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Molecular Research on 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 (31 August 2023) | Viewed by 14398

Special Issue Editors


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Guest Editor
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Interests: brain injury; neuroprotection; nutraceuticals

E-Mail Website
Guest Editor
1. Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
2. Department of Psychiatry, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Interests: brain injury; epilepsy; neurodegeneration

Special Issue Information

Dear Colleagues,

Injuries to the brain can happen in many ways and are classified into two main categories: traumatic and non-traumatic. Non-traumatic brain injuries can be caused by a variety of conditions including strokes, metabolic disorders, tumors, aneurysms, prolonged seizures, cardiac arrest, oxygen deprivation, and toxins, to name a few. In contrast to a traumatic brain injury (TBI), these injuries are not the result of an external physical force that impacts or penetrates the head. Nonetheless, the short- and long-term effects of a non-traumatic brain injury (non-TBI) occur as they do after a TBI. A closed head injury TBI, an injury to the brain caused by an external force, can be classified as mild, moderate or severe. TBIs can also be classified based on the mechanism that caused it, as a closed or penetrating head injury, or as a blast-induced TBI. Brain injuries disrupt the normal flow of complex communications and interactions between cells in the brain. The impacts of these injuries result in neurological deficits. These deficits involve motor, sensory, cognitive and/or emotional components. Numerous researchers have used molecular biology and electrophysiological methods to investigate the pathophysiological alterations that occur in the brain’s neuronal circuits that compromise function after injury. This open access Special Issue will bring together new research and review articles on molecular biological and electrophysiological mechanisms that alter normal brain function after brain injury. Delineating the molecular and electrophysiological mechanisms of the cells and environment surrounding the injury, and developing treatments using current molecular tools, including single-cell sequencing, will advance our understanding of the complex interactions and lead to the restoration of normal brain function. These results may lead to the discovery of new molecular diagnostics, novel therapeutic targets, and better outcomes.

Topics of interest for this Special Issue include:

  • Closed traumatic brain injury;
  • Penetrating traumatic brain injury;
  • Chronic traumatic encephalopathy;
  • Blast-induced traumatic brain injury;
  • Ischemic stroke;
  • Hemorrhagic stroke;
  • Status epilepticus;
  • Meningitis;
  • COVID-19-related brain injury;
  • AIDS-related brain injury;
  • Toxin-induced brain injury;
  • Multiple-sclerosis-induced brain injury;
  • Therapeutics on the horizon for brain injuries.

Dr. Ann M. Marini
Dr. Maria Fatima M. Braga
Guest Editors

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Keywords

  • brain injury
  • stroke
  • chronic traumatic encephalopathy
  • status epilepticus
  • oxygen deprivation
  • metabolic disorders
  • tumors
  • aneurysms
  • prolonged seizures
  • cardiac arrest
  • oxygen deprivation
  • meningitis
  • COVID-19 brain injury
  • AIDS-related brain injury
  • toxin-induced brain injury
  • multiple-sclerosis-induced brain injury

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Published Papers (6 papers)

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Research

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59 pages, 51081 KiB  
Article
Ultrastructural Study and Immunohistochemical Characteristics of Mesencephalic Tegmentum in Juvenile Chum Salmon (Oncorhynchus keta) Brain After Acute Traumatic Injury
by Evgeniya V. Pushchina, Evgeniya A. Pimenova, Ilya A. Kapustyanov and Mariya E. Bykova
Int. J. Mol. Sci. 2025, 26(2), 644; https://doi.org/10.3390/ijms26020644 - 14 Jan 2025
Viewed by 1011
Abstract
The ultrastructural organization of the nuclei of the tegmental region in juvenile chum salmon (Oncorhynchus keta) was examined using transmission electron microscopy (TEM). The dorsal tegmental nuclei (DTN), the nucleus of fasciculus longitudinalis medialis (NFLM), and the nucleus of the oculomotor [...] Read more.
The ultrastructural organization of the nuclei of the tegmental region in juvenile chum salmon (Oncorhynchus keta) was examined using transmission electron microscopy (TEM). The dorsal tegmental nuclei (DTN), the nucleus of fasciculus longitudinalis medialis (NFLM), and the nucleus of the oculomotor nerve (NIII) were studied. The ultrastructural examination provided detailed ultrastructural characteristics of neurons forming the tegmental nuclei and showed neuro–glial relationships in them. Neurons of three size types with a high metabolic rate, characterized by the presence of numerous mitochondria, polyribosomes, Golgi apparatus, and cytoplasmic inclusions (vacuoles, lipid droplets, and dense bodies), were distinguished. It was found that large interneurons of the NFLM formed contacts with protoplasmic astrocytes. Excitatory synaptic structures were identified in the tegmentum and their detailed characteristic are provided for the first time. Microglia-like cells were found in the NIII. The ultrastructural characteristics of neurogenic zones of the tegmentum of juvenile chum salmon were also determined for the first time. In the neurogenic zones of the tegmentum, adult-type neural stem progenitor cells (aNSPCs) corresponding to cells of types III and IVa Danio rerio. In the neurogenic zones of the tegmentum, neuroepithelial-like cells (NECs) corresponding to cells previously described from the zebrafish cerebellum were found and characterized. In the tegmentum of juvenile chum salmon, patterns of paracrine neurosecretion were observed and their ultrastructural characteristics were recorded. Patterns of apoptosis in large neurons of the tegmentum were examined by TEM. Using immunohistochemical (IHC) labeling of the brain lipid-binding protein (BLBP) and aromatase B (AroB), patterns of their expression in the tegmentum of intact animals and in the post-traumatic period after acute injury to the medulla oblongata were characterized. The response to brainstem injury in chum salmon was found to activate multiple signaling pathways, which significantly increases the BLBP and AroB expression in various regions of the tegmentum and valvula cerebelli. However, post-traumatic patterns of BLBP and AroB localizations are not the same. In addition to a general increase in BLBP expression in the tegmental parenchyma, BLBP overexpression was observed in the rostro-lateral tegmental neurogenic zone (RLTNZ), while AroB expression in the RLTNZ was completely absent. Another difference was the peripheral overexpression of AroB and the formation of dense reactive clusters in the ventro-medial zone of the tegmentum. Thus, in the post-traumatic period, various pathways were activated whose components were putative candidates for inducers of the “astrocyte-like” response in the juvenile chum salmon brain that are similar to those present in the mammalian brain. In this case, BLBP acted as a factor enhancing the differentiation of both radial glia and neurons. Estradiol from AroB+ astrocytes exerted paracrine neuroprotective effects through the potential inhibition of inflammatory processes. These results indicate a new role for neuronal aromatization as a mechanism preventing the development of neuroinflammation. Moreover, our findings support the hypothesis that BLBP is a factor enhancing neuronal and glial differentiation in the post-traumatic period in the chum salmon brain. Full article
(This article belongs to the Special Issue Molecular Research on Brain Injury)
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12 pages, 1327 KiB  
Article
Soluble Triggering Receptors Expressed on Myeloid Cells (sTREM) in Acute Ischemic Stroke: A Potential Pathway of sTREM-1 and sTREM-2 Associated with Disease Severity
by Greta Salafia, Angelica Carandina, Roberto Maria Sacco, Evelyn Ferri, Nicola Montano, Beatrice Arosio and Eleonora Tobaldini
Int. J. Mol. Sci. 2024, 25(14), 7611; https://doi.org/10.3390/ijms25147611 - 11 Jul 2024
Cited by 1 | Viewed by 1328
Abstract
In 2022, stroke emerged as the most significant cerebrovascular disorder globally, causing 6.55 million deaths. Microglia, crucial for CNS preservation, can exacerbate brain damage in ischemic stroke by triggering neuroinflammation. This process is mediated by receptors on microglia, triggering receptors expressed on myeloid [...] Read more.
In 2022, stroke emerged as the most significant cerebrovascular disorder globally, causing 6.55 million deaths. Microglia, crucial for CNS preservation, can exacerbate brain damage in ischemic stroke by triggering neuroinflammation. This process is mediated by receptors on microglia, triggering receptors expressed on myeloid cells (TREM-1 and TREM-2), which have contrasting roles in neuroinflammation. In this study, we recruited 38 patients within 4.5 h from the onset of ischemic stroke. The degree of severity was evaluated by means of the National Institutes of Health Stroke Scale (NIHSS) at admission (T0) and after one week of ischemic events (TW) and the Modified Rankin Scale (mRS) at three months. The plasma concentration of TREMs (sTREM) was analyzed by next-generation ELISA at T0 and TW. The sTREM-1 concentrations at T0 were associated with mRS, while the sTREM-2 concentrations at T0 were associated with both the NIHSS at T0 and the mRS. A strong correlation between sTREM-1 and sTREM-2 was observed, suggesting a dependent modulation of the levels. This study provides insights into the potential pathway of TREM-1 and TREM-2 as a future biomarker for stratifying high-risk patients with ischemic stroke. Full article
(This article belongs to the Special Issue Molecular Research on Brain Injury)
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32 pages, 5810 KiB  
Article
Treatment of Status Epilepticus after Traumatic Brain Injury Using an Antiseizure Drug Combined with a Tissue Recovery Enhancer Revealed by Systems Biology
by Natallie Kajevu, Anssi Lipponen, Pedro Andrade, Ivette Bañuelos, Noora Puhakka, Elina Hämäläinen, Teemu Natunen, Mikko Hiltunen and Asla Pitkänen
Int. J. Mol. Sci. 2023, 24(18), 14049; https://doi.org/10.3390/ijms241814049 - 13 Sep 2023
Cited by 3 | Viewed by 1904
Abstract
We tested a hypothesis that in silico-discovered compounds targeting traumatic brain injury (TBI)-induced transcriptomics dysregulations will mitigate TBI-induced molecular pathology and augment the effect of co-administered antiseizure treatment, thereby alleviating functional impairment. In silico bioinformatic analysis revealed five compounds substantially affecting TBI-induced transcriptomics [...] Read more.
We tested a hypothesis that in silico-discovered compounds targeting traumatic brain injury (TBI)-induced transcriptomics dysregulations will mitigate TBI-induced molecular pathology and augment the effect of co-administered antiseizure treatment, thereby alleviating functional impairment. In silico bioinformatic analysis revealed five compounds substantially affecting TBI-induced transcriptomics regulation, including calpain inhibitor, chlorpromazine, geldanamycin, tranylcypromine, and trichostatin A (TSA). In vitro exposure of neuronal-BV2-microglial co-cultures to compounds revealed that TSA had the best overall neuroprotective, antioxidative, and anti-inflammatory effects. In vivo assessment in a rat TBI model revealed that TSA as a monotherapy (1 mg/kg/d) or in combination with the antiseizure drug levetiracetam (LEV 150 mg/kg/d) mildly mitigated the increase in plasma levels of the neurofilament subunit pNF-H and cortical lesion area. The percentage of rats with seizures during 0–72 h post-injury was reduced in the following order: TBI-vehicle 80%, TBI-TSA (1 mg/kg) 86%, TBI-LEV (54 mg/kg) 50%, TBI-LEV (150 mg/kg) 40% (p < 0.05 vs. TBI-vehicle), and TBI-LEV (150 mg/kg) combined with TSA (1 mg/kg) 30% (p < 0.05). Cumulative seizure duration was reduced in the following order: TBI-vehicle 727 ± 688 s, TBI-TSA 898 ± 937 s, TBI-LEV (54 mg/kg) 358 ± 715 s, TBI-LEV (150 mg/kg) 42 ± 64 (p < 0.05 vs. TBI-vehicle), and TBI-LEV (150 mg/kg) combined with TSA (1 mg/kg) 109 ± 282 s (p < 0.05). This first preclinical intervention study on post-TBI acute seizures shows that a combination therapy with the tissue recovery enhancer TSA and LEV was safe but exhibited no clear benefit over LEV monotherapy on antiseizure efficacy. A longer follow-up is needed to confirm the possible beneficial effects of LEV monotherapy and combination therapy with TSA on chronic post-TBI structural and functional outcomes, including epileptogenesis. Full article
(This article belongs to the Special Issue Molecular Research on Brain Injury)
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17 pages, 1939 KiB  
Article
Preliminary Development of a Brainwave Model for K1 Kickboxers Using Quantitative Electroencephalography (QEEG) with Open Eyes
by Łukasz Rydzik, Tadeusz Ambroży, Tomasz Pałka, Wojciech Wąsacz, Michał Spieszny, Jacek Perliński, Paweł Król and Marta Kopańska
Int. J. Mol. Sci. 2023, 24(10), 8882; https://doi.org/10.3390/ijms24108882 - 17 May 2023
Cited by 6 | Viewed by 1956
Abstract
K1 kickboxing fighting is characterised by high injury rates due to the low restrictions of fighting rules. In recent years, much attention has been paid to research on changes in brain function among athletes, including those in combat sports. One of the tools [...] Read more.
K1 kickboxing fighting is characterised by high injury rates due to the low restrictions of fighting rules. In recent years, much attention has been paid to research on changes in brain function among athletes, including those in combat sports. One of the tools that are likely to help diagnose and assess brain function is quantitative electroencephalography (QEEG). Therefore, the aim of the present study was an attempt to develop a brainwave model using quantitative electroencephalography in competitive K1 kickboxers. A total of thirty-six male individuals were purposefully selected and then comparatively divided into two groups. The first group consisted of specialised K1 kickboxing athletes exhibiting a high level of sports performance (experimental group, n = 18, mean age: 29.83 ± 3.43), while the second group comprised healthy individuals not training competitively (control group, n = 18, mean age: 26.72 ± 1.77). Body composition assessment was performed in all participants before the main measurement process. Measurements were taken for kickboxers during the de-training period, after the sports competition phase. Quantitative electroencephalography of Delta, Theta, Alpha, sensimotor rhytm (SMR), Beta1 and Beta2 waves was performed using electrodes placed on nine measurement points (frontal: FzF3F4, central: CzC3C4, and parietal: PzP3P4) with open eyes. In the course of the analyses, it was found that the level of brain activity among the study population significantly differentiated the K1 formula competitors compared with the reference standards and the control group in selected measurement areas. For kickboxers, all results of the Delta amplitude activity in the area of the frontal lobe were significantly above the normative values for this wave. The highest value was recorded for the average value of the F3 electrode (left frontal lobe), exceeding the norm by 95.65%, for F4 by 74.45% and Fz by 50.6%, respectively. In addition, the Alpha wave standard value for the F4 electrode was exceeded by 14.6%. Normative values were found for the remaining wave amplitudes. Statistically significant differentiation of results, with a strong effect (d = 1.52–8.41), was shown for the activity of Delta waves of the frontal area and the central part of the parietal area (Fz,F3,F4,Cz—p < 0.001), Theta for the frontal area as well as the central and left parietal lobes (Fz,F3,F4—p < 0.001, Cz—p = 0.001, C3—p = 0.018; d = 1.05–3.18), Alpha for the frontal, parietal and occipital areas (for: Fz,F3—p < 0.001, F4—p = 0.036, Cz—p < 0.001, C3—p = 0.001, C4—p = 0.025, Pz—p = 0.010, P3—p < 0.001, P4—p = 0.038; d = 0.90–1.66), SMR for the central parietal and left occipital lobes (Cz—p = 0.043; d = 0.69, P3—p < 0.001; d = 1.62), Beta for the frontal area, occipital and central lobes and left parietal segment (Fz,F3—p < 0.001, F4—p = 0.008, Cz, C3, Pz, P3,P4—p < 0.001; d = 1.27–2.85) and Beta 2 for all measurement areas (Fz, F3, F4, Cz, C3, C4, Pz, P3, P4—p < 0.001; d = 1.90–3.35) among the study groups. Significantly higher results were shown in the kickboxer group compared to the control. In addition to problems with concentration or over-stimulation of neural structures, high Delta waves, with elevated Alpha, Theta and Beta 2 waves, can cause disorders in the limbic system and problems in the cerebral cortex. Full article
(This article belongs to the Special Issue Molecular Research on Brain Injury)
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17 pages, 2780 KiB  
Article
Dexmedetomidine Protects Cerebellar Neurons against Hyperoxia-Induced Oxidative Stress and Apoptosis in the Juvenile Rat
by Robert Puls, Clarissa von Haefen, Christoph Bührer and Stefanie Endesfelder
Int. J. Mol. Sci. 2023, 24(9), 7804; https://doi.org/10.3390/ijms24097804 - 25 Apr 2023
Cited by 5 | Viewed by 2040
Abstract
The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development [...] Read more.
The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development could be a crucial factor in neurodevelopmental disorders of prematurity. Recent studies have focused on dexmedetomidine (DEX), which has been associated with potential neuroprotective properties and is used as an off-label application in neonatal units. Wistar rats (P6) were exposed to 80% hyperoxia for 24 h and received as pretreatment a single dose of DEX (5µg/kg, i.p.). Analyses in the immature rat cerebellum immediately after hyperoxia (P7) and after recovery to room air (P9, P11, and P14) included examinations for cell death and inflammatory and oxidative responses. Acute exposure to high oxygen concentrations caused a significant oxidative stress response, with a return to normal levels by P14. A marked reduction of hyperoxia-mediated damage was demonstrated after DEX pretreatment. DEX produced a much earlier recovery than in controls, confirming a neuroprotective effect of DEX on alterations elicited by oxygen stress on the developing cerebellum. Full article
(This article belongs to the Special Issue Molecular Research on Brain Injury)
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Review

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20 pages, 1543 KiB  
Review
Succinyl-CoA Synthetase Dysfunction as a Mechanism of Mitochondrial Encephalomyopathy: More than Just an Oxidative Energy Deficit
by Makayla S. Lancaster and Brett H. Graham
Int. J. Mol. Sci. 2023, 24(13), 10725; https://doi.org/10.3390/ijms241310725 - 27 Jun 2023
Cited by 13 | Viewed by 5217
Abstract
Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. [...] Read more.
Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. SCS-deficient encephalomyopathy typically presents in infancy and early childhood, with many patients succumbing to the disease during childhood. Common symptoms include abnormal brain MRI, basal ganglia lesions and cerebral atrophy, severe hypotonia, dystonia, progressive psychomotor regression, and growth deficits. Although subunits of SCS were first identified as causal genes for progressive metabolic encephalomyopathy in the early 2000s, recent investigations are now beginning to unravel the pathomechanisms underlying this metabolic disorder. This article reviews the current understanding of SCS function within and outside the TCA cycle as it relates to the complex and multifactorial mechanisms underlying SCS-related mitochondrial encephalomyopathy. Full article
(This article belongs to the Special Issue Molecular Research on Brain Injury)
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