, AQP4, and glial scars have been studied most comprehensively, and all these factors are closely related to astrocytes. The role of astrocytes in ischemic stroke, therefore, can be analyzed more comprehensively. Key Message: The present review mainly summarized the current knowledge about astrocytes and their potential roles after ischemic stroke. 10.1159/000517378
    Effect of Tetrahedral Framework Nucleic Acids on Neurological Recovery via Ameliorating Apoptosis and Regulating the Activation and Polarization of Astrocytes in Ischemic Stroke. ACS applied materials & interfaces Astrocytes, as the most plentiful subtypes of glial cells, play an essential biphasic function in ischemic stroke (IS). However, although having beneficial effects on stroke via promoting nerve restoration and limiting lesion extension, astrocytes can unavoidably cause exacerbated brain damage due to their participation in the inflammatory response. Therefore, seeking an effective and safe drug/strategy for protecting and regulating astrocytes in stroke is urgent. Here, we employ tetrahedral framework nucleic acid (tFNA) nanomaterials for astrocytes in stroke, considering their excellent biological properties and outstanding biosafety. In vitro, tFNA can inhibit calcium overload and ROS regeneration triggered by oxygen-glucose deprivation/reoxygenation (OGD/R), which provides a protective effect against astrocytic apoptosis. Furthermore, morphological changes such as hyperplasia and hypertrophy of reactive astrocytes are restrained, and the astrocytic polarization from the proinflammatory A1 phenotype to the neuroprotective A2 phenotype is facilitated by tFNA, which further alleviates cerebral infarct volume and facilitates the recovery of neurological function in transient middle cerebral artery occlusion (tMCAo) rat models. Moreover, the TLRs/NF-κB signaling pathway is downregulated by tFNA, which may be the potential mechanism of tFNA for protecting astrocytes in stroke. Collectively, we demonstrate that tFNA can effectively mediate astrocytic apoptosis, activation, and polarization to alleviate brain injury, which represents a potential intervention strategy for IS. 10.1021/acsami.2c10364
    Characterization of Astrocytes in the Minocycline-Administered Mouse Photothrombotic Ischemic Stroke Model. Neurochemical research Astrocytes, together with microglia, play important roles in the non-infectious inflammation and scar formation at the brain infarct during ischemic stroke. After ischemia occurs, these become highly reactive, accumulate at the infarction, and release various inflammatory signaling molecules. The regulation of astrocyte reactivity and function surrounding the infarction largely depends on intercellular communication with microglia. However, the mechanisms involved remain unclear. Furthermore, recent molecular biological studies have revealed that astrocytes are highly divergent under both resting and reactive states, whereas it has not been well reported how the communication between microglia and astrocytes affects astrocyte divergency during ischemic stroke. Minocycline, an antibiotic that reduces microglial activity, has been used to examine the functional roles of microglia in mice. In this study, we used a mouse photothrombotic ischemic stroke model to examine the characteristics of astrocytes after the administration of minocycline during ischemic stroke. Minocycline increased astrocyte reactivity and affected the localization of astrocytes in the penumbra region. Molecular characterization revealed that the induced expression of mRNA encoding the fatty acid binding protein 7 (FABP7) by photothrombosis was enhanced by the minocycline administration. Meanwhile, minocycline did not significantly affect the phenotype or class of astrocytes. The expression of Fabp7 mRNA was well correlated with that of tumor-necrosis factor α (TNFα)-encoding Tnf mRNA, indicating that a correlated expression of FABP7 from astrocytes and TNFα is suppressed by microglial activity. 10.1007/s11064-022-03703-z