Transcriptomics of Traumatic Brain Injury: Gene Expression and Molecular Pathways of Different Grades of Insult in a Rat Organotypic Hippocampal Culture Model

AbstractTraumatic brain injury (TBI) is of significant concern in the realm of high impact contact sports, including mixed martial arts (MMA). Extracellular vesicles (EVs) travel between the brain and oral cavity and may be isolated from salivary samples as a noninvasive biomarker of TBI. Salivary EVs may highlight acute neurocognitive or neuropathological changes, which may be particularly useful as a biomarker in high impact sports. Pre and post-fight samples of saliva were isolated from 8 MMA fighters and 7 from controls. Real-time PCR of salivary EVs was done using the TaqMan Human Inflammatory array. Gene expression profiles were compared pre-fight to post-fight as well as pre-fight to controls. Largest signals were noted for fighters sustaining a loss by technical knockout (higher impact mechanism of injury) or a full match culminating in referee decision (longer length of fight), while smaller signals were noted for fighters winning by joint or choke submission (lower impact mechanism as well as less time). A correlation was observed between absolute gene information signals and fight related markers of head injury severity. Gene expression was also significantly different in MMA fighters pre-fight compared to controls. Our findings suggest that salivary EVs as a potential biomarker in the acute period following head injury to identify injury severity and can help elucidate pathophysiological processes involved in TBI.

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Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01226-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Amer Toutonji ◽

Mamatha Mandava ◽

Silvia Guglietta ◽

Stephen Tomlinson

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Complement System ◽

Classical Pathway ◽

Post Injury ◽

Complement Inhibition ◽

Time Points ◽

Complement Gene ◽

The Complement System

AbstractActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

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Effects of AAV-mediated knockdown of nNOS and GPx-1 gene expression in rat hippocampus after traumatic brain injury

PLoS ONE ◽

10.1371/journal.pone.0185943 ◽

2017 ◽

Vol 12 (10) ◽

pp. e0185943 ◽

Cited By ~ 5

Author(s):

Deborah R. Boone ◽

Jeanna M. Leek ◽

Michael T. Falduto ◽

Karen E. O. Torres ◽

Stacy L. Sell ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Rat Hippocampus

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miR-29a-5p Alleviates Traumatic Brain Injury (TBI)-Induced Permeability Disruption Via Regulating NLRP3 Pathway

10.21203/rs.3.rs-334899/v1 ◽

2021 ◽

Author(s):

Aijun Zhang ◽

Youming Lu ◽

Lei Yuan ◽

Pengqi Zhang ◽

Dongdong Zou ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Endothelial Cell ◽

Brain Injury ◽

Inflammasome Activation ◽

Caspase 1 ◽

Promising Strategy ◽

Pathway Activation ◽

Nlrp3 Expression

Abstract Blood-brain barrier (BBB) dysfunction is presented during traumatic brain injury (TBI) and is dependent upon the activation of the NLRP3/Caspase-1 inflammasome pathway. MicroRNA (miRNA) was proved to inhibit signaling pathway activation by targeting gene expression and we predicated in the database that miR-29a targets to NLRP3. Herein, this study aims to define the regulating role of miR-29a in NLRP3 expression and NLRP3/Caspase-1 inflammasome activation in TBI-induced BBB dysfunction. Our results indicated that miR-29a-5p alleviates TBI-induced the increased permeability of endothelial cell and BBB via suppressing NLRP3 expression and NLRP3/Caspase-1 inflammasome activation, providing a promising strategy for relieving TBI via inhibiting NLRP3/Caspase-1 inflammasome activation.

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Fresh Frozen Plasma Modulates Brain Gene Expression in a Swine Model of Traumatic Brain Injury and Shock: A Network Analysis

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2016.09.015 ◽

2017 ◽

Vol 224 (1) ◽

pp. 49-58 ◽

Cited By ~ 9

Author(s):

Martin Sillesen ◽

Ted Bambakidis ◽

Simone E. Dekker ◽

Yongqing Li ◽

Hasan B. Alam

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Network Analysis ◽

Fresh Frozen Plasma ◽

Swine Model ◽

Brain Gene Expression ◽

Fresh Frozen ◽

Frozen Plasma

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Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

Journal of Trauma and Acute Care Surgery ◽

10.1097/ta.0000000000000345 ◽

2014 ◽

Vol 77 (6) ◽

pp. 906-912 ◽

Cited By ~ 24

Author(s):

Simone E. Dekker ◽

Ted Bambakidis ◽

Martin Sillesen ◽

Baoling Liu ◽

Craig N. Johnson ◽

...

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Swine Model ◽

Brain Gene Expression ◽

The Brain

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Gene Expression Profiling for Discovery of Novel Targets in Human Traumatic Brain Injury

Biological Research For Nursing ◽

10.1177/1099800410385671 ◽

2010 ◽

Vol 13 (2) ◽

pp. 140-153 ◽

Cited By ~ 10

Author(s):

Taura L. Barr ◽

Sheila Alexander ◽

Yvette Conley

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Clinical Trials ◽

Brain Injury ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Treatment Strategies ◽

Biological Pathways ◽

Human Response ◽

Novel Targets

Several clinical trials have failed to demonstrate a significant effect on outcome following human traumatic brain injury (TBI) despite promising results obtained in preclinical animal studies. These failures may be due in part to a misinterpretation of the findings obtained in preclinical animal models of TBI, a misunderstanding of the complexity of the human response to TBI, limited knowledge about the biological pathways that interact to contribute to good and bad outcomes after brain injury, and the effects of genomic variability and environment on individual recovery. Recent publications suggest that data obtained from gene expression profiling studies of complex neurological diseases such as stroke, multiple sclerosis (MS), Alzheimer’s and Parkinson’s may contribute to a more informed understanding of what affects outcome following TBI. These data may help to bridge the gap between successful preclinical studies and negative clinical trials in humans to reveal novel targets for therapy. Gene expression profiling has the capability to identify biomarkers associated with response to TBI, elucidate complex genetic interactions that may play a role in outcome following TBI, and reveal biological pathways related to brain health. This review highlights the current state of the literature on gene expression profiling for neurological disease and discusses its ability to aid in unraveling the variable human response to TBI and the potential for it to offer treatment strategies in an area where we currently have limited therapeutic options primarily based on supportive care.

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