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Neuropathology and Cellular Mechanisms in Traumatic Brain Injury
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Neuropathology and Cellular Mechanisms in Traumatic Brain Injury

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: closed (15 January 2023) | Viewed by 21767

Special Issue Editor

Dr. Firas Kobeissy

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Guest Editor
Center for Neurotrauma, Multiomics & Biomarkers, Department of Neurobiology & Neuroscience Institute, Morehouse School of Medicine (MSM), 720 Westview Drive, SW, Atlanta, GA 30310, USA
Interests: biological psychiatry; neuroscience, pharmacogenomics; brain injury, toxicology; substance abuse neurodegeneration; inflammation; antioxidants; multi-omics; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Traumatic Brain Injury (TBI) is a worldwide health problem leading to a series of complex, inter-related neurological and behavioral alterations that affect the brain and spinal cord. TBI presents a major socioeconomic burden, with an estimated 1.7 million civilians sustaining a TBI in the United States annually, with approximately 50,000 deaths and 200,000 moderate-to-severe injuries resulting in ~USD 70 billion in hospitalization costs.

Over the last decade, neurotrauma has witnessed significant advances, especially at the molecular, cellular, and behavioral levels. However, there are no FDA-approved effective pharmacological treatments available due to the complex secondary injury cascades involving neuroinflammation, glutamate toxicity, blood–brain barrier breach, lipid peroxidation, and release of reactive oxygen species (ROS) as well as mitochondrial dysfunction. These neuropathological outcomes create predisposition to other neurodegenerative disorders, including Alzheimer’s disease, Parkinson's Disease, and chronic traumatic encephalopathy. Thus, there is a continual quest to decipher novel pathways, mechanisms, and biomarkers involved in brain injury pathology to achieve effective rehabilitation and neuroprotective strategies.

This Special Issue invites researchers and clinicians to discuss neurotrauma mechanisms, biomarker discovery, neurocognitive/neurobehavioral and neurorehabilitation, and treatment approaches in the areas of TBI as well as other forms of TBI-induced disorders (CTE, AD, and PTE). We welcome original research or review papers demonstrating the mechanisms of neuroprotection in clinical and experimental TBI in clinical settings. Submissions focusing on neuropathological molecular mechanisms involving proteomic, metabolomic, and imaging studies are encouraged.

Dr. Firas Kobeissy
Guest Editor

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Keywords

  • traumatic brain injury
  • blood–brain barrier
  • neuroinflammation
  • glutamate toxicity
  • Alzheimer’s disease
  • Parkinson's disease
  • chronic traumatic encephalopathy
  • neurocognitive
  • neurobehavioral
  • neurorehabilitation

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Published Papers (7 papers)

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Research

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20 pages, 7683 KiB  
Article
Carvacrol Inhibits Expression of Transient Receptor Potential Melastatin 7 Channels and Alleviates Zinc Neurotoxicity Induced by Traumatic Brain Injury
by Minwoo Lee, Song Hee Lee, Seunghyuk Choi, Bo Young Choi and Sang Won Suh
Int. J. Mol. Sci. 2022, 23(22), 13840; https://doi.org/10.3390/ijms232213840 - 10 Nov 2022
Cited by 10 | Viewed by 1966
Abstract
Carvacrol is a monoterpenoid phenol produced by aromatic plants such as oregano. Although the exact mechanism by which carvacrol acts has not yet been established, it appears to inhibit transient receptor potential melastatin 7 (TRPM7), which modulates the homeostasis of metal ions such [...] Read more.
Carvacrol is a monoterpenoid phenol produced by aromatic plants such as oregano. Although the exact mechanism by which carvacrol acts has not yet been established, it appears to inhibit transient receptor potential melastatin 7 (TRPM7), which modulates the homeostasis of metal ions such as zinc and calcium. Several studies have demonstrated that carvacrol has protective effects against zinc neurotoxicity after ischemia and epilepsy. However, to date, no studies have investigated the effect of carvacrol on traumatic brain injury (TBI)-induced zinc neurotoxicity. In the present study, we investigated the therapeutic potential of carvacrol for the prevention of zinc-induced neuronal death after TBI. Rats were subjected to a controlled cortical impact, and carvacrol was injected at a dose of 50 mg/kg. Histological analysis was performed at 12 h, 24 h, and 7 days after TBI. We found that carvacrol reduced TBI-induced TRPM7 over-expression and free zinc accumulation. As a result, subsequent oxidative stress, dendritic damage, and neuronal degeneration were decreased. Moreover, carvacrol not only reduced microglial activation and delayed neuronal death but also improved neurological outcomes after TBI. Taken together, these findings suggest that carvacrol administration may have therapeutic potential after TBI by preventing neuronal death through the inhibition of TRPM7 expression and alleviation of zinc neurotoxicity. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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14 pages, 1975 KiB  
Article
Saffron Extract Attenuates Anxiogenic Effect and Improves Cognitive Behavior in an Adult Zebrafish Model of Traumatic Brain Injury
by Victoria Chaoul, Maria Awad, Frederic Harb, Fadia Najjar, Aline Hamade, Rita Nabout and Jihane Soueid
Int. J. Mol. Sci. 2022, 23(19), 11600; https://doi.org/10.3390/ijms231911600 - 1 Oct 2022
Cited by 6 | Viewed by 3791
Abstract
Traumatic brain injury (TBI) has the highest mortality rates worldwide, yet effective treatment remains unavailable. TBI causes inflammatory responses, endoplasmic reticulum stress, disruption of the blood–brain barrier and neurodegeneration that lead to loss of cognition, memory and motor skills. Saffron (Crocus sativus [...] Read more.
Traumatic brain injury (TBI) has the highest mortality rates worldwide, yet effective treatment remains unavailable. TBI causes inflammatory responses, endoplasmic reticulum stress, disruption of the blood–brain barrier and neurodegeneration that lead to loss of cognition, memory and motor skills. Saffron (Crocus sativus L.) is known for its anti-inflammatory and neuroprotective effects, which makes it a potential candidate for TBI treatment. Zebrafish (Danio rerio) shares a high degree of genetic homology and cell signaling pathways with mammals. Its active neuro-regenerative function makes it an excellent model organism for TBI therapeutic drug identification. The objective of this study was to assess the effect of saffron administration to a TBI zebrafish model by investigating behavioral outcomes such as anxiety, fear and memory skills using a series of behavioral tests. Saffron exhibited anxiolytic effect on anxiety-like behaviors, and showed prevention of fear inhibition observed after TBI. It improved learning and enhanced memory performance. These results suggest that saffron could be a novel therapeutic enhancer for neural repair and regeneration of networks post-TBI. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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23 pages, 9495 KiB  
Article
Characterization of Calpain and Caspase-6-Generated Glial Fibrillary Acidic Protein Breakdown Products Following Traumatic Brain Injury and Astroglial Cell Injury
by Zhihui Yang, Rawad Daniel Arja, Tian Zhu, George Anis Sarkis, Robert Logan Patterson, Pammela Romo, Disa S. Rathore, Ahmed Moghieb, Susan Abbatiello, Claudia S. Robertson, William E. Haskins, Firas Kobeissy and Kevin K. W. Wang
Int. J. Mol. Sci. 2022, 23(16), 8960; https://doi.org/10.3390/ijms23168960 - 11 Aug 2022
Cited by 8 | Viewed by 2784
Abstract
Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown [...] Read more.
Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown products (GBDP) of 46-40K then 38K following pro-necrotic (A23187) and pro-apoptotic (staurosporine) challenges to primary cultured astroglia or neuron-glia mixed cells. In addition, with another pro-apoptotic challenge (EDTA) where caspases are activated but not calpain, GFAP was fragmented internally, generating a C-terminal GBDP of 20 kDa. Following controlled cortical impact in mice, GBDP of 46-40K and 38K were formed from day 3 to 28 post-injury. Purified GFAP protein treated with calpain-1 and -2 generates (i) major N-terminal cleavage sites at A-56*A-61 and (ii) major C-terminal cleavage sites at T-383*Q-388, producing a limit fragment of 38K. Caspase-6 treated GFAP was cleaved at D-78/R-79 and D-225/A-226, where GFAP was relatively resistant to caspase-3. We also derived a GBDP-38K N-terminal-specific antibody which only labels injured astroglia cell body in both cultured astroglia and mouse cortex and hippocampus after TBI. As a clinical translation, we observed that CSF samples collected from severe human TBI have elevated levels of GBDP-38K as well as two C-terminally released GFAP peptides (DGEVIKES and DGEVIKE). Thus, in addition to intact GFAP, both the GBDP-38K as well as unique GFAP released C-terminal proteolytic peptides species might have the potential in tracking brain injury progression. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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19 pages, 3816 KiB  
Article
ILB®, a Low Molecular Weight Dextran Sulphate, Restores Glutamate Homeostasis, Amino Acid Metabolism and Neurocognitive Functions in a Rat Model of Severe Traumatic Brain Injury
by Giacomo Lazzarino, Valentina Di Pietro, Marco Rinaudo, Zsuzsanna Nagy, Nicholas M. Barnes, Lars Bruce, Stefano Signoretti, Renata Mangione, Miriam Wissam Saab, Barbara Tavazzi, Antonio Belli, Giuseppe Lazzarino, Angela Maria Amorini and Ann Logan
Int. J. Mol. Sci. 2022, 23(15), 8460; https://doi.org/10.3390/ijms23158460 - 30 Jul 2022
Cited by 2 | Viewed by 3324
Abstract
In a previous study, we found that administration of ILB®, a new low molecular weight dextran sulphate, significantly improved mitochondrial functions and energy metabolism, as well as decreased oxidative/nitrosative stress, of brain tissue of rats exposed to severe traumatic brain injury [...] Read more.
In a previous study, we found that administration of ILB®, a new low molecular weight dextran sulphate, significantly improved mitochondrial functions and energy metabolism, as well as decreased oxidative/nitrosative stress, of brain tissue of rats exposed to severe traumatic brain injury (sTBI), induced by the closed-head weight-drop model of diffused TBI. Using aliquots of deproteinized brain tissue of the same animals of this former study, we here determined the concentrations of 24 amino acids of control rats, untreated sTBI rats (sacrificed at 2 and 7 days post-injury) and sTBI rats receiving a subcutaneous ILB® administration (at the dose levels of 1, 5 and 15 mg/kg b.w.) 30 min post-impact (sacrificed at 2 and 7 days post-injury). Additionally, in a different set of experiments, new groups of control rats, untreated sTBI rats and ILB®-treated rats (administered 30 min after sTBI at the dose levels of 1 or 5 mg/kg b.w.) were studied for their neurocognitive functions (anxiety, locomotor capacities, short- and long-term memory) at 7 days after the induction of sTBI. Compared to untreated sTBI animals, ILB® significantly decreased whole brain glutamate (normalizing the glutamate/glutamine ratio), glycine, serine and γ-aminobutyric acid. Furthermore, ILB® administration restored arginine metabolism (preventing nitrosative stress), levels of amino acids involved in methylation reactions (methionine, L-cystathionine, S-adenosylhomocysteine), and N-acetylaspartate homeostasis. The macroscopic evidences of the beneficial effects on brain metabolism induced by ILB® were the relevant improvement in neurocognitive functions of the group of animals treated with ILB® 5 mg/kg b.w., compared to the marked cognitive decline measured in untreated sTBI animals. These results demonstrate that ILB® administration 30 min after sTBI prevents glutamate excitotoxicity and normalizes levels of amino acids involved in crucial brain metabolic functions. The ameliorations of amino acid metabolism, mitochondrial functions and energy metabolism in ILB®-treated rats exposed to sTBI produced significant improvement in neurocognitive functions, reinforcing the concept that ILB® is a new effective therapeutic tool for the treatment of sTBI, worth being tested in the clinical setting. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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11 pages, 1298 KiB  
Article
Long-Term Changes in Axon Calibers after Injury: Observations on the Mouse Corticospinal Tract
by Athanasios S. Alexandris, Yiqing Wang, Constantine E. Frangakis, Youngrim Lee, Jiwon Ryu, Zahra Alam and Vassilis E. Koliatsos
Int. J. Mol. Sci. 2022, 23(13), 7391; https://doi.org/10.3390/ijms23137391 - 2 Jul 2022
Cited by 3 | Viewed by 1994
Abstract
White matter pathology is common across a wide spectrum of neurological diseases. Characterizing this pathology is important for both a mechanistic understanding of neurological diseases as well as for the development of neuroimaging biomarkers. Although axonal calibers can vary by orders of magnitude, [...] Read more.
White matter pathology is common across a wide spectrum of neurological diseases. Characterizing this pathology is important for both a mechanistic understanding of neurological diseases as well as for the development of neuroimaging biomarkers. Although axonal calibers can vary by orders of magnitude, they are tightly regulated and related to neuronal function, and changes in axon calibers have been reported in several diseases and their models. In this study, we utilize the impact acceleration model of traumatic brain injury (IA-TBI) to assess early and late changes in the axon diameter distribution (ADD) of the mouse corticospinal tract using Airyscan and electron microscopy. We find that axon calibers follow a lognormal distribution whose parameters significantly change after injury. While IA-TBI leads to 30% loss of corticospinal axons by day 7 with a bias for larger axons, at 21 days after injury we find a significant redistribution of axon frequencies that is driven by a reduction in large-caliber axons in the absence of detectable degeneration. We postulate that changes in ADD features may reflect a functional adaptation of injured neural systems. Moreover, we find that ADD features offer an accurate way to discriminate between injured and non-injured mice. Exploring injury-related ADD signatures by histology or new emerging neuroimaging modalities may offer a more nuanced and comprehensive way to characterize white matter pathology and may also have the potential to generate novel biomarkers of injury. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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19 pages, 2220 KiB  
Article
Formation of False Context Fear Memory Is Regulated by Hypothalamic Corticotropin-Releasing Factor in Mice
by Emi Kasama, Miho Moriya, Ryuma Kamimura, Tohru Matsuki and Kenjiro Seki
Int. J. Mol. Sci. 2022, 23(11), 6286; https://doi.org/10.3390/ijms23116286 - 3 Jun 2022
Cited by 2 | Viewed by 2845
Abstract
Traumatic events frequently produce false fear memories. We investigated the effect of hypothalamic corticotropin-releasing factor (CRF) knockdown (Hy-Crf-KD) or overexpression (Hy-CRF-OE) on contextual fear memory, as fear stress-released CRF and hypothalamic–pituitary–adrenal axis activation affects the memory system. Mice were placed in [...] Read more.
Traumatic events frequently produce false fear memories. We investigated the effect of hypothalamic corticotropin-releasing factor (CRF) knockdown (Hy-Crf-KD) or overexpression (Hy-CRF-OE) on contextual fear memory, as fear stress-released CRF and hypothalamic–pituitary–adrenal axis activation affects the memory system. Mice were placed in a chamber with an electric footshock as a conditioning stimulus (CS) in Context A, then exposed to a novel chamber without CS, as Context B, at 3 h (B-3h) or 24 h (B-24h). The freezing response in B-3h was intensified in the experimental mice, compared to control mice not exposed to CS, indicating that a false fear memory was formed at 3 h. The within-group freezing level at B-24h was higher than that at B-3h, indicating that false context fear memory was enhanced at B-24h. The difference in freezing levels between B-3h and B-24h in Hy-Crf-KD mice was larger than that of controls. In Hy-CRF-OE mice, the freezing level at B-3h was higher than that of control and Hy-Crf-KD mice, while the freezing level in B-24h was similar to that in B-3h. Locomotor activity before CS and freezing level during CS were similar among the groups. Therefore, we hypothesized that Hy-Crf-KD potentiates the induction of false context fear memory, while Hy-CRF-OE enhances the onset of false fear memory formation. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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Review

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14 pages, 544 KiB  
Review
Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies
by Benjamin F. Gruenbaum, Alexander Zlotnik, Ilya Fleidervish, Amit Frenkel and Matthew Boyko
Int. J. Mol. Sci. 2022, 23(17), 9628; https://doi.org/10.3390/ijms23179628 - 25 Aug 2022
Cited by 19 | Viewed by 3813
Abstract
Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients’ lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes [...] Read more.
Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients’ lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes to the development of neuropsychiatric conditions. We hypothesize that TBI causes long-term blood–brain barrier (BBB) dysfunction lasting many years and even decades. We propose that dysfunction in the BBB is the central factor that modulates increased glutamate after TBI and ultimately leads to neurodegenerative processes and subsequent manifestation of neuropsychiatric conditions. Here, we have identified factors that determine the upper and lower levels of glutamate concentration in the brain after TBI. Furthermore, we consider treatments of disruptions to BBB integrity, including repairing the BBB and controlling excess glutamate, as potential therapeutic modalities for the treatment of acute and chronic neuropsychiatric conditions and symptoms. By specifically focusing on the BBB, we hypothesize that restoring BBB integrity will alleviate neurotoxicity and related neurological sequelae. Full article
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
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