scholarly journals Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuhua Chen ◽  
Kai Gong ◽  
Limin Guo ◽  
Bingchang Zhang ◽  
Sifang Chen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Physiological Mechanism ◽  
Neurological Deficits ◽  
Phosphoglycerate Mutase ◽  
Inflammasome Activation ◽  
Secondary Brain Injury

AbstractTraumatic brain injury (TBI) is considered as the most common cause of disability and death, and therefore an effective intervention of cascade pathology of secondary brain injury promptly can be a potential therapeutic direction for TBI prognosis. Further study of the physiological mechanism of TBI is urgent and important. Phosphoglycerate mutase 5 (Pgam5), a mitochondrial protein, mediate mitochondrial homeostasis, cellular senescence, and necroptosis. This study evaluated the effects of Pgam5 on neurological deficits and neuroinflammation of controlled cortical impact-induced TBI mouse model in vivo and LPS + ATP-induced microglia model in vitro. Pgam5 was overexpressed post-TBI. Pgam5 depletion reduced pyroptosis-related molecules and improved microglia activation, neuron damage, tissue lesion, and neurological dysfunctions in TBI mice. RNA-seq analysis and molecular biology experiments demonstrated that Pgam5 might regulate inflammatory responses by affecting the post-translational modification and protein expression of related genes, including Nlrp3, caspase1, Gsdmd, and Il-1β. In microglia, Pgam5-sh abrogated LPS + ATP-induced Il-1β secretion through Asc oligomerization-mediated caspase-1 activation, which was independent of Rip3. The data demonstrate the critical role Pgam5 plays in nerve injury in the progression of TBI, which regulates Asc polymerization and subsequently caspase1 activation, and thus reveals a fundamental mechanism linking microglial inflammasome activation to Asc/caspase1-generated Il-1β-mediated neuroinflammation. Thus, our data indicate Pgam5 worsens physiological and neurological outcomes post-TBI, which may be a potential therapeutic target to improve neuroinflammation after TBI.

scholarly journals Human Lung Cell Pyroptosis Following Traumatic Brain Injury

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 69 ◽  
Author(s):  
Nadine Kerr ◽  
Juan de Rivero Vaccari ◽  
Oliver Umland ◽  
M. Bullock ◽  
Gregory Conner ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Endothelial Cell ◽  
Brain Injury ◽  
Lung Injury ◽  
Critical Role ◽  
Gunshot Wounds ◽  
Extracellular Vesicle ◽  
Inflammasome Activation ◽  
Trauma Patients ◽  
Severe Tbi

Approximately 30% of traumatic brain injured patients suffer from acute lung injury or acute respiratory distress syndrome. Our previous work revealed that extracellular vesicle (EV)-mediated inflammasome signaling plays a crucial role in the pathophysiology of traumatic brain injury (TBI)-induced lung injury. Here, serum-derived EVs from severe TBI patients were analyzed for particle size, concentration, origin, and levels of the inflammasome component, an apoptosis-associated speck-like protein containing a caspase-recruiting domain (ASC). Serum ASC levels were analyzed from EV obtained from patients that presented lung injury after TBI and compared them to EV obtained from patients that did not show any signs of lung injury. EVs were co-cultured with lung human microvascular endothelial cells (HMVEC-L) to evaluate inflammasome activation and endothelial cell pyroptosis. TBI patients had a significant increase in the number of serum-derived EVs and levels of ASC. Severe TBI patients with lung injury had a significantly higher level of ASC in serum and serum-derived EVs compared to individuals without lung injury. Only EVs isolated from head trauma patients with gunshot wounds were of neural origin. Delivery of serum-derived EVs to HMVEC-L activated the inflammasome and resulted in endothelial cell pyroptosis. Thus, serum-derived EVs and inflammasome proteins play a critical role in the pathogenesis of TBI-induced lung injury, supporting activation of an EV-mediated neural-respiratory inflammasome axis in TBI-induced lung injury.

Vagus Nerve Stimulation Attenuates Early Traumatic Brain Injury by Regulating the NF-κB/NLRP3 Signaling Pathway

2020 ◽  
Vol 34 (9) ◽  
pp. 831-843
Author(s):  
Yunliang Tang ◽  
Xiaoyang Dong ◽  
Gengfa Chen ◽  
Wen Ye ◽  
Junwei Kang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Vagus Nerve ◽  
Signaling Pathway ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Critical Role ◽  
Neurological Deficits ◽  
Receptor Protein

Background Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Oxidative stress, inflammation, and apoptosis are vital pathophysiological features post-TBI. Objectives Research has shown that vagus nerve stimulation (VNS) can attenuate oxidative stress in various diseases. However, the critical role of VNS in TBI is still not completely understood. This study investigated the protective effects and potential mechanism of VNS on TBI. Methods Male Sprague-Dawley rats were randomized into 3 groups: sham, TBI, and TBI + VNS. The TBI model was induced in rats by the free-fall drop method. The vagal nerve trunk was separated, and VNS was performed after establishing the TBI model. Results The results showed that VNS significantly ameliorated tissue damage, neurological deficits, and cerebral edema, compared with the sham VNS group. Additionally, VNS alleviated oxidative stress, inflammation, and apoptosis in the pericontusive cortex of rats after TBI. VNS also significantly suppressed expression of the nuclear factor-κB (NF-κB) protein in the nucleus and activation of the nucleotide-binding domain–like receptor protein 3 (NLRP3) inflammasome. Conclusions Taken together, the present study indicates that VNS may attenuate brain damage after TBI by inhibiting oxidative stress, inflammation, and apoptosis, possibly through the NF-κB/NLRP3 signaling pathway.

scholarly journals Adenosine A3 receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Susan A. Farr ◽  
Salvatore Cuzzocrea ◽  
Emanuela Esposito ◽  
Michela Campolo ◽  
Michael L. Niehoff ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Tissue Injury ◽  
Pathological Condition ◽  
Brain Infarction ◽  
Inflammasome Activation ◽  
Secondary Brain Injury ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Secondary Tissue

Abstract Background Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A3 adenosine receptor (A3AR) can provide antiinflammatory and neuroprotective effects. However, the role of A3AR in TBI has not been investigated. Methods Using the selective A3AR agonist, MRS5980, we evaluated the effects of A3AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. Results When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4+ and CD8+ T cell influx. Moreover, when measured 4–5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. Conclusion Our results provide support for the beneficial effects of small molecule A3AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.

scholarly journals SS-31 Provides Neuroprotection by Reversing Mitochondrial Dysfunction after Traumatic Brain Injury

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yihao Zhu ◽  
Handong Wang ◽  
Jiang Fang ◽  
Wei Dai ◽  
Jiang Zhou ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Nuclear Translocation ◽  
Neurological Diseases ◽  
Neurological Deficits ◽  
Secondary Brain Injury ◽  
Neuroprotective Effects ◽  
Weight Drop ◽  
Ros Scavenger

SS-31, a novel mitochondria-targeted peptide, has been proven to provide neuroprotection in a variety of neurological diseases. Its role as a mitochondrial reactive oxygen species (ROS) scavenger and the underlying pathophysiological mechanisms in traumatic brain injury (TBI) are still not well understood. The aim of the designed study was to investigate the potential neuroprotective effects of SS-31 and fulfill our understanding of the process of the mitochondrial change in the modified Marmarou weight-drop model of TBI. Mice were randomly divided into sham, TBI, TBI + vehicle, and TBI + SS-31 groups in this study. Peptide SS-31 (5 mg/kg) or vehicle was intraperitoneally administrated 30 min after TBI with brain samples harvested 24 h later for further analysis. SS-31 treatment significantly reversed mitochondrial dysfunction and ameliorated secondary brain injury caused by TBI. SS-31 can directly decrease the ROS content, restore the activity of superoxide dismutase (SOD), and decrease the level of malondialdehyde (MDA) and the release of cytochrome c, thus attenuating neurological deficits, brain water content, DNA damage, and neural apoptosis. Moreover, SS-31 restored the expression of SIRT1 and upregulated the nuclear translocation of PGC-1α, which were proved by Western blot and immunohistochemistry. Taken together, these data demonstrate that SS-31 improves the mitochondrial function and provides neuroprotection in mice after TBI potentially through enhanced mitochondrial rebiogenesis. The present study gives us an implication for further clinical research.

scholarly journals Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 199
Author(s):  
Ryan D. Readnower ◽  
William Brad Hubbard ◽  
Olivia J. Kalimon ◽  
James W. Geddes ◽  
Patrick G. Sullivan
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Critical Role ◽  
Neurological Deficits ◽  
Cyclophilin D ◽  
Cortical Tissue ◽  
Post Injury ◽  
Mptp Opening

Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI.

Optimising the management of severe Traumatic Brain Injury in the military maritime environment

2014 ◽  
Vol 100 (3) ◽  
pp. 293-300
Author(s):  
IA Edgar ◽  
G Hadjipavlou ◽  
JE Smith
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Severe Traumatic Brain Injury ◽  
Healthcare Systems ◽  
Secondary Brain Injury ◽  
Eye Protection ◽  
Alternative Approaches ◽  
The Military ◽  
Primary Injury ◽  
Maritime Environment

AbstractSevere Traumatic Brain Injury (sTBI) is a devastating cause of morbidity and mortality, especially among those aged less than 45 years. Advances in clinical practice continue to focus on preventing primary injury through developing ballistic head and eye protection, and through minimising secondary brain injury (secondary prevention).Managing sTBI is challenging in well-developed, well-resourced healthcare systems. Achieving management aims in the military maritime environment poses even greater challenges.Strategies for the management of sTBI in the maritime environment should be in keeping with current best evidence. Provision of specialist interventions for sTBI in military maritime environments may require alternative approaches matched to the skills of the staff and environmental restrictions.

scholarly journals Rhein Protects Against Neurological Deficits After Traumatic Brain Injury in Mice via Inhibiting Neuronal Pyroptosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fangfang Bi ◽  
Huaifen Ma ◽  
Chen Ji ◽  
Cuicui Chang ◽  
Wenbo Liu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurological Deficits

scholarly journals 217 The end-tidal and arterial carbon dioxide gradient in serious traumatic brain injury after pre-hospital emergency anaesthesia: a retrospective observational study

2020 ◽  
Vol 37 (12) ◽  
pp. 847.1-847
Author(s):  
James Price ◽  
Daniel Sandbach ◽  
Ari Ercole ◽  
Alastair Wilson ◽  
Ed Barnard
Keyword(s):  
Carbon Dioxide ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Thoracic Injury ◽  
Secondary Brain Injury ◽  
Hospital Emergency ◽  
Hospital Arrival ◽  
Arterial Blood ◽  
End Tidal ◽  
Emergency Anaesthesia

Aims/Objectives/BackgroundIn the United Kingdom (UK), 20% of patients with severe traumatic brain injury (TBI) receive pre-hospital emergency anaesthesia (PHEA). Current guidance recommends an end-tidal carbon dioxide (ETCO2) of 4.0–4.5kPa to achieve a low-normal arterial partial pressure of CO2 (PaCO2), and reduce secondary brain injury. This recommendation assumes a 0.5kPa ETCO2-PaCO2 gradient. However, the gradient in the acute phase of TBI is unknown. Our primary aim was to report the ETCO2-PaCO2 gradient of TBI patients at hospital arrival.Methods/DesignA retrospective cohort study of adult patients with serious TBI, who received a PHEA by a pre-hospital critical care team in the East of England between 1st April 2015 to 31st December 2017. Linear regression was performed to test for correlation and reported as R-squared (R2). A Bland-Altman plot was used to test for paired ETCO2 and PaCO2 agreement and reported with 95% confidence intervals (95%CI). ETCO2-PaCO2 gradient data were compared with a two-tailed, unpaired, t-test.Results/Conclusions107 patients were eligible for inclusion. Sixty-seven patients did not receive a PaCO2 sample within 30 minutes of hospital arrival and were therefore excluded. Forty patients had complete data and were included in the final analysis; per protocol.The mean ETCO2-PaCO2 gradient was 1.7 (±1.0) kPa, with only moderate correlation of ETCO2 and PaCO2 at hospital arrival (R2=0.23, p=0.002). The Bland-Altman bias was 1.7 (95%CI 1.4–2.0) kPa with upper and lower limits of agreement of 3.6 (95%CI 3.0–4.1) kPa and -0.2 (95%CI -0.8–0.3) kPa respectively. There was no significant gradient correlation in patients with a co-existing serious thoracic injury (R2=0.13, p=0.10), and this cohort had a larger ETCO2-PaCO2 gradient, 2.0 (±1.1) kPa, p=0.01. Patients who underwent pre-hospital arterial blood sampling had an arrival PaCO2 of 4.7 (±0.2) kPa.Lower ETCO2 targets than previously recommended may be safe and appropriate. The use of pre-hospital PaCO2 measurement is advocated.

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.

Severe Traumatic Brain Injury

2018 ◽  
Author(s):  
Ryan Martin ◽  
Lara Zimmermann ◽  
Kee D. Kim ◽  
Marike Zwienenberg ◽  
Kiarash Shahlaie
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Intracranial Pressure ◽  
Severe Traumatic Brain Injury ◽  
Neurocritical Care ◽  
Secondary Brain Injury ◽  
Brain Oxygenation ◽  
Barbiturate Coma ◽  
Blast Traumatic Brain Injury ◽  
Penetrating Traumatic Brain Injury

Traumatic brain injury remains a leading cause of death and disability worldwide. Patients with severe traumatic brain injury are best treated with a multidisciplinary, evidence-based, protocol-directed approach, which has been shown to decrease mortality and improve functional outcomes. Therapy is directed at the prevention of secondary brain injury through optimizing cerebral blood flow and the delivery of metabolic fuel (ie, oxygen and glucose). This is accomplished through the measurement and treatment of elevated intracranial pressure (ICP), the strict avoidance of hypotension and hypoxemia, and in some instances, surgical management. The treatment of elevated ICP is approached in a protocolized, tiered manner, with escalation of care occurring in the setting of refractory intracranial hypertension, culminating in either decompressive surgery or barbiturate coma. With such an approach, the rates of mortality secondary to traumatic brain injury are declining despite an increasing incidence of traumatic brain injury. This review contains 3 figures, 5 tables and 69 reference Key Words: blast traumatic brain injury, brain oxygenation, cerebral perfusion pressure, decompressive craniectomy, hyperosmolar therapy, intracranial pressure, neurocritical care, penetrating traumatic brain injury, severe traumatic brain injury

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