NAAA inhibitor F96 attenuates BBB disruption and secondary injury after traumatic brain injury (TBI)

Advancements in the critical care of patients with various forms of acute brain injury (traumatic brain injury, subarachnoid hemorrhage, stroke, etc.) in its current evolution recognizes that in addition to the initial insult, there is a secondary cascade of physiological events in the injured brain that contribute significantly to morbidity and mortality. Multimodality monitoring (MMM) in neurocritical care aims to recognize this secondary cascade in a timely manner. With early recognition, critical care of brain-injured patients may then be tailored to preventing and alleviating this secondary injury. MMM includes a variety of invasive and noninvasive techniques aimed at monitoring brain physiologic parameters such as intracranial pressure, perfusion, oxygenation, blood flow, metabolism, and electrical activity. This chapter provides an overview of these techniques and offers a practical guide to their integration and use in the intensive care setting.

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Traumatic brain injury in dogs and cats

Companion Animal ◽

10.12968/coan.2019.0015 ◽

2019 ◽

Vol 24 (9) ◽

pp. 480-487 ◽

Cited By ~ 1

Author(s):

Neus Elias ◽

Ana-Maria Rotariu ◽

Tobias Grave

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Traffic Accidents ◽

Road Traffic ◽

Companion Animals ◽

Treatment Strategies ◽

Secondary Injury ◽

Different Types ◽

Veterinary Surgeon ◽

Primary Injury

Traumatic brain injury is common in companion animals and can occur from many different types of trauma such as road traffic accidents or bites. Following the primary injury, which is beyond control of the clinician, secondary injury occurs minutes to days following the trauma. The secondary injury will lead to neuronal death, and is the focus of treatment strategies for the emergency veterinary surgeon. Treatment of traumatic brain injury includes nursing strategies, intravenous fluid therapy, hyperosmolar therapy and diuretics, pain management, maintenance of oxygenation and ventilation, temperature regulation, anticonvulsant therapy and glycaemic control. All of these are discussed in this clinical review.

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Inhibition of p21-activated kinase 1 by IPA-3 attenuates secondary injury after traumatic brain injury in mice

Brain Research ◽

10.1016/j.brainres.2014.08.026 ◽

2014 ◽

Vol 1585 ◽

pp. 13-22 ◽

Cited By ~ 4

Author(s):

Xinran Ji ◽

Wei Zhang ◽

Lihai Zhang ◽

Licheng Zhang ◽

Yiling Zhang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Secondary Injury ◽

P21 Activated Kinase

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The Role of Free Radicals in Traumatic Brain Injury

Biological Research For Nursing ◽

10.1177/1099800411431823 ◽

2012 ◽

Vol 15 (3) ◽

pp. 253-263 ◽

Cited By ~ 24

Author(s):

Karen M. O’Connell ◽

Marguerite T. Littleton-Kearney

Keyword(s):

Traumatic Brain Injury ◽

Free Radicals ◽

Free Radical ◽

Brain Injury ◽

Current Knowledge ◽

Cellular Level ◽

Secondary Brain Injury ◽

Secondary Injury ◽

The Military

Traumatic brain injury (TBI) is a significant cause of death and disability in both the civilian and the military populations. The primary impact causes initial tissue damage, which initiates biochemical cascades, known as secondary injury, that expand the damage. Free radicals are implicated as major contributors to the secondary injury. Our review of recent rodent and human research reveals the prominent role of the free radicals superoxide anion, nitric oxide, and peroxynitrite in secondary brain injury. Much of our current knowledge is based on rodent studies, and the authors identified a gap in the translation of findings from rodent to human TBI. Rodent models are an effective method for elucidating specific mechanisms of free radical-induced injury at the cellular level in a well-controlled environment. However, human TBI does not occur in a vacuum, and variables controlled in the laboratory may affect the injury progression. Additionally, multiple experimental TBI models are accepted in rodent research, and no one model fully reproduces the heterogeneous injury seen in humans. Free radical levels are measured indirectly in human studies based on assumptions from the findings from rodent studies that use direct free radical measurements. Further study in humans should be directed toward large samples to validate the findings in rodent studies. Data obtained from these studies may lead to more targeted treatment to interrupt the secondary injury cascades.

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Screening of Biochemical and Molecular Mechanisms of Secondary Injury and Repair in the Brain after Experimental Blast-Induced Traumatic Brain Injury in Rats

Journal of Neurotrauma ◽

10.1089/neu.2013.2862 ◽

2013 ◽

Vol 30 (11) ◽

pp. 920-937 ◽

Cited By ~ 68

Author(s):

Patrick M. Kochanek ◽

C. Edward Dixon ◽

David K. Shellington ◽

Samuel S. Shin ◽

Hülya Bayır ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Molecular Mechanisms ◽

Secondary Injury ◽

Injury And Repair ◽

The Brain

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The Role of S100B/RAGE-Enhanced ADAM17 Activation in Endothelial Glycocalyx Shedding After Traumatic Brain Injury

10.21203/rs.3.rs-927255/v1 ◽

2021 ◽

Author(s):

Zhimin Zou ◽

Li Li ◽

Qin Li ◽

Kun Zhang ◽

Chengyong Liu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endothelial Cells ◽

Brain Injury ◽

Lung Injury ◽

Cultured Cells ◽

Cell Model ◽

Endothelial Glycocalyx ◽

Pharmacological Intervention ◽

Secondary Injury ◽

Rat Serum

Abstract Background: Traumatic brain injury (TBI) remains one of the main causes for disability and death worldwide. While the primary mechanical injury cannot be avoided, the prevention of secondary injury is the focus of TBI research. Present study aimed to elucidate the effects and mechanisms of S100B and its receptor RAGE on mediating secondary injury after TBI. Methods: This study established TBI animal model by fluid percussion injury in rats, cell model by stretch-injured in astrocytes, and endothelial injury model with conditioned medium stimulation. Pharmacological intervention was applied to interfere the activities of S100B/RAGE/ADAM17 signaling pathway, respectively. The expressions or contents of S100B, RAGE, syndecan-1 and ADAM17 in brain and serum, as well as in cultured cells and medium, were detected by western blot. The distribution of relative molecules was observed with immunofluorescence. Results: We found that TBI could activate the release of S100B, mostly from astrocytes, and S100B and RAGE could mutually regulate their expression and activation. Most importantly, present study revealed an obvious increase of syndecan-1 in rat serum or in endothelial cultured medium after injury, and a significant decrease in tissue and in cultured endothelial cells, indicating TBI-induced shedding of endothelial glycocalyx. The data further proved that the activation of S100B/RAGE signaling could promote the shedding of endothelial glycocalyx by enhancing the expression, translocation and activity of ADAM17, an important sheddase, in endothelial cells. The damage of endothelial glycocalyx consequently aggravated blood brain barrier (BBB) dysfunction and systemic vascular hyper-permeability, overall resulting in secondary brain and lung injury. Conclusions: TBI triggers the activation of S100B/RAGE signal pathway. The regulation S100B/RAGE on ADAM17 expression, translocation and activation further promotes the shedding of endothelial glycocalyx, aggravates the dysfunction of BBB, and increases the vascular permeability, leading to secondary brain and lung injury. Present study may open a new corridor for the more in-depth understanding of the molecular processes responsible for cerebral and systemic vascular barrier impairment and secondary injury after TBI.

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Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.629910 ◽

2021 ◽

Vol 14 ◽

Author(s):

Huan Huang ◽

Anqi Xia ◽

Li Sun ◽

Chun Lu ◽

Ying Liu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Tumor Necrosis Factor ◽

Western Blotting ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Secondary Injury ◽

Expression Levels ◽

Cultured Astrocytes ◽

Necrosis Factor

Neuroinflammation contributes to delayed (secondary) neurodegeneration following traumatic brain injury (TBI). Tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling may promote post-TBI neuroinflammation, thereby exacerbating secondary injury. This study investigated the pathogenic functions of TRAF6 signaling following TBI in vivo and in vitro. A rat TBI model was established by air pressure contusion while lipopolysaccharide (LPS) exposure was used to induce inflammatory-like responses in cultured astrocytes. Model rats were examined for cell-specific expression of TRAF6, NF-κB, phosphorylated (p)-NF-κB, MAPKs (ERK, JNK, and p38), p-MAPKs, chemokines (CCL2 and CXCL1), and chemokine receptors (CCR2 and CXCR2) by immunofluorescence, RT-qPCR, western blotting, and ELISA, for apoptosis by TUNEL staining, and spatial cognition by Morris water maze testing. These measurements were compared between TBI model rats receiving intracerebral injections of TRAF6-targeted RNAi vector (AAV9-TRAF6-RNAi), empty vector, MAPK/NF-κB inhibitors, or vehicle. Primary astrocytes were stimulated with LPS following TRAF6 siRNA or control transfection, and NF-κB, MAPKs, chemokine, and chemokine receptor expression levels evaluated by western blotting and ELISA. TRAF6 was expressed mainly in astrocytes and neurons of injured cortex, peaking 3 days post-TBI. Knockdown by AAV9-TRAF6-RNAi improved spatial learning and memory, decreased TUNEL-positive cell number in injured cortex, and downregulated expression levels of p-NF-κB, p-ERK, p-JNK, p-p38, CCL2, CCR2, CXCL1, and CXCR2 post-TBI. Inhibitors of NF-κB, ERK, JNK, and p38 significantly suppressed CCL2, CCR2, CXCL1, and CXCR2 expression following TBI. Furthermore, TRAF6-siRNA inhibited LPS-induced NF-κB, ERK, JNK, p38, CCL2, and CXCL1 upregulation in cultured astrocytes. Targeting TRAF6-MAPKs/NF-κB-chemokine signaling pathways may provide a novel therapeutic approach for reducing post-TBI neuroinflammation and concomitant secondary injury.

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The Link Between Traumatic Brain Injury and Neurodegenerative Diseases

Neurotrauma ◽

10.1093/med/9780190279431.003.0016 ◽

2018 ◽

pp. 165-180

Author(s):

Richard Rubenstein

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurodegenerative Diseases ◽

Clinical Symptoms ◽

Chronic Traumatic Encephalopathy ◽

Closed Head Injury ◽

Secondary Injury ◽

The Central Nervous System ◽

Physical Impact ◽

Primary Injury

Traumatic brain injury (TBI) is a physical impact to the head usually in the form of a single or repetitive closed head injury. TBI is classified as mild, moderate, and severe based on neurological assessment which may include neuroimaging. TBI is a heterogeneous injury, with most cases being mild and difficult to diagnose. TBI can be separated into a primary injury and secondary injury. Primary injury is a result of the physical head impact, whereas secondary injury can occur as long as months to years later and is the result of pathophysiological changes in the central nervous system. TBI is considered a risk factor for chronic neurodegenerative diseases (Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, chronic traumatic encephalopathy) in spite of each disease having unique clinical symptoms, pathologies, and specific discriminating proteins. To date, little is known about the pathological changes responsible for linking TBI to neurodegenerative diseases.

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