scholarly journals HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Si-Wei Tan ◽  
Yan Zhao ◽  
Ping Li ◽  
Ya-Lei Ning ◽  
Zhi-Zhong Huang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cognitive Impairment ◽  
Brain Injury ◽  
Nlrp3 Inflammasome ◽  
Late Stage ◽  
Long Term Potentiation ◽  
Neuronal Cultures ◽  
Inflammasome Activation ◽  
Post Injury

Abstract Background Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4–8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear. Methods Mice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI. Levels of NLRP3 inflammasome and inflammatory factors such as IL-1β and HMGB1 were detected in post-injury hippocampal tissue, as well as long-term potentiation. Behaviors were assessed by T-maze test, novel object recognition, and nesting tests. Glycyrrhizin was used to antagonize HMGB1. Calcium imaging were performed on primary neuronal cultures. Results By using the NLRP3-knockout TBI model, we found that the continuous activation of the NLRP3 inflammasome and high mobility group box 1 (HMGB1) release were closely related to cognitive impairment. We also found that inhibition of HMGB1 improved LTP reduction and cognitive function by increasing the phosphorylation level of the NMDAR1 subunit at serine 896 while reducing NLRP3 inflammasome activation. Conclusion NLRP3 inflammasome damages memory in the late stage of TBI primarily through HMGB1 upregulation and provides an explanation for the long-term progression of cognitive dysfunction.

Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release

2018 ◽  
Vol 119 (1) ◽  
pp. 305-311 ◽  
Author(s):  
Wei Chen ◽  
Yijun Guo ◽  
Wenjin Yang ◽  
Lei Chen ◽  
Dabin Ren ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Gap Junction ◽  
Connexin 43 ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Cx43 Expression ◽  
Term Potentiation ◽  
Junction Protein

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using Western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results imply that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release. NEW & NOTEWORTHY We have demonstrated in rat traumatic brain injury (TBI) models that both phosphorylated connexin 43 (p-Cx43) expression and exosome release were elevated in the hippocampus following TBI. The promoted exosome release depends on the phosphorylation of Cx43 and requires ERK signaling activation. Exosome treatment could partially restore the attenuated long-term potentiation. Our results provide new insight for future therapeutic direction on the functional recovery of TBI by promoting p-Cx43-dependent exosome release but limiting the gap junction-mediated bystander effect.

scholarly journals Long-Term Survival Following Traumatic Brain Injury: A Population-Based Parametric Survival Analysis

2016 ◽  
Vol 47 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Gordon W. Fuller ◽  
Jeanine Ransom ◽  
Jay Mandrekar ◽  
Allen W. Brown
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
General Population ◽  
Life Expectancy ◽  
Health Planning ◽  
Population Based ◽  
Post Injury ◽  
Term Survival ◽  
Parametric Survival

Background: Long-term mortality may be increased following traumatic brain injury (TBI); however, the degree to which survival could be reduced is unknown. We aimed at modelling life expectancy following post-acute TBI to provide predictions of longevity and quantify differences in survivorship with the general population. Methods: A population-based retrospective cohort study using data from the Rochester Epidemiology Project (REP) was performed. A random sample of patients from Olmsted County, Minnesota with a confirmed TBI between 1987 and 2000 was identified and vital status determined in 2013. Parametric survival modelling was then used to develop a model to predict life expectancy following TBI conditional on age at injury. Survivorship following TBI was also compared with the general population and age- and gender-matched non-head injured REP controls. Results: Seven hundred and sixty nine patients were included in complete case analyses. The median follow-up time was 16.1 years (interquartile range 9.0-20.4) with 120 deaths occurring in the cohort during the study period. Survival after acute TBI was well represented by a Gompertz distribution. Victims of TBI surviving for at least 6 months post-injury demonstrated a much higher ongoing mortality rate compared to the US general population and non-TBI controls (hazard ratio 1.47, 95% CI 1.15-1.87). US general population cohort life table data was used to update the Gompertz model's shape and scale parameters to account for cohort effects and allow prediction of life expectancy in contemporary TBI. Conclusions: Survivors of TBI have decreased life expectancy compared to the general population. This may be secondary to the head injury itself or result from patient characteristics associated with both the propensity for TBI and increased early mortality. Post-TBI life expectancy estimates may be useful to guide prognosis, in public health planning, for actuarial applications and in the extrapolation of outcomes for TBI economic models.

scholarly journals Exosomal MicroRNA Differential Expression in Plasma of Young Adults with Chronic Mild Traumatic Brain Injury and Healthy Control

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 36
Author(s):  
Rany Vorn ◽  
Maiko Suarez ◽  
Jacob C. White ◽  
Carina A. Martin ◽  
Hyung-Suk Kim ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Young Adults ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Pathophysiological Mechanism ◽  
Post Injury ◽  
Persistent Symptoms ◽  
Healthy Control ◽  
Underlying Mechanisms

Chronic mild traumatic brain injury (mTBI) has long-term consequences, such as neurological disability, but its pathophysiological mechanism is unknown. Exosomal microRNAs (exomiRNAs) may be important mediators of molecular and cellular changes involved in persistent symptoms after mTBI. We profiled exosomal microRNAs (exomiRNAs) in plasma from young adults with or without a chronic mTBI to decipher the underlying mechanisms of its long-lasting symptoms after mTBI. We identified 25 significantly dysregulated exomiRNAs in the chronic mTBI group (n = 29, with 4.48 mean years since the last injury) compared to controls (n = 11). These miRNAs are associated with pathways of neurological disease, organismal injury and abnormalities, and psychological disease. Dysregulation of these plasma exomiRNAs in chronic mTBI may indicate that neuronal inflammation can last long after the injury and result in enduring and persistent post-injury symptoms. These findings are useful for diagnosing and treating chronic mTBIs.

scholarly journals Proteasome and Autophagy-Mediated Impairment of Late Long-Term Potentiation (l-LTP) after Traumatic Brain Injury in the Somatosensory Cortex of Mice

2019 ◽  
Vol 20 (12) ◽  
pp. 3048 ◽  
Author(s):  
Feldmann ◽  
Le Prieult ◽  
Felzen ◽  
Thal ◽  
Engelhard ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Protein Degradation ◽  
Long Term Potentiation ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Ipsilateral Hemisphere ◽  
Term Potentiation ◽  
Theta Burst

Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation.The acute phase (24–48 h) after TBI is often characterized by neural dysfunction in the vicinity ofthe lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is crucialfor synaptic long-term plasticity including the protein degradation systems, proteasome andautophagy. Still, little is known about the acute effects of TBI on synaptic long-term plasticity andprotein degradation. Thus, we investigated TBI in a controlled cortical impact (CCI) model in themotor and somatosensory cortex of mice ex vivo-in vitro. Late long-term potentiation (l-LTP) wasinduced by theta-burst stimulation in acute brain slices after survival times of 1–2 days. Proteinlevels for the plasticity related protein calcium/calmodulin-dependent protein kinase II (CaMKII)was quantified by Western blots, and the protein degradation activity by enzymatical assays. Weobserved missing maintenance of l-LTP in the ipsilateral hemisphere, however not in thecontralateral hemisphere after TBI. Protein levels of CaMKII were not changed but, interestingly,the protein degradation revealed bidirectional changes with a reduced proteasome activity and anincreased autophagic flux in the ipsilateral hemisphere. Finally, LTP recordings in the presence ofpharmacologically modified protein degradation systems also led to an impaired synaptic plasticity:bath-applied MG132, a proteasome inhibitor, or rapamycin, an activator of autophagy, bothadministered during theta burst stimulation, blocked the induction of LTP. These data indicate thatalterations in protein degradation pathways likely contribute to cognitive deficits in the acute phaseafter TBI, which could be interesting for future approaches towards neuroprotective treatmentsearly after traumatic brain injury.

scholarly journals Outcomes after Complicated and Uncomplicated Mild Traumatic Brain Injury at Three-and Six-Months Post-Injury: Results from the CENTER-TBI Study

2020 ◽  
Vol 9 (5) ◽  
pp. 1525 ◽  
Author(s):  
Daphne C. Voormolen ◽  
Marina Zeldovich ◽  
Juanita A. Haagsma ◽  
Suzanne Polinder ◽  
Sarah Friedrich ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Functional Outcome ◽  
Mild Traumatic Brain Injury ◽  
Intracranial Injury ◽  
Post Injury ◽  
Long Term Outcome ◽  
Sf 36 ◽  
Disease Specific

The objective of this study was to provide a comprehensive examination of the relation of complicated and uncomplicated mild traumatic brain injury (mTBI) with multidimensional outcomes at three- and six-months after TBI. We analyzed data from the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) research project. Patients after mTBI (Glasgow Coma scale (GCS) score of 13–15) enrolled in the study were differentiated into two groups based on computed tomography (CT) findings: complicated mTBI (presence of any traumatic intracranial injury on first CT) and uncomplicated mTBI (absence of any traumatic intracranial injury on first CT). Multidimensional outcomes were assessed using seven instruments measuring generic and disease-specific health-related quality of life (HRQoL) (SF-36 and QOLIBRI), functional outcome (GOSE), and psycho-social domains including symptoms of post-traumatic stress disorder (PTSD) (PCL-5), depression (PHQ-9), and anxiety (GAD-7). Data were analyzed using a multivariate repeated measures approach (MANOVA-RM), which inspected mTBI groups at three- and six-months post injury. Patients after complicated mTBI had significantly lower GOSE scores, reported lower physical and mental component summary scores based on the SF-36 version 2, and showed significantly lower HRQoL measured by QOLIBRI compared to those after uncomplicated mTBI. There was no difference between mTBI groups when looking at psychological outcomes, however, a slight improvement in PTSD symptoms and depression was observed for the entire sample from three to six months. Patients after complicated mTBI reported lower generic and disease specific HRQoL and worse functional outcome compared to individuals after uncomplicated mTBI at three and six months. Both groups showed a tendency to improve from three to six months after TBI. The complicated mTBI group included more patients with an impaired long-term outcome than the uncomplicated group. Nevertheless, patients, clinicians, researchers, and decisions-makers in health care should take account of the short and long-term impact on outcome for patients after both uncomplicated and complicated mTBI.

Links Between Mild Traumatic Brain Injury, Cognitive Impairment and Social Inference Four Years Post-Injury

2018 ◽  
Vol 99 (11) ◽  
pp. e140
Author(s):  
Alice Theadom ◽  
Kelly Jones ◽  
Nicola Starkey ◽  
Skye McDonald ◽  
Suzanne Barker-Collo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cognitive Impairment ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Post Injury ◽  
Social Inference

TP2-3 Long-term survival and five year hospital resource usage following traumatic brain injury in scotland from 1997–2015: a population-based retrospective cohort study

2019 ◽  
Vol 90 (3) ◽  
pp. e14.2-e14
Author(s):  
JJM Loan ◽  
NW Scott ◽  
JO Jansen
Keyword(s):  
Traumatic Brain Injury ◽  
Cohort Study ◽  
Brain Injury ◽  
Population Based ◽  
Resource Usage ◽  
Hospital Resource ◽  
Post Injury ◽  
Term Survival ◽  
Long Term Survival

AimTo determine if survival and hospital resource usage differ following traumatic brain injury (TBI) compared with head injury without neurological injury(HI).MethodsThis retrospective population-based cohort study included all 25 319 patients admitted to a Scottish NHS hospital from 1997–2015 with TBI. Participants were identified using previously validated ICD-10 based definitions. For comparison, all 194 049 HI cases were identified. Our main outcome measures were hazards of all-cause mortality after TBI, compared with HI, over 18 years follow-up period; and odds of mortality at one month post-injury. Number of days spent as inpatients and number of outpatient attendances per surviving month post-injury were used as measures of resource utilisation.ResultsThe adjusted odds ratio for mortality in the first month post-injury for TBI was 7.12 (95% confidence interval [CI] 6.73–7.52; p<0.001). For the remaining 18 year study period, the hazards of morality after TBI were 0.93 (CI 0.90–0.96; p<0.001). TBI was associated with 2.15 (CI 2.10–2.20; p<0.001) more days spent as inpatient and 1.09 times more outpatient attendances (CI 1.07–1.11; p<0.001) than HI.ConclusionsAlthough initial mortality following TBI is high, survivors of the first month can achieve comparable long-term survival to HI. However this is associated with increased utilisation of hospital services in the TBI group.

scholarly journals NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Merry W. Ma ◽  
Jing Wang ◽  
Krishnan M. Dhandapani ◽  
Darrell W. Brann
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Nlrp3 Inflammasome ◽  
Healing Process ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Nadph Oxidase 2

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1β (IL-1β), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.

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