Endothelial Regulation by Exogenous Annexin A1 in Inflammatory Response and BBB Integrity Following Traumatic Brain Injury

Background and TargetFollowing brain trauma, blood–brain barrier (BBB) disruption and inflammatory response are critical pathological steps contributing to secondary injury, leading to high mortality and morbidity. Both pathologies are closely associated with endothelial remodeling. In the present study, we concentrated on annexin A1 (ANXA1) as a novel regulator of endothelial function after traumatic brain injury.MethodsAfter establishing controlled cortical impact (CCI) model in male mice, human recombinant ANXA1 (rANXA1) was administered intravenously, followed by assessments of BBB integrity, brain edema, inflammatory response, and neurological deficits.ResultAnimals treated with rANXA1 (1 μg/kg) at 1 h after CCI exhibited optimal BBB protection including alleviated BBB disruption and brain edema, as well as endothelial junction proteins loss. The infiltrated neutrophils and inflammatory cytokines were suppressed by rANXA1, consistent with decreased adhesive and transmigrating molecules from isolated microvessels. Moreover, rANXA1 attenuated the neurological deficits induced by CCI. We further found that the Ras homolog gene family member A (RhoA) inhibition has similar effect as rANXA1 in ameliorating brain injuries after CCI, whereas rANXA1 suppressed CCI-induced RhoA activation.ConclusionOur findings suggest that the endothelial remodeling by exogenous rANXA1 corrects BBB disruption and inflammatory response through RhoA inhibition, hence improving functional outcomes in CCI mice.

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Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20246125 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6125 ◽

Cited By ~ 5

Author(s):

Ning Liu ◽

Yinghua Jiang ◽

Joon Yong Chung ◽

Yadan Li ◽

Zhanyang Yu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Neurovascular Unit ◽

Annexin A2 ◽

Tissue Loss ◽

Neurological Deficits ◽

Endogenous Factors ◽

The Brain

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

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Lack of mitochondrial ferritin aggravated neurological deficits via enhancing oxidative stress in a traumatic brain injury murine model

Bioscience Reports ◽

10.1042/bsr20170942 ◽

2017 ◽

Vol 37 (6) ◽

Cited By ~ 9

Author(s):

Ligang Wang ◽

Libo Wang ◽

Zhibo Dai ◽

Pei Wu ◽

Huaizhang Shi ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Knockout Mice ◽

Brain Injuries ◽

Brain Infarction ◽

Neurological Deficits ◽

Important Correlation ◽

The Brain ◽

And Oxidative Stress

Oxidative stress has been strongly implicated in the pathogenesis of traumatic brain injury (TBI). Mitochondrial ferritin (Ftmt) is reported to be closely related to oxidative stress. However, whether Ftmt is involved in TBI-induced oxidative stress and neurological deficits remains unknown. In the present study, the controlled cortical impact model was established in wild-type and Ftmt knockout mice as a TBI model. The Ftmt expression, oxidative stress, neurological deficits, and brain injury were measured. We found that Ftmt expression was gradually decreased from 3 to 14 days post-TBI, while oxidative stress was gradually increased, as evidenced by reduced GSH and superoxide dismutase levels and elevated malondialdehyde and nitric oxide levels. Interestingly, the extent of reduced Ftmt expression in the brain was linearly correlated with oxidative stress. Knockout of Ftmt significantly exacerbated TBI-induced oxidative stress, intracerebral hemorrhage, brain infarction, edema, neurological severity score, memory impairment, and neurological deficits. However, all these effects in Ftmt knockout mice were markedly mitigated by pharmacological inhibition of oxidative stress using an antioxidant, N-acetylcysteine. Taken together, these results reveal an important correlation between Ftmt and oxidative stress after TBI. Ftmt deficiency aggravates TBI-induced brain injuries and neurological deficits, which at least partially through increasing oxidative stress levels. Our data suggest that Ftmt may be a promising molecular target for the treatment of TBI.

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FGF20 protected against BBB disruption after traumatic brain injury by activating the AKT/GSK3β pathway to upregulate junction protein expression and inhibiting JNK/NFκB-dependent neuroinflammation

10.21203/rs.2.19529/v1 ◽

2019 ◽

Author(s):

Jun Chen ◽

Xue Wang ◽

Jian Hu ◽

Wenting Huang ◽

Confidence Dordoe ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Brain Edema ◽

Microvascular Endothelial Cell ◽

Potential Candidate ◽

Protective Effects ◽

Tnf Α ◽

Junction Protein

Abstract Background ：Blood-brain barrier (BBB) disruption and the cerebral inflammatory response are two reciprocal mechanisms that work together to mediate the degree of brain edema, which is responsible for the majority of deaths after traumatic brain injury (TBI), and facilitate further brain damage, which leads to long-term TBI complications. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in the development of dopaminergic neurons in Parkinson disease (PD). However, little is known about the role of FGF20 in TBI. The aim of the current study was to assess the protective effects of FGF20 in TBI through protecting the BBB. Methods: We explored the relationship between FGF20 and BBB function in controlled cortical impact (CCI)-induced TBI mice model and TNF-α-induced human brain microvascular endothelial cell (HBMEC) in vitro BBB disruption model. We also explored the mechanisms of these interactions and the signaling processes involved in BBB function and neuroinflammation. Results: In this study, we demonstrate that recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema and Evans Blue penetration in vivo after TBI. In an in vitro BBB disruption model of, rhFGF20 could reverse changes to TNF-α-induced HBMEC morphology, reduce Transwell permeability, and increase transendothelial electrical resistance (TEER). In both a TBI mouse model and in vitro , rhFGF20 upregulated the expression of BBB-associated tight junction (TJ) protein and adherens junction (AJ) protein via the AKT/GSK3β pathway. In addition, rhFGF20 inhibited the cerebral inflammatory response through regulating the JNK/NFκB pathway and further protected the function of the BBB. Conclusions : Our results contribute to a new treatment strategy in TBI research. FGF20 is a potential candidate to treat TBI as it protects the BBB via regulating the AKT/GSK3β and JNK/NFκB signaling pathways.

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Manajemen Anestesia pada Evakuasi Epidural Haemorrhage (EDH) dengan Pendarahan Masif

Jurnal Neuroanestesi Indonesia ◽

10.24244/jni.v10i1.329 ◽

2021 ◽

Vol 10 (1) ◽

pp. 29-39

Author(s):

Nurul Huda ◽

◽

Buyung Hartiyo Laksono

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Head Injury ◽

Brain Injuries ◽

Good Condition ◽

Massive Bleeding ◽

Red Blood Cell Transfusion ◽

Mortality And Morbidity ◽

Hemodynamic Status ◽

Poor Outcome

Traumatic brain injury causes mortality and morbidity worldwide. Epidural Haemorrhage (EDH) is a form of head injury where time is an indicator that must be considered in its management. The main focus during traumatic brain injury management is patient stabilization and control of intracranial pressure, as well as maintaining brain oxygenation and perfusion. Subsequently, surgical decompression was performed. Evacuation and bleeding control should be done in a short time to avoid further injury. The practice of neuroanesthesia, as a support in the management of traumatic brain injuries, is often associated with blood loss that results in anemia during the intraoperative and postoperative periods. Although anemia correlates with poor outcome in brain-injured patients, red blood cell transfusion to correct anemia also correlates with poor outcome in patients. There are still no clear recommendations regarding the administration of transfusions, whether restrictive or massive, regarding the benefits provided. Male patient, age 51 years with complaints of decreased consciousness and vomiting, referred from the previous hospital with a diagnosis of moderate head injury 225 with 96cc temporoparietal EDH, 11mm midline shift to the right, and cerebral edema. During the operation period, there was massive bleeding that interfered with the hemodynamic status so that blood components were transfused until a stable hemodynamic status was obtained. In postoperative care in the ICU, the patient is relatively in good condition.

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Fisetin has Inhibitory Effects on the TLR 4/NF-κB-Mediated Inflammatory Pathway After Traumatic Brain Injury in Mice: A Potential Neuroprotective Role

10.21203/rs.3.rs-776980/v1 ◽

2021 ◽

Author(s):

Chenhui Zhou ◽

Sheng Nie ◽

Zhepei Wang ◽

Fanyong Gong ◽

Jingmi Wu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Edema ◽

Inflammatory Cytokines ◽

Nuclear Factor Κb ◽

Neuroprotective Effects ◽

Inflammatory Pathway ◽

Mortality And Morbidity ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Inflammatory response contributes to the high mortality and morbidity of traumatic brain injury (TBI). Potent anti-inflammatory effects can alleviate brain injury after TBI. Fisetin has anti-inflammatory properties in several brain injury models, but the effects of fisetin on inflammation after TBI is still unclear. Our study aimed to investigate the neuroprotective effects of fisetin against inflammation after TBI in mice.Fisetin (25 mg/kg, 50 mg/kg or 75 mg/kg) or equal volume of vehicle was given via intraperitoneal injection 30 min after TBI. The neurological severity score, brain edema and blood brain barrier (BBB) permeability were assayed after TBI. In further mechanistic studies, changes in the toll-like receptor 4 (TLR 4)/nuclear factor-κB (NF-κB) pathway and the expression of pro-inflammatory cytokines were measured. Fisetin significantly improved behavioral outcomes and reduced brain edema after TBI. These changes were associated with significant reductions in TLR 4 expression and NF-κB activity. In addition, changes in the expression of pro-inflammatory cytokines were detected 24 h after TBI. Our study provided the first evidence that fisetin exerted neuroprotective effects by inhibiting the TLR 4/NF-κB–mediated inflammatory pathway after TBI in mice.

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Abstract W P260: Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

Stroke ◽

10.1161/str.46.suppl_1.wp260 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Alexander V Glushakov ◽

Jawad A Fazal ◽

Shuh Narumiya ◽

Sylvain Dore

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Young Adult ◽

Brain Injuries ◽

Neurological Deficits ◽

Cortical Lesions ◽

Brain Pathology ◽

Adult Mice ◽

Ep1 Receptor

Introduction: Brain injuries promote upregulation of so-called proinflammatory prostaglandin E2 leading to overactivation of a class of its cognate G-protein coupled receptors, notably EP1, which is considered as a promising target for treatment of ischemic stroke and, possibly, other neurological disorders involving excitotoxicity. However, our recent data suggest that of EP1 receptor in intracerebral hemorrhage may play a protective role. The goal of this study was to investigate a translational potential of EP1 receptor for treatment of traumatic brain injury (TBI). Methods: The acute brain injury was induced using controlled cortical impact (CCI) in wildtype (WT) and genetic EP1 receptor knockout mice (EP1-/-). Neurological deficit scores (NDS) and anatomical brain pathology were accessed at 48h after injury. Results: CCI resulted in significant cortical lesions, localized hippocampal edema and neurological deficits compared to animals from sham group underwent craniotomy only. The NDS after CCI were significantly higher in older mice (7-11mo) compared to young adult animals (2-4mo) in both WT and EP1-/- groups. Treatment with a selective antagonist SC-51089 with repeated doses of 20-100μg/kg after CCI had no significant effects on cortical lesions, hippocampal edema and NDS in young adult mice of both WT and EP1-/- genotypes. Post-treatment with 17-pt-PGE2 (300μg/kg) had no significant effects on anatomical brain pathology in young adult mice, but improved NDS at 24h in WT but not in EP1-/- mice. Immunohistochemistry revealed significant increases in GFAP and Iba1 immunoreactivity in selected brain regions surrounding injury suggesting astrogliosis and microglia activation. EP1 receptor knockout had no effects on GFAP and Iba1 expression in young adult mice, whereas lead to a significant attenuation of GFAP immunoreactivity in older mice. Conclusions: This study provides, for the first time, a clarification on the role of EP1 receptor in a preclinical model of contusive TBI. The results suggest that EP1 receptor might be involved in complex pathways differentially associated with neurological deficits. In addition, this study provides further clarification on clinical use of EP1 receptor ligands for treatment of acute brain injuries.

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Head Trauma in the Cat: 2. Assessment and Management of Traumatic Brain Injury

Journal of Feline Medicine and Surgery ◽

10.1016/j.jfms.2011.09.003 ◽

2011 ◽

Vol 13 (11) ◽

pp. 815-823 ◽

Cited By ~ 7

Author(s):

Laurent Garosi ◽

Sophie Adamantos

Keyword(s):

Traumatic Brain Injury ◽

General Practice ◽

Brain Injury ◽

Head Trauma ◽

Brain Injuries ◽

Experimental Studies ◽

Clinical Signs ◽

Evidence Base ◽

Neurological Deficits ◽

Current Evidence

Practical relevance Feline trauma patients are commonly seen in general practice and frequently have sustained some degree of brain injury. Clinical challenges Cats with traumatic brain injuries may have a variety of clinical signs, ranging from minor neurological deficits to life-threatening neurological impairment. Appropriate management depends on prompt and accurate patient assessment, and an understanding of the pathophysiology of brain injury. The most important consideration in managing these patients is maintenance of cerebral perfusion and oxygenation. For cats with severe head injury requiring decompressive surgery, early intervention is critical. Evidence base There is a limited clinical evidence base to support the treatment of traumatic brain injury in cats, despite its relative frequency in general practice. Appropriate therapy is, therefore, controversial in veterinary medicine and mostly based on experimental studies or human head trauma studies. This review, which sets out to describe the specific approach to diagnosis and management of traumatic brain injury in cats, draws on the current evidence, as far as it exists, as well as the authors' clinical experience.

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History, Overview, and Human Anatomical Pathology of Traumatic Brain Injury

Neurotrauma ◽

10.1093/med/9780190279431.003.0001 ◽

2018 ◽

pp. 3-12

Author(s):

Kentaro Shimoda ◽

Shoji Yokobori ◽

Ross Bullock

Keyword(s):

Traumatic Brain Injury ◽

Young Adults ◽

Intensive Care ◽

Brain Injury ◽

Brain Injuries ◽

Research Effort ◽

Intensive Care Treatment ◽

Mortality And Morbidity ◽

Severe Tbi ◽

Anatomical Pathology

Traumatic brain injury (TBI) is one of the oldest and commonest causes of medical distress in humans. However, despite much research effort, the prognosis for severe TBI patients remains poor. Worldwide, TBI is recognized as the leading cause of mortality and morbidity in young adults. TBI is a major worldwide health and socioeconomic problem. The most important factor in the prognosis of TBI patients is the severity of the "primary" brain injury. Additional delayed "secondary" brain damage continues from the time of traumatic impact in TBI patients, and the two combine to determine outcome. This chapter discusses the incidence of TBI, trends in morbidity and mortality, shifts in causes of TBI, its economic burden on society, and the pathophysiology of primary and secondary brain injuries. The authors discuss indications for surgical and intensive care treatment for intracranial hypertension and mass lesion management in TBI patients.

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Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury

Science Advances ◽

10.1126/sciadv.aax8847 ◽

2020 ◽

Vol 6 (22) ◽

pp. eaax8847 ◽

Cited By ~ 4

Author(s):

Kumar Vaibhav ◽

Molly Braun ◽

Katelyn Alverson ◽

Hesam Khodadadi ◽

Ammar Kutiyanawalla ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neutrophil Extracellular Traps ◽

Dnase I ◽

Cerebral Hypoperfusion ◽

Neurological Deficits ◽

Neurological Injury ◽

Injury Incidence ◽

Mortality And Morbidity ◽

Extracellular Traps

Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.

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