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Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 7591

Special Issue Editor

Dr. Ibolja Cernak

E-Mail Website
Guest Editor
The Thomas F. Frist, Jr. College of Medicine, Belmont University, Nashville, TN 37212, USA
Interests: neurotrauma; blood-brain barrier; traumatic brain injury; brain injury; blast modeling; cognition; psychological resilience; stress response; trauma; multiple trauma

Special Issue Information

Dear Colleagues,

Blast injuries attracted increased research interest after World War I. While blast-induced neurotrauma (BINT) research started in parallel with studies addressing other blast-related injuries, it shifted out of focus until the Balkan wars and the Global War on Terrorism. Since early 2000s, the BINT research has been intensified, recognizing the importance of the brain’s response in the development of complex multi-organ responses to blast exposure(s). One of the greatest challenges, constant in BINT research, is the limitation of relying on animal models to reproduce real-life operational injury scenarios and clinically relevant pathology; this often limits the experimental findings’ translational value to the clinical arena. The main goal of the Special Issue is to reflect our current understanding of molecular mechanisms underlying BINT and its neurological consequences, gained through clinical and experimental research, and discuss whether there is an alignment between findings gained using experimental models and those experienced in patients’ population. Identifying the extent of the agreement between experimental and clinical findings is the first step in facilitating the progress of BINT research and reaching the ultimate goal: efficient early diagnosis and successful treatments.

Dr. Ibolja Cernak
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • blast injuries
  • blast-induced neurotrauma
  • experimental research
  • experimental models
  • clinical research
  • molecular mechanisms
  • biomarkers
  • imaging
  • neurological deficits
  • treatment

Published Papers (6 papers)

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Research

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16 pages, 2152 KiB  
Article
Temporal Alterations in Cerebrovascular Glycocalyx and Cerebral Blood Flow after Exposure to a High-Intensity Blast in Rats
by Ye Chen, Ming Gu, Jacob Patterson, Ruixuan Zhang, Jonathan K. Statz, Eileen Reed, Rania Abutarboush, Stephen T. Ahlers and Usmah Kawoos
Int. J. Mol. Sci. 2024, 25(7), 3580; https://doi.org/10.3390/ijms25073580 - 22 Mar 2024
Viewed by 438
Abstract
The glycocalyx is a proteoglycan–glycoprotein structure lining the luminal surface of the vascular endothelium and is susceptible to damage due to blast overpressure (BOP) exposure. The glycocalyx is essential in maintaining the structural and functional integrity of the vasculature and regulation of cerebral [...] Read more.
The glycocalyx is a proteoglycan–glycoprotein structure lining the luminal surface of the vascular endothelium and is susceptible to damage due to blast overpressure (BOP) exposure. The glycocalyx is essential in maintaining the structural and functional integrity of the vasculature and regulation of cerebral blood flow (CBF). Assessment of alterations in the density of the glycocalyx; its components (heparan sulphate proteoglycan (HSPG/syndecan-2), heparan sulphate (HS), and chondroitin sulphate (CS)); CBF; and the effect of hypercapnia on CBF was conducted at 2–3 h, 1, 3, 14, and 28 days after a high-intensity (18.9 PSI/131 kPa peak pressure, 10.95 ms duration, and 70.26 PSI·ms/484.42 kPa·ms impulse) BOP exposure in rats. A significant reduction in the density of the glycocalyx was observed 2–3 h, 1-, and 3 days after the blast exposure. The glycocalyx recovered by 28 days after exposure and was associated with an increase in HS (14 and 28 days) and in HSPG/syndecan-2 and CS (28 days) in the frontal cortex. In separate experiments, we observed significant decreases in CBF and a diminished response to hypercapnia at all time points with some recovery at 3 days. Given the role of the glycocalyx in regulating physiological function of the cerebral vasculature, damage to the glycocalyx after BOP exposure may result in the onset of pathogenesis and progression of cerebrovascular dysfunction leading to neuropathology. Full article
(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)
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16 pages, 2346 KiB  
Article
Association of Blast Exposure in Military Breaching with Intestinal Permeability Blood Biomarkers Associated with Leaky Gut
by Qingkun Liu, Zhaoyu Wang, Shengnan Sun, Jeffrey Nemes, Lisa A. Brenner, Andrew Hoisington, Maciej Skotak, Christina R. LaValle, Yongchao Ge, Walter Carr and Fatemeh Haghighi
Int. J. Mol. Sci. 2024, 25(6), 3549; https://doi.org/10.3390/ijms25063549 - 21 Mar 2024
Viewed by 2115
Abstract
Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene [...] Read more.
Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene expression and IP biomarker data were generated from “breachers” exposed to controlled, low-level explosive blast during training. Samples from 30 male participants at pre-, post-, and follow-up blast exposure the next day were assayed via RNA-seq and ELISA. A battery of symptom data was also collected at each of these time points that acutely showed elevated symptom reporting related to headache, concentration, dizziness, and taking longer to think, dissipating ~16 h following blast exposure. Evidence for bacterial translocation into circulation following blast exposure was detected by significant stepwise increase in microbial diversity (measured via alpha-diversity p = 0.049). Alterations in levels of IP protein biomarkers (i.e., Zonulin, LBP, Claudin-3, I-FABP) assessed in a subset of these participants (n = 23) further evidenced blast exposure associates with IP. The observed symptom profile was consistent with mild traumatic brain injury and was further associated with changes in bacterial translocation and intestinal permeability, suggesting that IP may be linked to a decrease in cognitive functioning. These preliminary findings show for the first time within real-world military operational settings that exposures to blast can contribute to IP. Full article
(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)
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28 pages, 5132 KiB  
Article
The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression
by Marcus Jackson, Shanyan Chen, Thao Thi Nguyen, Heather R. Siedhoff, Ashley Balderrama, Amitai Zuckerman, Runting Li, C. Michael Greenlief, Gregory Cole, Sally A. Frautschy, Jiankun Cui and Zezong Gu
Int. J. Mol. Sci. 2024, 25(6), 3338; https://doi.org/10.3390/ijms25063338 - 15 Mar 2024
Viewed by 647
Abstract
Blast-induced neurotrauma (BINT) is a pressing concern for veterans and civilians exposed to explosive devices. Affected personnel may have increased risk for long-term cognitive decline and developing tauopathies including Alzheimer’s disease-related disorders (ADRD) or frontal-temporal dementia (FTD). The goal of this study was [...] Read more.
Blast-induced neurotrauma (BINT) is a pressing concern for veterans and civilians exposed to explosive devices. Affected personnel may have increased risk for long-term cognitive decline and developing tauopathies including Alzheimer’s disease-related disorders (ADRD) or frontal-temporal dementia (FTD). The goal of this study was to identify the effect of BINT on molecular networks and their modulation by mutant tau in transgenic (Tg) mice overexpressing the human tau P301L mutation (rTg4510) linked to FTD or non-carriers. The primary focus was on the phosphoproteome because of the prominent role of hyperphosphorylation in neurological disorders. Discrimination learning was assessed following injury in the subsequent 6 weeks, using the automated home-cage monitoring CognitionWall platform. At 40 days post injury, label-free phosphoproteomics was used to evaluate molecular networks in the frontal cortex of mice. Utilizing a weighted peptide co-expression network analysis (WpCNA) approach, we identified phosphopeptide networks tied to associative learning and mossy-fiber pathways and those which predicted learning outcomes. Phosphorylation levels in these networks were inversely related to learning and linked to synaptic dysfunction, cognitive decline, and dementia including Atp6v1a and Itsn1. Low-intensity blast (LIB) selectively increased pSer262tau in rTg4510, a site implicated in initiating tauopathy. Additionally, individual and group level analyses identified the Arhgap33 phosphopeptide as an indicator of BINT-induced cognitive impairment predominantly in rTg4510 mice. This study unveils novel interactions between ADRD genetic susceptibility, BINT, and cognitive decline, thus identifying dysregulated pathways as targets in potential precision-medicine focused therapeutics to alleviate the disease burden among those affected by BINT. Full article
(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)
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21 pages, 2681 KiB  
Article
Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy
by Jack L. Browning, Kelsey A. Wilson, Oleksii Shandra, Xiaoran Wei, Dzenis Mahmutovic, Biswajit Maharathi, Stefanie Robel, Pamela J. VandeVord and Michelle L. Olsen
Int. J. Mol. Sci. 2024, 25(5), 2880; https://doi.org/10.3390/ijms25052880 - 01 Mar 2024
Viewed by 888
Abstract
Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased [...] Read more.
Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE+), those without epilepsy (PTE−), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE+ and PTE− relative to sham. Focusing on protein pathways unique to PTE+, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE−. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI. Full article
(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)
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Review

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40 pages, 12420 KiB  
Review
The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma
by Gregory A. Elder, Miguel A. Gama Sosa, Rita De Gasperi, Georgina Perez Garcia, Gissel M. Perez, Rania Abutarboush, Usmah Kawoos, Carolyn W. Zhu, William G. M. Janssen, James R. Stone, Patrick R. Hof, David G. Cook and Stephen T. Ahlers
Int. J. Mol. Sci. 2024, 25(2), 1150; https://doi.org/10.3390/ijms25021150 - 17 Jan 2024
Viewed by 1792
Abstract
Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, [...] Read more.
Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable. Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood–brain barrier permeability, and glymphatic flow. Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury. Full article
(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)
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15 pages, 884 KiB  
Review
Effects of Low-Level Blast on Neurovascular Health and Cerebral Blood Flow: Current Findings and Future Opportunities in Neuroimaging
by Madison O. Kilgore and W. Brad Hubbard
Int. J. Mol. Sci. 2024, 25(1), 642; https://doi.org/10.3390/ijms25010642 - 04 Jan 2024
Viewed by 1154
Abstract
Low-level blast (LLB) exposure can lead to alterations in neurological health, cerebral vasculature, and cerebral blood flow (CBF). The development of cognitive issues and behavioral abnormalities after LLB, or subconcussive blast exposure, is insidious due to the lack of acute symptoms. One major [...] Read more.
Low-level blast (LLB) exposure can lead to alterations in neurological health, cerebral vasculature, and cerebral blood flow (CBF). The development of cognitive issues and behavioral abnormalities after LLB, or subconcussive blast exposure, is insidious due to the lack of acute symptoms. One major hallmark of LLB exposure is the initiation of neurovascular damage followed by the development of neurovascular dysfunction. Preclinical studies of LLB exposure demonstrate impairment to cerebral vasculature and the blood–brain barrier (BBB) at both early and long-term stages following LLB. Neuroimaging techniques, such as arterial spin labeling (ASL) using magnetic resonance imaging (MRI), have been utilized in clinical investigations to understand brain perfusion and CBF changes in response to cumulative LLB exposure. In this review, we summarize neuroimaging techniques that can further our understanding of the underlying mechanisms of blast-related neurotrauma, specifically after LLB. Neuroimaging related to cerebrovascular function can contribute to improved diagnostic and therapeutic strategies for LLB. As these same imaging modalities can capture the effects of LLB exposure in animal models, neuroimaging can serve as a gap-bridging diagnostic tool that permits a more extensive exploration of potential relationships between blast-induced changes in CBF and neurovascular health. Future research directions are suggested, including investigating chronic LLB effects on cerebral perfusion, exploring mechanisms of dysautoregulation after LLB, and measuring cerebrovascular reactivity (CVR) in preclinical LLB models. Full article
(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)
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