Metabolic disorders on cognitive dysfunction after traumatic brain injury

Lai, Jinqing; Shi, Yan‐Chuan; Lin, Shu; Chen, Xiangrong

doi:10.1016/j.tem.2022.04.003

Cited by 42 publications

(21 citation statements)

References 96 publications

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“…Most patients with TBI exhibit long-term memory and attention deficits, depression, and fatigue. As mortality rates have declined for severe TBI, attention has focused on the cognitive, affective, and behavioural sequelae of TBI [ 61 – 63 ]. In animal models, learning and memory decline and psychiatric disorders often emerge in the chronic phase after TBI [ 42 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

Jin

Zhang

Wang

et al. 2022

J Neuroinflammation

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Background Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model. Methods Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study. Results The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion. Conclusions Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

Jin

Zhang

Wang

et al. 2022

J Neuroinflammation

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“…Although the mortality of TBI has decreased due to more personalized clinical management and novel neuroprotective medicines, the chronic effect of TBI on the quality of life of patients has not been fully eliminated [ 2 ]. Many TBI survivors suffer from poor cognitive status and behavioral and psychiatric sequelae in their subsequent life, which causes a huge burden on their families and social economics [ 3 ]. The prognosis of TBI patients is not only influenced by the initial brain injury severity but also affected by various complications developed during hospitalizations.…”

Section: Introductionmentioning

confidence: 99%

Initial Serum Magnesium Level Is Associated with Mortality Risk in Traumatic Brain Injury Patients

Wang

2022

Nutrients

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Background: Electrolyte disorder is prevalent in traumatic brain injury (TBI) patients. This study is designed to explore the association between initial serum magnesium levels and mortality of TBI patients. Methods: TBI patients recorded in the Medical Information Mart for Intensive Care-III database were screened for this study. Logistic regression analysis was used to explore risk factors for mortality of included TBI patients. The restricted cubic spline (RCS) was applied to fit the correlation between initial serum magnesium level and mortality of TBI. Results: The 30-day mortality of included TBI patients was 17.0%. Patients with first-tertile and third-tertile serum magnesium levels had higher mortality than those of the second tertile. Univariate regression analysis showed that the serum magnesium level was not associated with mortality. Unadjusted RCS indicated the relationship between serum magnesium level mortality was U-shaped. After adjusting confounding effects, multivariate regression analysis presented that serum magnesium level was positively associated with mortality. Conclusion: TBI patients with abnormally low or high levels of serum magnesium both have a higher incidence of mortality. At the same time, a higher initial serum magnesium level is independently associated with mortality in TBI patients. Physicians should pay attention to the clinical management of TBI patients, especially those with higher serum magnesium levels.

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“…It has been shown that lipid transport and metabolism play an important roles during brain development, hemostasias and injury. [27][28][29] Interestingly, experimental studies showed that the lipid transport protein APOE3, but not APOE4 secreted from astrocytes can protect the integrity of the brain-blood barrier and ameliorate brain injury. 30,31 Products of lipolysis and peroxidation by phospholipid enzymes was shown to mediate brain energy metabolism, mitochondrial damage and neuron ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that lipid transport and metabolism play an important roles during brain development, hemostasias and injury 27–29. Interestingly, experimental studies showed that the lipid transport protein APOE3, but not APOE4 secreted from astrocytes can protect the integrity of the brain–blood barrier and ameliorate brain injury 30,31.…”

Section: Discussionmentioning

confidence: 99%

High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI

Moheimani

et al. 2022

Annals of Surgery

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Objectives: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. Background: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. Methods: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. Results: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). Conclusions: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation.

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Metabolic disorders on cognitive dysfunction after traumatic brain injury

Cited by 42 publications

References 96 publications

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

Initial Serum Magnesium Level Is Associated with Mortality Risk in Traumatic Brain Injury Patients

High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI

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