Traumatic Brain Injury Altered Normal Brain Signaling Pathways: Implications for Novel Therapeutics Approaches

Rana, Arti; Singh, Shamsher; Sharma, Ruchika; Kumar, Anoop

doi:10.2174/1570159x16666180911121847

Cited by 26 publications

(16 citation statements)

References 97 publications

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“…3,4 Primary injury due to initial impact is the main factor determining TBI prognosis, whereas secondary injury, which is triggered by primary injury, the results from neurochemical processes and intracellular signaling pathways, such as oxidative stress, inflammatory response, neuronal apoptosis and other detrimental factors, which aggravate brain primary injury after TBI. 5 Therefore, alleviating secondary injury by intervening in neurochemical processes and intracellular signaling pathways is very important in the treatment of TBI.…”

Section: Introductionmentioning

confidence: 99%

<p>Antiapoptotic and Anti-Inflammatory Effects of CPCGI in Rats with Traumatic Brain Injury</p>

Niu¹,

Ke²,

Qi³

et al. 2020

NDT

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Section: Introductionmentioning

confidence: 99%

<p>Antiapoptotic and Anti-Inflammatory Effects of CPCGI in Rats with Traumatic Brain Injury</p>

Niu¹,

Ke²,

Qi³

et al. 2020

NDT

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“…On the other hand, the mammalian target of rapamycin (mTOR) pathway plays an important role in a variety of physiological functions of the nervous system, such as nerve cell growth, survival, development of dendritic cells during differentiation, and synaptic plasticity (Don et al, 2012 ). Some studies have shown that mTOR inhibition prevents neuronal injury and death after TBI, while others have shown that increased mTOR signaling after injury promotes cell regeneration and functional recovery (Rana et al, 2019 ). The occurrence of mitochondrial autophagy has been reported after TBI and is a powerful target (Chu et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Signature of Traumatic Brain Injury

Liu

Ruan

et al. 2021

Front. Genet.

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Background: Traumatic brain injury (TBI) is a brain function change caused by external forces, which is one of the main causes of death and disability worldwide. The aim of this study was to identify early diagnostic markers and potential therapeutic targets for TBI.Methods: Differences between TBI and controls in GSE89866 and GSE104687 were analyzed. The two groups of differentially expressed genes (DEGs) were combined for coexpression analysis, and the modules of interest were performed using enrichment analysis. Hub genes were identified by calculating area under curve (AUC) values of module genes, PPI network analysis, and functional similarity. Finally, the difference in immune cell infiltration between TBI and control was calculated by ssGSEA.Results: A total of 4,817 DEGs were identified in GSE89866 and 1,329 DEGs in GSE104687. They were clustered into nine modules. The genes of modules 1, 4, and 7 had the most crosstalk and were identified as important modules. Enrichment analysis revealed that they were mainly associated with neurodevelopment and immune inflammation. In the PPI network constructed by genes with top 50 AUC values in module genes, we identified the top 10 genes with the greatest connectivity. Among them, down-regulated RPL27, RPS4X, RPL23A, RPS15A, and RPL7A had similar functions and were identified as hub genes. In addition, DC and Tem were significantly up-regulated and down-regulated between TBI and control, respectively.Conclusion: We found that hub genes may have a diagnostic role for TBI. Molecular dysregulation mechanisms of TBI are associated with neurological and immune inflammation. These results may provide new ideas for the diagnosis and treatment of TBI.

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“…TBI causes multiple functional de cits in the brain, such as sensory, motor, and cognitive functions, which related to the damaged regions [2]. Neurons and glial cells in damaged tissue release excessive glutamate leading to excitatory toxicity; energy metabolism disorder results in ATP depletion, mitochondrial dysfunction, oxidative stress, and other events leading to neuron death [3][4][5][6]. Besides, in ammatory mediators produced by damaged cells recruit cerebral microglia and peripheral immune cells which release in ammatory factors, thus promoting secondary neuronal damage [7].…”

Section: Introductionmentioning

confidence: 99%

Cordycepin Confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

Wei

Huang

Luo

et al. 2021

Preprint

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Background Traumatic brain injury (TBI) secondary injury, especially white matter injury (WMI), is highly sensitive to neuroinflammation, which further leads to unfavored long-term outcomes. Although the cross-talk between the three active events, immune cell infiltration, BBB breakdown, and proinflammatory microglial/macrophage polarization, play a role in the vicious cycle, its mechanisms are not fully understood. It has been reported that cordycepin, an extract from cordyceps militaris, can inhibit TBI-induced neuroinflammation although the long-term effects of cordycepin remain unknown. Here, we report our investigation of cordycepin’s long-term neuroprotective function and its underlying immunological mechanism. Methods TBI mice model was established with a controlled cortical impact (CCI) method. Cordycepin was intraperitoneally administered twice daily for a week. Neurological outcomes were assessed by behavioral tests, including grid walking test, cylinder test, wire hang test, and rotarod test. Immunofluorescence staining, transmission electron microscopy, and electrophysiology recording were employed to assess histological and functional lesions. Quantitative-PCR and flow cytometry were used to detect neuroinflammation. The tracers of Sulfo-NHS-biotin and Evans blue were assessed for the Blood-brain barrier (BBB) leakage. Western blot and gelatin zymography were used to analyze protein activity or expression. Neutrophil depletion in vivo was performed via using Ly6G antibody intraperitoneal injection. Results Cordycepin administration ameliorated long-term neurological deficits and reduced neuronal tissue loss in TBI mice. Meanwhile, the long-term integrity of white matter was also preserved, which was revealed in multiple dimensions, such as morphology, histology, ultrastructure, and electrical conductivity. Cordycepin administration inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization after TBI. BBB breach was attenuated by cordycepin administration at 3d after TBI. Cordycepin suppressed the activities of MMP-2 and MMP-9 and the neutrophil infiltration at 3d after TBI. Moreover, neutrophil depletion provided a cordycepin-like effect, and cordycepin administration united with neutrophil depletion didn’t show a benefit of superposition. Conclusions The long-term neuroprotective function of cordycepin was via suppressing neutrophil infiltration, thereby preserving BBB integrity and changing microglia/macrophage polarization. These findings provide significant clinical potentials to improve the quality of life for TBI patients.

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Traumatic Brain Injury Altered Normal Brain Signaling Pathways: Implications for Novel Therapeutics Approaches

Cited by 26 publications

References 97 publications

<p>Antiapoptotic and Anti-Inflammatory Effects of CPCGI in Rats with Traumatic Brain Injury</p>

<p>Antiapoptotic and Anti-Inflammatory Effects of CPCGI in Rats with Traumatic Brain Injury</p>

Gene Expression Signature of Traumatic Brain Injury

Cordycepin Confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

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