scholarly journals Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

2019 ◽  
Author(s):  
Mengya Jiao ◽  
Xiangyong Li ◽  
Xiaodi Wang ◽  
Liying Chen ◽  
Baohong Yuan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Injury ◽  
Neurotrophic Factor ◽  
Inflammatory Responses ◽  
Neuroprotective Effect ◽  
Brain Infarction ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Ischemic Brain

Abstract Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia, and treated with IL-33 at a dose of 0.2 μg/day i.p. for three days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells, cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 d after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

scholarly journals Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

2020 ◽  
Author(s):  
Mengya Jiao ◽  
Xiangyong Li ◽  
Liying Chen ◽  
Xiaodi Wang ◽  
Baohong Yuan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Injury ◽  
Neurotrophic Factor ◽  
Inflammatory Responses ◽  
Neuroprotective Effect ◽  
Brain Infarction ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Ischemic Brain

Abstract Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action.Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia, and treated with IL-33 at a dose of 0.2 μg/day i.p. for three days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells, cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes.Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 d after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

scholarly journals Toll-Like Receptor 9: A New Target of Ischemic Preconditioning in the Brain

2008 ◽  
Vol 28 (5) ◽  
pp. 1040-1047 ◽  
Author(s):  
Susan L Stevens ◽  
Thomas MP Ciesielski ◽  
Brenda J Marsh ◽  
Tao Yang ◽  
Delfina S Homen ◽  
...  
Keyword(s):  
Brain Injury ◽  
Ischemic Injury ◽  
Ischemic Brain Injury ◽  
Dependent Manner ◽  
Cpg Odn ◽  
Toll Like Receptor ◽  
Ischemic Brain ◽  
Cpg Oligodeoxynucleotide ◽  
Tlr9 Ligand

Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)α-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFα levels before MCAO and that TNFα is required for subsequent reduction in damage, as mice lacking TNFα are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.

Abstract W P199: Deficiency of Glia Maturation Factor Abrogates Brain Injury and Inflammation in a Murine Model of Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Glia Maturation Factor ◽  
Western Blots ◽  
Ischemic Brain ◽  
Maturation Factor

Background and purpose: Glia maturation factor (GMF), a brain specific protein, discovered and characterized in our laboratory, induces expression of proinflammatory cytokines/ chemokines in the central nervous system (CNS). Recently, it has been demonstrated that deficiency of GMF mitigates neuronal damage in tissue culture cell and animal models of neurodegeneration. Since, GMF expression in brain enhances inflammation; we tested the hypothesis that deficiency of GMF abrogates the inflammatory responses in experimental model of ischemic stroke. Methods: Transient focal cerebral ischemia was induced by 1 hour of occlusion of the right middle cerebral artery (MCAO) with a 7.0 monofilament in GMF-containing wild type (Wt) and GMF-deficient (GMF-KO) mice. Mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the infarct volume and estimation of inflammatory responses. Immunohistochemistry and western blots were used to analyze the expression and activation of glial cells, and levels of NF-κB in ischemic brain hemisphere. Results: We found that levels of GMF significantly increased in MCAO mice compared to saline treated control mice. Next we found that GMF-KO mice exhibited significantly decreased infarct volume, and reduced neurological deficits compared to Wt mice. The decrease in infarct volume and neurological deficits in GMF-KO mice were correlated with a less activation of glia cells, downregulation of NF-κB and suppression of proinflammatory cytokines/chemokine in the ischemic region. Conclusions: In conclusion, present study provides the first evidence that deficiency of GMF reduces brain injury and inflammation after ischemic stroke and suggests that the effective suppression of endogenous GMF-function will prove to be an effective and selective strategy to slow deleterious inflammatory processes in ischemic brain injury. Keywords: Glia maturation factor; Ischemic stroke; Inflammation; Nuclear factor-κB; Cytokines

scholarly journals Neuroprotective Effects of Resveratrol in Ischemic Brain Injury

NeuroSci ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 305-319
Author(s):  
Noelia D. Machado ◽  
Gorka Villena Armas ◽  
Mariana A. Fernández ◽  
Santiago Grijalvo ◽  
David Díaz Díaz
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
De Novo ◽  
Neuroprotective Effect ◽  
Ischemic Brain Injury ◽  
In Vivo Models ◽  
Ischemic Brain ◽  
Number Of Patients

Cerebral ischemia represents the third cause of death and the first cause of disability in adults. This process results from decreasing cerebral blood flow levels as a result of the occlusion of a major cerebral artery. This restriction in blood supply generates low levels of oxygen and glucose, which leads to a decrease in the energy metabolism of the cell, producing inflammation, and finally, neurological deterioration. Currently, blood restoration of flow is the only effective approach as a therapy in terms of ischemic stroke. However, a significant number of patients still have a poor prognosis, probably owing to the increase in the generation of reactive oxygen species (ROS) during the reperfusion of damaged tissue. Oxidative stress and inflammation can be avoided by modulating mitochondrial function and have been identified as potential targets for the treatment of cerebral ischemia. In recent years, the beneficial actions of flavonoids and polyphenols against cerebrovascular diseases have been extensively investigated. The use of resveratrol (RSV) has been shown to markedly decrease brain damage caused by ischemia in numerous studies. According to in vitro and in vivo experiments, there is growing evidence that RSV is involved in several pathways, including cAMP/AMPK/SIRT1 regulation, JAK/ERK/STAT signaling pathway modulation, TLR4 signal transduction regulation, gut/brain axis modulation, GLUT3 up-regulation inhibition, neuronal autophagy activation, and de novo SUR1 expression inhibition. In this review, we summarize the recent outcomes based on the neuroprotective effect of RSV itself and RSV-loaded nanoparticles in vitro and in vivo models focusing on such mechanisms of action as well as describing the potential therapeutic strategies in which RSV plays an active role in cases of ischemic brain injury.

Abstract WP133: L-serine Treatment Confers Neuroprotection Against Permanent Focal Cerebral Ischemia In Rats Via Improving Regional Cerebral Blood Flow

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Guohua Wang ◽  
Zhenglin Jiang ◽  
Taojie Ren ◽  
Xia Li ◽  
Yunfeng Zhang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Potassium Channels ◽  
Regional Cerebral Blood Flow ◽  
Neuroprotective Effect ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Regional Cerebral Blood ◽  
Ischemic Brain ◽  
Calcium Activated Potassium Channels

Introduction: L-serine plays critical roles in neuronal development and function. We have recently reported that L-serine protected against ischemic neuronal injury in vivo and in vitro. The mechanism underlying the neuroprotective effect of L-serine remains unclear. L-serine has been documented to induce a fall in mean arterial pressure through activation of small- and intermediate-conductance calcium-activated potassium channels on the endothelium. Such vasodilating action of L-serine in cerebral blood vessels has not been investigated. Hypothesis: Improving regional cerebral blood flow (rCBF) by L-serine contributes to its neuroprotection on the brain after permanent middle cerebral artery occlusion (pMCAO). Methods: Adult male Sprague-Dawley rats were randomly assigned to sham, vehicle or L-serine-treated groups. pMCAO was induced while monitoring rCBF. The neurological deficit scores, brain infarct volumes and physiological parameters were assessed. L-serine and D-serine content in the cortex was measured with high performance liquid chromatography. Results: Compared to vehicle treatment, administration of L-serine improved rCBF in the ischemic cortex and reduced the neurological deficits, infarct volume and cortical neuronal loss in a dose- and time-dependent manner. The improvement of rCBF and neuroprotective effect of L-serine were abolished by apamin plus charybdotoxin, which blocks the calcium-activated potassium channels on the endothelium, but not influenced by strychnine, an antagonist of glycine receptors. HPLC results shows that L-serine treatment increased the content of both L-serine and D-serine in the ischemic cortex. However, inhibiting the conversion of L-serine to D-serine by aminooxyacetic acid did not affect the L-serine-afforded protection, suggesting that the neuroprotective efficacy of L-serine is not related to the conversion of L-serine to D-serine. Conclusions: L-serine displayed a neuroprotective effect in the ischemic brain, at least partly due to an elevation in rCBF through cerebral blood vessel dilation mediated by the calcium-activated potassium channels on the endothelial cells. L-serine may be a potential novel therapy for ischemic brain injury.

scholarly journals TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yan Zhou ◽  
Tao Tao ◽  
Guangjie Liu ◽  
Xuan Gao ◽  
Yongyue Gao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Therapeutic Target ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Early Brain Injury ◽  
Neurological Deficits ◽  
Human Brain Tissue

AbstractNeuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

scholarly journals The Carbamate, Physostigmine does not Impair Axonal Transport in Rat Cortical Neurons

2021 ◽  
Vol 16 ◽  
pp. 263310552110202
Author(s):  
Sean X Naughton ◽  
Wayne D Beck ◽  
Zhe Wei ◽  
Guangyu Wu ◽  
Peter W Baas ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cortical Neurons ◽  
Acetylcholinesterase Inhibitors ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Cortical Neurons ◽  
Toxicological Mechanism

Among the various chemicals that are commonly used as pesticides, organophosphates (OPs), and to a lesser extent, carbamates, are most frequently associated with adverse long-term neurological consequences. OPs and the carbamate, pyridostigmine, used as a prophylactic drug against potential nerve agent attacks, have also been implicated in Gulf War Illness (GWI), which is often characterized by chronic neurological symptoms. While most OP- and carbamate-based pesticides, and pyridostigmine are relatively potent acetylcholinesterase inhibitors (AChEIs), this toxicological mechanism is inadequate to explain their long-term health effects, especially when no signs of acute cholinergic toxicity are exhibited. Our previous work suggests that a potential mechanism of the long-term neurological deficits associated with OPs is impairment of axonal transport (AXT); however, we had not previously evaluated carbamates for this effect. Here we thus evaluated the carbamate, physostigmine (PHY), a highly potent AChEI, on AXT using an in vitro neuronal live imaging assay that we have previously found to be very sensitive to OP-related deficits in AXT. We first evaluated the OP, diisopropylfluorophosphate (DFP) (concentration range 0.001-10.0 µM) as a reference compound that we found previously to impair AXT and subsequently evaluated PHY (concentration range 0.01-100 nM). As expected, DFP impaired AXT in a concentration-dependent manner, replicating our previously published results. In contrast, none of the concentrations of PHY (including concentrations well above the threshold for impairing AChE) impaired AXT. These data suggest that the long-term neurological deficits associated with some carbamates are not likely due to acute impairments of AXT.

scholarly journals Effect of curcumin in the acute phase of ischemia in chronic cerebral hypoperfusion in rats

2018 ◽  
Vol 17 (1) ◽  
pp. 69-73
Author(s):  
N. S. Shcherbak ◽  
M. A. Popovetskiy ◽  
G. Yu. Yukina ◽  
M. M. Galagudza
Keyword(s):  
Brain Injury ◽  
Acute Phase ◽  
Wistar Rats ◽  
Neuroprotective Effect ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Ischemic Brain Injury ◽  
Protective Effects ◽  
Single Application ◽  
Ischemic Brain

Curcumin presents antioxidant and anti-inflammatory properties and can be considered as a neuroprotector. Data on doses and duration of application of curcumin to achieve protective effects in various types of ischemic brain injury is controversial. The purpose was to study the neuroprotective properties of curcumin in the acute phase of ischemia in chronic cerebral hypoperfusion in rats. It is shown that a single application of curcumin (300 mg/kg, i.p.) is not has neuroprotective effect in the acute phase of ischemia in chronic hypoperfusion in Wistar rats. The results allow to conclude that the neuroprotective effect of a single application of curcumin.

scholarly journals Electrospun Polydioxanone Loaded With Chloroquine Modulates Template-Induced NET Release and Inflammatory Responses From Human Neutrophils

2021 ◽  
Vol 9 ◽  
Author(s):  
Allison E. Fetz ◽  
Shannon E. Wallace ◽  
Gary L. Bowlin
Keyword(s):  
Growth Factor ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Early Time ◽  
Human Neutrophils ◽  
Late Time ◽  
Dependent Manner ◽  
Blood Neutrophils ◽  
Net Release

The implantation of a biomaterial quickly initiates a tissue repair program initially characterized by a neutrophil influx. During the acute inflammatory response, neutrophils release neutrophil extracellular traps (NETs) and secrete soluble signals to modulate the tissue environment. In this work, we evaluated chloroquine diphosphate, an antimalarial with immunomodulatory and antithrombotic effects, as an electrospun biomaterial additive to regulate neutrophil-mediated inflammation. Electrospinning of polydioxanone was optimized for rapid chloroquine elution within 1 h, and acute neutrophil-biomaterial interactions were evaluated in vitro with fresh human peripheral blood neutrophils at 3 and 6 h before quantifying the release of NETs and secretion of inflammatory and regenerative factors. Our results indicate that chloroquine suppresses NET release in a biomaterial surface area–dependent manner at the early time point, whereas it modulates signal secretion at both early and late time points. More specifically, chloroquine elution down-regulates interleukin 8 (IL-8) and matrix metalloproteinase nine secretion while up-regulating hepatocyte growth factor, vascular endothelial growth factor A, and IL-22 secretion, suggesting a potential shift toward a resolving neutrophil phenotype. Our novel repurposing of chloroquine as a biomaterial additive may therefore have synergistic, immunomodulatory effects that are advantageous for biomaterial-guided in situ tissue regeneration applications.

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