Fecal Transplantation from db/db Mice Treated with Sodium Butyrate Attenuates Ischemic Stroke Injury

Ischemic stroke is a major global health burden, and T2D is a well-known comorbidity that aggravates brain injury after ischemic stroke. However, the underlying mechanism by which T2D exacerbates stroke injury has not been completely elucidated.

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Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?

Journal of Neuroinflammation ◽

10.1186/s12974-021-02105-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Kimberly F. Young ◽

Rebeca Gardner ◽

Victoria Sariana ◽

Susan A. Whitman ◽

Mitchell J. Bartlett ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Western Blot ◽

Calcium Binding ◽

Transmembrane Protein ◽

Brain Regions ◽

Morphological Data ◽

Cell Populations ◽

Male And Female ◽

Female Mice

AbstractBackgroundIschemic stroke is an acquired brain injury with gender-dependent outcomes. A persistent obstacle in understanding the sex-specific neuroinflammatory contributions to ischemic brain injury is distinguishing between resident microglia and infiltrating macrophages—both phagocytes—and determining cell population-specific contributions to injury evolution and recovery processes. Our purpose was to identify microglial and macrophage populations regulated by ischemic stroke using morphology analysis and the presence of microglia transmembrane protein 119 (TMEM119). Second, we examined sex and menopause differences in microglia/macrophage cell populations after an ischemic stroke.MethodsMale and female, premenopausal and postmenopausal, mice underwent either 60 min of middle cerebral artery occlusion and 24 h of reperfusion or sham surgery. The accelerated ovarian failure model was used to model postmenopause. Brain tissue was collected to quantify the infarct area and for immunohistochemistry and western blot methods. Ionized calcium-binding adapter molecule, TMEM119, and confocal microscopy were used to analyze the microglia morphology and TMEM119 area in the ipsilateral brain regions. Western blot was used to quantify protein quantity.ResultsPost-stroke injury is increased in male and postmenopause female mice vs. premenopause female mice (p< 0.05) with differences primarily occurring in the caudal sections. After stroke, the microglia underwent a region, but not sex group, dependent transformation into less ramified cells (p< 0.0001). However, the number of phagocytic microglia was increased in distal ipsilateral regions of postmenopausal mice vs. the other sex groups (p< 0.05). The number of TMEM119-positive cells was decreased in proximity to the infarct (p< 0.0001) but without a sex group effect. Two key findings prevented distinguishing microglia from systemic macrophages. First, morphological data were not congruent with TMEM119 immunofluorescence data. Cells with severely decreased TMEM119 immunofluorescence were ramified, a distinguishing microglia characteristic. Second, whereas the TMEM119 immunofluorescence area decreased in proximity to the infarcted area, the TMEM119 protein quantity was unchanged in the ipsilateral hemisphere regions using western blot methods.ConclusionsOur findings suggest that TMEM119 is not a stable microglia marker in male and female mice in the context of ischemic stroke. Until TMEM119 function in the brain is elucidated, its use to distinguish between cell populations following brain injury with cell infiltration is cautioned.

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Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Journal of Neuroinflammation ◽

10.1186/s12974-021-02170-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Dong-Ling Liu ◽

Zhi Hong ◽

Jing-Ying Li ◽

Yu-Xin Yang ◽

Chu Chen ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Middle Cerebral Artery ◽

Combined Treatment ◽

Scavenger Receptor ◽

Hemorrhagic Transformation ◽

Microglial Cells ◽

Peroxiredoxin 1 ◽

Macrophage Scavenger Receptor ◽

Tissue Plasminogen

Abstract Background Hemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells. Methods The tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1−/−) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1−/− mice. Results Seventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1−/− mice, respectively. Conclusion The phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

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Global health burden of ambient PM2.5 and the contribution of anthropogenic black carbon and organic aerosols

Environment International ◽

10.1016/j.envint.2021.107020 ◽

2022 ◽

Vol 159 ◽

pp. 107020

Author(s):

Sourangsu Chowdhury ◽

Andrea Pozzer ◽

Andy Haines ◽

Klaus Klingmüller ◽

Thomas Münzel ◽

...

Keyword(s):

Global Health ◽

Black Carbon ◽

Organic Aerosols ◽

Health Burden

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Replicating infant astrocyte behavior in the adult after brain injury improves outcomes

10.1101/2020.05.14.096974 ◽

2020 ◽

Author(s):

Leon Teo ◽

Anthony G. Boghdadi ◽

Jihane Homman-Ludiye ◽

Iñaki Carril-Mundiñano ◽

William C. Kwan ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Brain Injuries ◽

Adult Patients ◽

Long Term Outcomes ◽

Neuroprotective Effects ◽

Age Dependent ◽

Underlying Mechanisms ◽

Glial Scarring

AbstractInfants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adult patients after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was associated only with infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged ischemic stroke significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

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Effect of isoflurane post-treatment on tPA-exaggerated brain injury in a rat ischemic stroke model

Korean Journal of Anesthesiology ◽

10.4097/kjae.2015.68.3.281 ◽

2015 ◽

Vol 68 (3) ◽

pp. 281 ◽

Cited By ~ 7

Author(s):

Eun Jung Kim ◽

So Yeon Kim ◽

Jae Hoon Lee ◽

Jeong Min Kim ◽

Jin-Soo Kim ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Post Treatment ◽

Stroke Model

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Large animal models of stroke and traumatic brain injury as translational tools

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00163.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. R165-R190 ◽

Cited By ~ 24

Author(s):

Annabel J. Sorby-Adams ◽

Robert Vink ◽

Renée J. Turner

Keyword(s):

Traumatic Brain Injury ◽

Ischemic Stroke ◽

Brain Injury ◽

Animal Models ◽

Animal Species ◽

Experimental Models ◽

Clinical Translation ◽

Large Animal ◽

Large Animal Models ◽

Significant Burden

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the preclinical screening of over 1,000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of preclinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains. However, the use of large animal species such as nonhuman primates, sheep, and pigs, which have large gyrencephalic human-like brains, may provide an avenue to improve clinical translation due to similarities in neuroanatomical structure when compared with widely adopted rodent models. This purpose of this review is to provide an overview of large animal models of TBI and ischemic stroke, including the surgical considerations, key benefits, and limitations of each approach.

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Clinical application of perfusion computed tomography in neurosurgery

Journal of Neurosurgery ◽

10.3171/2013.10.jns13103 ◽

2014 ◽

Vol 120 (2) ◽

pp. 473-488 ◽

Cited By ~ 23

Author(s):

Abel Po-Hao Huang ◽

Jui-Chang Tsai ◽

Lu-Ting Kuo ◽

Chung-Wei Lee ◽

Hong-Shiee Lai ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Head Injury ◽

Clinical Decision Making ◽

Case Series ◽

Perfusion Ct ◽

Imaging Biomarker ◽

Original Research ◽

Pertinent Literature ◽

Selection For

Object Currently, perfusion CT (PCT) is a valuable imaging technique that has been successfully applied to the clinical management of patients with ischemic stroke and aneurysmal subarachnoid hemorrhage (SAH). However, recent literature and the authors' experience have shown that PCT has many more important clinical applications in a variety of neurosurgical conditions. Therefore, the authors share their experiences of its application in various diseases of the cerebrovascular, neurotraumatology, and neurooncology fields and review the pertinent literature regarding expanding PCT applications for neurosurgical conditions, including pitfalls and future developments. Methods A pertinent literature search was conducted of English-language articles describing original research, case series, and case reports from 1990 to 2011 involving PCT and with relevance and applicability to neurosurgical disorders. Results In the cerebrovascular field, PCT is already in use as a diagnostic tool for patients suspected of having an ischemic stroke. Perfusion CT can be used to identify and define the extent of the infarct core and ischemic penumbra core, and thus aid patient selection for acute reperfusion therapy. For patients with aneurysmal SAH, PCT provides assessment of early brain injury, cerebral ischemia, and infarction, in addition to vasospasm. It may also be used to aid case selection for aggressive treatment of patients with poor SAH grade. In terms of oncological applications, PCT can be used as an imaging biomarker to assess angiogenesis and response to antiangiogenetic treatments, differentiate between glioma grades, and distinguish recurrent tumor from radiation necrosis. In the setting of traumatic brain injury, PCT can detect and delineate contusions at an early stage. In patients with mild head injury, PCT results have been shown to correlate with the severity and duration of postconcussion syndrome. In patients with moderate or severe head injury, PCT results have been shown to correlate with patients' functional outcome. Conclusions Perfusion CT provides quantitative and qualitative data that can add diagnostic and prognostic value in a number of neurosurgical disorders, and also help with clinical decision making. With emerging new technical developments in PCT, such as characterization of blood-brain barrier permeability and whole-brain PCT, this technique is expected to provide more and more insight into the pathophysiology of many neurosurgical conditions.

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Abstract T MP18: In Vivo Expansion of Regulatory T cells with Interleukin-2/Interleukin-2-antibody Complex Protects against Transient Ischemic Stroke

Stroke ◽

10.1161/str.46.suppl_1.tmp18 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Haiyue Zhang ◽

Peiying Li ◽

Yanqin Gao ◽

Jun Chen ◽

Xiaoming Hu

Keyword(s):

T Cells ◽

Ischemic Stroke ◽

Brain Injury ◽

Regulatory T Cells ◽

Interleukin 2 ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Treg Population ◽

Antibody Complex

Background and Purpose: Our previous work documents the transfer of regulatory T cells (Tregs) in rodent models of ischemic stroke protects acute ischemic brain injury by regulating poststroke inflammatory response and thereby ameliorating BBB disruption. However, the low number of Tregs restricts the clinical feasibility of Treg transfer. Recently, in vivo expansion of Tregs with IL-2/IL-2-antibody complex (IL-2/IL-2Ab) was validated protective in autoimmune diseases model,renal ischemia reperfusion model and atherosclerosis. Here we investigate the beneficial effect of IL-2/IL-2Ab on ischemic stroke and decipher the underlying mechanisms. Methods: IL-2/IL-2Ab or isotype IgG was ip injected into C57/BL6 mice for 3 consecutive days. The mice are then subjected to 60-minute middle cerebral artery occlusion (MCAO) or sham operation. Brain infarction, inflammation and neurological performance was assessed up to 7 days after reperfusion. Results: Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ Tregs in the blood, lymph nodes and spleens collected from IL-2/IL-2Ab-treated mice as compared to those from isotype-treated controls. Such Treg elevation could be observed since 3 days after IL-2/IL-2Ab injection and lasts until 7 days after MCAO. Immunochemistry staining confirms the increased number of Foxp3+ cells in the spleen at 3 days after MCAO in IL-2/IL-2Ab-treated mice. IL-2/IL-2Ab promotes function recovery up to 7 days after stroke, as revealed by significantly improved performance in corner test (n=6-9, ***p<0.001), rotarod test (n=8, **p<0.01), cylinder test (n=8, **p<0.01) and adhesive removal test (n=3, *p<0.05). Quantification of TTC staining and microtubule-associated protein (MAP2) staining shows reductions in brain infarct volume at 3 days (n=5-9,*p<0.05) and 7 days (n=7-9,*p<0.01), respectively, after MCAO. Meanwhile, we observed reduced infiltration of peripheral immune cells (CD3+ T cells, MPO+ neutrophils and F4/80+ macrophages) into the ischemic brain. Conclusions: Our finding suggests that IL-2/IL-2Ab treatment is a novel and clinical feasible immune therapy to expand Treg population in vivo, reduce post-stroke inflammatory responses and protect against ischemic brain injury.

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Abstract P747: Gpr68 Play a Protective Role in Ischemic Stroke in Mice

Stroke ◽

10.1161/str.52.suppl_1.p747 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

tao wang ◽

Guokun Zhou ◽

mingdi he ◽

yuanyuan xu ◽

w.g. Rusyniak ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Neuronal Injury ◽

Protective Role ◽

Functional Screening ◽

Rt Pcr ◽

Brain Neurons ◽

Acid Sensing Ion Channels ◽

The Brain

Introduction: Acidosis is one prevalent phenomenon in ischemic stroke. The literature has shown that protons directly gate acid-sensing ion channels (ASICs) and proton-activated chloride channel, both lead to neuronal injury However, it is unclear whether protons activate metabotropic pathways in brain neurons. There are four proton-sensitive G-protein coupled receptors (GPCRs): GPR4, GPR65, GPR68 and GPR132. It remains unknown whether any of these GPCRs mediate acid-induced signals in brain neurons or whether they contribute to ischemia-induced brain injury. Methods: Total RNA from human cortical tissue or mouse brain was isolated using TRIzol and an RNase Kit. Standard RT-PCR was performed to determine the expression of these GPCRs in the brain. An in vitro slice injury model was used for functional screening. To determine the effect of ischemia, WT and knockout male mice were subjected to MCAO. To study brain injury, brains were sectioned coronally at 1 mm intervals and stained by vital dye immersion: (2%) 2,3,5-triphenyltetrazolium hydrochloride (TTC). Locomotor analysis and corner test were used to assess behavior outcome. Adeno-associated virus (AAV) -mediated gene delivery was used to determine the outcome of GPR68 overexpression. Results: RT-PCR showed that brain tissue expressed GPR4, -65, and -68. The expression of GPR68 was evident at 30 cycles. In organotypic slices, compared to the WT, deleting GPR4 or GPR65 had no effect while deleting GPR68 significantly increased acidosis-induced neuronal injury. At both 24 hour and 72 hour after 45 minutes MCAO, GPR68 deletion increased brain injury (p=0.0020 for 24hour, p=0.0392 for 72hour, Mann-Whitney U test). WT and GPR68-/- mice did not differ in baseline locomotor activities or corner test. On the third day following MCAO, GPR68-/- exhibited significantly more left rotations (p=0.0287, Mann-Whitney U test) than WT animals. Lastly, mice receiving AAV-GPR68 exhibited an average infarct of 21.97 ± 12.4%, significantly (p = 0.0022, Mann-Whitney U test) smaller than those receiving AAV-GFP (37.2 ± 6.8%). Conclusion: These data showed that GPR68 functions as a neuroprotective proton receptor in the brain.

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Abstract TP269: Lncrna-u90926 Aggravates Ischemic Brain Injury via Promoting Neutrophils Infiltration After Experimental Stroke

Stroke ◽

10.1161/str.51.suppl_1.tp269 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Jian Chen ◽

Yun Xu

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Expression Level ◽

Neurological Deficits ◽

Neurological Injury ◽

Experimental Stroke ◽

Ischemic Brain Injury ◽

Triphenyltetrazolium Chloride ◽

Ischemic Brain ◽

Severity Scores

Background: Long non-coding RNAs (LncRNAs) are expressed at high levels in the brain in a variety of neuropathologic conditions, including stroke. However, the potential role of LncRNAs in ischemic stroke-associated microglial biological function and neurological injury remains largely unknown. Methods: Oxygen-glucose deprivation and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as in vitro and in vivo ischemic stroke models. Microarray analysis was performed to explore the overall expression level changes of LncRNAs. Real-time polymerase chain reaction (RT-qPCR) was used to detect expression level of LncU90926 in brain, plasma and microglia. ShRNA-LncU90926 in lentivirus and microglia specific Adeno-associated virus (AAV) were used to knockdown LncU90926 in vitro and in vivo separately. Infarct volumes and neurological impairments were assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining, Neurological Severity Scores (NSS), rotarod test and grip strength respectively. Immunofluorescence staining and flow cytometry were performed to detect the number of neutrophils recruited to brain. RT-qPCR was used to detect the level of chemokines (CXCL, CCL2) and inflammatory mediators associated with neutrophils (MPO, MMP3 and TIMP1). Results: (1). LncU90926 was markedly up-regulated in the infarcted brain and plasma after MCAO. Both MCAO and OGD treatment induced remarkable up-regulation of LncU90926 in microglia. (2). LncU90926 knockdown definitely attenuated brain infarct size and neurological deficits after ischemic stroke. (3). LncU90926 knockdown in microglia reduced the number of neutrophils recruited to brain, and CXCL1 and CCL2 were down-regulated in both MCAO and OGD models. LncU90926 knockdown also induced reduction of MPO, MMP3 and TIMP1 in the infarcted brain. Conclusions: LncU90926 was up-regulated in microglia after experimental stroke, and aggravates ischemic brain injury through facilitating neutrophils infiltration via up-regulating microglial chemokine.

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