scholarly journals C-terminal binding proteins 1 and 2 in traumatic brain injury-induced inflammation and their inhibition as an approach for anti-inflammatory treatment

2019 ◽  
Author(s):  
Hong Li ◽  
Caiguo Zhang ◽  
Chunxia Yang ◽  
Melanie Blevins ◽  
David Norris ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Dependent Manner ◽  
Blood Leukocytes ◽  
Cellular Processes ◽  
Transcriptional Coregulators ◽  
The Central Nervous System

AbstractTraumatic brain injury (TBI) induces an acute inflammatory response in the central nervous system that involves both resident and peripheral immune cells. The ensuing chronic neuroinflammation causes cell death and tissue damage and may contribute to neurodegeneration. The molecular mechanisms involved in the maintenance of this chronic inflammation state remain underexplored. C-terminal binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Unexpectedly, we find that the CtBPs can transactivate a common set of proinflammatory genes both in lipopolysaccharide-activated microglia, astrocytes and macrophages, and in a mouse model of the mild form of TBI. We also find that the expression of these genes is markedly enhanced by a single mild injury in both brain and peripheral blood leukocytes in a severity- and time-dependent manner. Moreover, we were able to demonstrate that specific inhibitors of the CtBPs effectively suppress the expression of the CtBP target genes and thus improve neurological outcome in mice receiving single and repeated mild TBIs. This discovery suggests new avenues for therapeutic modulation of the inflammatory response to brain injury.

scholarly journals Histones of Neutrophil Extracellular Traps (NETs) Activate Brain Pericyte via Dectin-1 in Traumatic Brain Injury

2021 ◽  
Author(s):  
Yang-Wuyue Liu ◽  
Jingyu Zhang ◽  
Wanda Bi ◽  
Mi Zhou ◽  
Jiabo Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Molecular Mechanisms ◽  
Promoter Sequence ◽  
Neutrophil Infiltration ◽  
Neutrophil Extracellular Traps ◽  
Immunohistochemical Method ◽  
Dependent Manner ◽  
Extracellular Traps ◽  
Factor C

Abstract BackgroundBlood-brain barrier (BBB) disruption and leukocyte infiltration are two pathological features post traumatic brain injury (TBI). However, the role of circulating leukocytes in BBB disruption and the crosstalk between them are not fully elucidated. Neutrophil is the most abundant circulating cell type that migrates into brain tissue when TBI occurs instantly, while brain pericyte occupies a strategic position between circulating cell and interstitial space in BBB. Understanding their interactions is essential to provide insight into the intrinsic relationship and identify biological targets for TBI treatments. MethodsBy analyzing brain tissues from TBI patients and mouse TBI model through immunohistochemical method and flow cytometry, we build the relationship between neutrophils, neutrophil extracellular traps (NETs) and brain pericyte. The components of NETs-related medium were investigated by proteomics and metabolomics to decipher the factors directly regulating pericytes. The molecular mechanisms were deeply explored by WB/CHIP/RT-PCR in primary brain pericyte/pericyte cell line MBVP treated with NETs-formed medium or specific NETs components. In mice TBI model, we also explored the possible therapeutic approaches for TBI treatment that targeting at the axis of neutrophil-NETs-pericyte. ResultsNETs formation is highly enhanced post TBI, inducing the appearance of CD11b expressing brain pericyte simultaneously. This novel CD11b+ pericyte subset is characterized with increased permeability and pro-inflammatory profiles. Mechanistically, recognition of histones from NETs by Dectin-1 on pericyte contributes to CD11b induction in protein kinase C (PKC)-c-Jun-dependent manner. Transcription factor c-Jun directly binds to the promoter sequence of CD11b to enhance its expression in pericyte, conferring pericyte activation, BBB disruption and aggravated neutrophil infiltration post TBI. Either inhibiting NETs formation by Cl-Amidine or blocking Dectin-1 by Laminarin are both beneficial for decreasing neutrophil infiltration and brain pericyte activation post TBI. ConclusionsThese results unfold that “neutrophil-NETs-pericyte” and “histones-Dectin-1-CD11b” are possible cellular and molecular mechanisms for building connection between BBB damage and neutrophil infiltration. Targeting at NETs formation and Dectin-1 are promising treatments for improving neurological outcomes of TBI patients.

scholarly journals Systems spatiotemporal dynamics of traumatic brain injury at single cell resolution reveals humanin as a therapeutic target

2021 ◽  
Author(s):  
Douglas Arneson ◽  
Guanglin Zhang ◽  
In Sook Ahn ◽  
Zhe Ying ◽  
Graciel Diamante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Frontal Cortex ◽  
Single Cell ◽  
Target Genes ◽  
Expression Patterns ◽  
Brain Regions ◽  
Cellular Heterogeneity ◽  
Blood Leukocytes

Abstract The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24hr) and chronic (7days) phases of mTBI at single cell resolution and demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling identified astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.

scholarly journals Effect of Soluble Complement Receptor-1 on Neutrophil Accumulation after Traumatic Brain Injury in Rats

1995 ◽  
Vol 15 (5) ◽  
pp. 860-864 ◽  
Author(s):  
Susan L. Kaczorowski ◽  
Joanne K. Schiding ◽  
Carol A. Toth ◽  
Patrick M. Kochanek
Keyword(s):  
Traumatic Brain Injury ◽  
Central Nervous System ◽  
Nervous System ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Acute Inflammatory Response ◽  
Complement Receptor ◽  
Neutrophil Accumulation ◽  
The Central Nervous System ◽  
The Brain

As part of the acute inflammatory response, neutrophils accumulate in the central nervous system after injury. Recently, a soluble human recombinant complement receptor (sCR1; BRL 55730; T Cell Sciences, Inc., Cambridge, MA, U.S.A.) has been developed that inhibits the activation of both the classical and the alternative pathways of complement. sCR1 attenuates the effects of the acute inflammatory response in several models of injury outside the central nervous system. The role of complement in traumatic brain injury, however, remains undefined. We hypothesized that treatment with sCR1 would attenuate neutrophil accumulation in the brain after cerebral trauma. Using a randomized, blinded protocol, 18 anesthetized Sprague–Dawley rats were pretreated with sCR1 or saline (control) at both 2 h and 2 min before trauma (weight drop) to the exposed right parietal cortex. A third dose of sCR1 (or saline) was given 6 h after trauma. Coronal brain sections centered on the site of trauma were obtained at 24 h after trauma and analyzed for myeloperoxidase (MPO) activity as a marker of neutrophil accumulation. Complete blood counts with differential were obtained before treatment with sCR1 and at 24 h after trauma. At 24 h after trauma, brain MPO activity was reduced by 41% in sCR1-treated rats compared with control rats [0.1599 ± 0.102 versus 0.27(2 ± 0.178 U/g (mean ± SD); p = 0.02]. The neutrophil count in peripheral blood increased approximately twofold in both groups. Neutrophil accumulation occurring in the brain after trauma is inhibited by sCR1 treatment. This suggests that complement activation is involved in the local inflammatory response to traumatic brain injury and plays an important role in neutrophil accumulation in the injured brain.

scholarly journals Effect of Xenon Treatment on Gene Expression in Brain Tissue after Traumatic Brain Injury in Rats

2021 ◽  
Vol 11 (7) ◽  
pp. 889
Author(s):  
Anton D. Filev ◽  
Denis N. Silachev ◽  
Ivan A. Ryzhkov ◽  
Konstantin N. Lapin ◽  
Anastasiya S. Babkina ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Tissue ◽  
Target Genes ◽  
Neural Function ◽  
Stress Genes ◽  
Expression Of Genes ◽  
Delayed Recovery ◽  
The Brain ◽  
Lower Expression

The overactivation of inflammatory pathways and/or a deficiency of neuroplasticity may result in the delayed recovery of neural function in traumatic brain injury (TBI). A promising approach to protecting the brain tissue in TBI is xenon (Xe) treatment. However, xenon’s mechanisms of action remain poorly clarified. In this study, the early-onset expression of 91 target genes was investigated in the damaged and in the contralateral brain areas (sensorimotor cortex region) 6 and 24 h after injury in a TBI rat model. The expression of genes involved in inflammation, oxidation, antioxidation, neurogenesis and neuroplasticity, apoptosis, DNA repair, autophagy, and mitophagy was assessed. The animals inhaled a gas mixture containing xenon and oxygen (ϕXe = 70%; ϕO2 25–30% 60 min) 15–30 min after TBI. The data showed that, in the contralateral area, xenon treatment induced the expression of stress genes (Irf1, Hmox1, S100A8, and S100A9). In the damaged area, a trend towards lower expression of the inflammatory gene Irf1 was observed. Thus, our results suggest that xenon exerts a mild stressor effect in healthy brain tissue and has a tendency to decrease the inflammation following damage, which might contribute to reducing the damage and activating the early compensatory processes in the brain post-TBI.

scholarly journals Influence of Glutamine on Intestinal Inflammatory Response, Mucosa Structure Alterations and Apoptosis following Traumatic Brain Injury in Rats

2007 ◽  
Vol 35 (5) ◽  
pp. 644-656 ◽  
Author(s):  
D Feng ◽  
W Xu ◽  
G Chen ◽  
C Hang ◽  
H Gao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Intestinal Inflammation ◽  
Glutamine Supplementation ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Tissue Samples ◽  
Weight Drop ◽  
Factor Α

Traumatic brain injury (TBI) can induce a persistent inflammatory response, histopathological changes and apoptosis in the intestine. Glutamine has been shown to reduce bacterial translocation and maintain intestine mucosal integrity, but its effects on the inflammatory response, structural alterations and apoptosis in intestinal mucosa following TBI have not been previously investigated. Using the weight-drop method, a right parietal cortical contusion was induced in rats and, for the next 5 days, they were fed either chow alone or chow mixed with glutamine. Intestinal tissue samples were then removed for analysis. Following TBI, glutamine supplementation was found to: decrease intestinal concentrations of interleukin (IL) −1β, tumour necrosis factor-α (TNF-α) and IL-6; downregulate intercellular adhesion molecule-1 (ICAM-1) expression; attenuate TBI-induced damage to the intestine structure; and reduce apoptosis. These results suggest that post-TBI glutamine administration could suppress intestinal inflammation, protect intestinal mucosal structure and reduce mucosal apoptosis.

scholarly journals Moderate and severe traumatic brain injury: effect of blood alcohol concentration on Glasgow Coma Scale score and relation to computed tomography findings

2015 ◽  
Vol 122 (1) ◽  
pp. 211-218 ◽  
Author(s):  
Nils Petter Rundhaug ◽  
Kent Gøran Moen ◽  
Toril Skandsen ◽  
Kari Schirmer-Mikalsen ◽  
Stine B. Lund ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Injury Severity ◽  
Blood Alcohol Concentration ◽  
Alcohol Concentration ◽  
Dependent Manner ◽  
Blood Alcohol ◽  
Severe Tbi ◽  
Gcs Score ◽  
Dose Dependent

OBJECT The influence of alcohol is assumed to reduce consciousness in patients with traumatic brain injury (TBI), but research findings are divergent. The aim of this investigation was to study the effects of different levels of blood alcohol concentration (BAC) on the Glasgow Coma Scale (GCS) scores in patients with moderate and severe TBI and to relate the findings to brain injury severity based on the admission CT scan. METHODS In this cohort study, 265 patients (age range 16–70 years) who were admitted to St. Olavs University Hospital with moderate and severe TBI during a 7-year period were prospectively registered. Of these, 217 patients (82%) had measured BAC. Effects of 4 BAC groups on GCS score were examined with ordinal logistic regression analyses, and the GCS scores were inverted to give an OR > 1. The Rotterdam CT score based on admission CT scan was used to adjust for brain injury severity (best score 1 and worst score 6) by stratifying patients into 2 brain injury severity groups (Rotterdam CT scores of 1–3 and 4–6). RESULTS Of all patients with measured BAC, 91% had intracranial CT findings and 43% had BAC > 0 mg/dl. The median GCS score was lower in the alcohol-positive patients (6.5, interquartile range [IQR] 4–10) than in the alcohol-negative patients (9, IQR 6–13; p < 0.01). No significant differences were found between alcohol-positive and alcohol-negative patients regarding other injury severity variables. Increasing BAC was a significant predictor of lower GCS score in a dose-dependent manner in age-adjusted analyses, with OR 2.7 (range 1.4–5.0) and 3.2 (range 1.5–6.9) for the 2 highest BAC groups (p < 0.01). Subgroup analyses showed an increasing effect of BAC group on GCS scores in patients with Rotterdam CT scores of 1–3: OR 3.1 (range 1.4–6.6) and 6.7 (range 2.7–16.7) for the 2 highest BAC groups (p < 0.01). No such relationship was found in patients with Rotterdam CT scores of 4–6 (p = 0.14–0.75). CONCLUSIONS Influence of alcohol significantly reduced the GCS score in a dose-dependent manner in patients with moderate and severe TBI and with Rotterdam CT scores of 1–3. In patients with Rotterdam CT scores of 4–6, and therefore more CT findings indicating increased intracranial pressure, the brain injury itself seemed to overrun the depressing effect of the alcohol on the CNS. This finding is in agreement with the assumption of many clinicians in the emergency situation.

Novel Synthetic and Natural Therapies for Traumatic Brain Injury

2021 ◽  
Vol 19 ◽  
Author(s):  
Denise Battaglini ◽  
Dorota Siwicka-Gieroba ◽  
Patricia RM Rocco ◽  
Fernanda Ferreira Cruz ◽  
Pedro Leme Silva ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Damage ◽  
Molecular Mechanisms ◽  
Antioxidant Properties ◽  
Secondary Brain Injury ◽  
Specific Recommendation ◽  
Novel Therapies ◽  
Secondary Brain Damage ◽  
Late Treatment

: Traumatic brain injury (TBI) is a major cause of disability and death worldwide. The initial mechanical insult results in tissue and vascular disruption with hemorrhages and cellular necrosis that is followed by a dynamic secondary brain damage that presumably results in additional destruction of the brain. In order to minimize deleterious consequences of the secondary brain damage-such as inflammation, bleeding or reduced oxygen supply. The old concept of the -staircase approach- has been updated in recent years by most guidelines and should be followed as it is considered the only validated approach for the treatment of TBI. Besides, a variety of novel therapies have been proposed as neuroprotectants. The molecular mechanisms of each drug involved in inhibition of secondary brain injury can result as potential target for the early and late treatment of TBI. However, no specific recommendation is available on their use in clinical setting. The administration of both synthetic and natural compounds, which act on specific pathways involved in the destructive processes after TBI, even if usually employed for the treatment of other diseases, can show potential benefits. This review represents a massive effort towards current and novel therapies for TBI that have been investigated in both pre-clinical and clinical settings. This review aims to summarize the advancement in therapeutic strategies basing on specific and distinct -target of therapies-: brain edema, ICP control, neuronal activity and plasticity, anti-inflammatory and immunomodulatory effects, cerebral autoregulation, antioxidant properties, and future perspectives with the adoption of mesenchymal stromal cells.

Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury

2021 ◽  
Vol 28 ◽  
Author(s):  
Lucas Alexandre Santos Marzano ◽  
Fabyolla Lúcia Macedo de Castro ◽  
Caroline Amaral Machado ◽  
João Luís Vieira Monteiro de Barros ◽  
Thiago Macedo e Cordeiro ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Cognitive Outcomes ◽  
Adult Hippocampal Neurogenesis ◽  
The Brain

: Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

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