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Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 8858

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Prof. Dr. Wojciech Dąbrowski

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Guest Editor

Faculty of Medicine, Medical University in Lublin, Lublin 20-090, Poland
Interests: brain injury

Dr. Katarzyna Kotfis

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Guest Editor

Department of Anesthesiology, Intensive Care and Pain Management, Pomeranian Medical University, 70-111 Szczecin, Poland
Interests: ICU delirium; post-operative delirium; pain; post-intensive care syndrome; delirium biomarkers; frailty; cognitive dysfunction; perioperative safety
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Dear Colleagues,

Traumatic brain injury (TBI) is frequently associated with multi-extracerebral organ dysfunction. It is commonly known as the brain-heart, brain-lung, brain-gut or brain-kidney interactions. Despite several studies describing these relationships, detailed pathomechanisms are not well recognized. Interestingly, TBI-induced extracerebral organ dysfunction may also intensify brain injury. Disorders of the autonomic nervous system, general inflammatory response to brain injury and/or hormonal dysregulation resulting from disorders of the hypothalamic-pituitary-adrenal axis seem to play a crucial role in peripheral organ injury. Commonly used treatment may also affect brain function. All of these problems are subject to discussion and investigation, therefore it is worthwhile to fully discuss each of the concepts of molecular pathomechanisms for TBI-related extracerebral organ dysfunction, as well as the effect of TBI-inducted multiorgan dysfunction on posttraumatic brain recovery and function. The present issue will also describe the molecular disorders of the central nervous system resulting from commonly used treatments, and the therapeutic proposal to reduce secondary brain damage.

Prof. Dr. Wojciech Dąbrowski
Dr. Katarzyna Kotfis
Guest Editors

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Keywords

traumatic brain injury
brain-peripheral organ interactions
hyperosmolar therapy
secondary brain injury
hyperoxia
hypoxia
cerebral

Published Papers (6 papers)

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Research

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40 pages, 11791 KiB

Open AccessArticle

Post-Traumatic Expressions of Aromatase B, Glutamine Synthetase, and Cystathionine-Beta-Synthase in the Cerebellum of Juvenile Chum Salmon, Oncorhynchus keta

by Evgeniya V. Pushchina, Mariya E. Bykova and Anatoly A. Varaksin

Int. J. Mol. Sci. 2024, 25(6), 3299; https://doi.org/10.3390/ijms25063299 - 14 Mar 2024

Cited by 2 | Viewed by 750

Abstract

In adult fish, neurogenesis occurs in many areas of the brain, including the cerebellum, with the ratio of newly formed cells relative to the total number of brain cells being several orders of magnitude greater than in mammals. Our study aimed to compare the expressions of aromatase B (AroB), glutamine synthetase (GS), and cystathionine-beta-synthase (CBS) in the cerebellum of intact juvenile chum salmon, Oncorhynchus keta. To identify the dynamics that determine the involvement of AroB, GS, and CBS in the cellular mechanisms of regeneration, we performed a comprehensive assessment of the expressions of these molecular markers during a long-term primary traumatic brain injury (TBI) and after a repeated acute TBI to the cerebellum of O. keta juveniles. As a result, in intact juveniles, weak or moderate expressions of AroB, GS, and CBS were detected in four cell types, including cells of the neuroepithelial type, migrating, and differentiated cells (graphic abstract, A). At 90 days post injury, local hypercellular areas were found in the molecular layer containing moderately labeled AroB+, GS+, and CBS+ cells of the neuroepithelial type and larger AroB+, GS+, and CBS+ cells (possibly analogous to the reactive glia of mammals); patterns of cells migration and neovascularization were also observed. A repeated TBI caused the number of AroB+, GS+, and CBS+ cells to further increase; an increased intensity of immunolabeling was recorded from all cell types (graphic abstract, C). Thus, the results of this study provide a better understanding of adult neurogenesis in teleost fishes, which is expected to clarify the issue of the reactivation of adult neurogenesis in mammalian species. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury)

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16 pages, 4460 KiB

Open AccessArticle

Sex-Specific and Traumatic Brain Injury Effects on Dopamine Receptor Expression in the Hippocampus

by Jaclyn Iannucci, Katherine O’Neill, Xuehua Wang, Sanjib Mukherjee, Jun Wang and Lee A. Shapiro

Int. J. Mol. Sci. 2023, 24(22), 16084; https://doi.org/10.3390/ijms242216084 - 8 Nov 2023

Cited by 1 | Viewed by 1944

Abstract

Traumatic brain injury (TBI) is a major health concern. Each year, over 50 million individuals worldwide suffer from TBI, and this leads to a number of acute and chronic health issues. These include affective and cognitive impairment, as well as an increased risk of alcohol and drug use. The dopaminergic system, a key component of reward circuitry, has been linked to alcohol and other substance use disorders, and previous research indicates that TBI can induce plasticity within this system. Understanding how TBI modifies the dopaminergic system may offer insights into the heightened substance use and reward-seeking behavior following TBI. The hippocampus, a critical component of the reward circuit, is responsible for encoding and integrating the spatial and salient aspects of rewarding stimuli. This study explored TBI-related changes in neuronal D2 receptor expression within the hippocampus, examining the hypothesis that sex differences exist in both baseline hippocampal D2 receptor expression and its response to TBI. Utilizing D2-expressing tdTomato transgenic male and female mice, we implemented either a sham injury or the lateral fluid percussion injury (FPI) model of TBI and subsequently performed a region-specific quantification of D2 expression in the hippocampus. The results show that male mice exhibit higher baseline hippocampal D2 expression compared to female mice. Additionally, there was a significant interaction effect between sex and injury on the expression of D2 in the hippocampus, particularly in regions of the dentate gyrus. Furthermore, TBI led to significant reductions in hippocampal D2 expression in male mice, while female mice remained mostly unaffected. These results suggest that hippocampal D2 expression varies between male and female mice, with the female dopaminergic system demonstrating less susceptibility to TBI-induced plasticity. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury)

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13 pages, 3130 KiB

Open AccessArticle

Oxidative Stress Markers in Human Brain and Placenta May Reveal the Timing of Hypoxic-Ischemic Injury: Evidence from an Immunohistochemical Study

by Benedetta Baldari, Stefania De Simone, Luigi Cipolloni, Paolo Frisoni, Letizia Alfieri, Stefano D’Errico, Vittorio Fineschi, Emanuela Turillazzi, Pantaleo Greco, Amerigo Vitagliano, Gennaro Scutiero and Margherita Neri

Int. J. Mol. Sci. 2023, 24(15), 12221; https://doi.org/10.3390/ijms241512221 - 30 Jul 2023

Viewed by 1417

Abstract

During pregnancy, reactive oxygen species (ROS) serve as crucial signaling molecules for fetoplacental circulatory physiology. Oxidative stress is thought to sustain the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). A retrospective study was performed on the brains and placentas of fetuses and newborns between 36–42 weeks of gestation (Group_1: Fetal intrauterine deaths, Group_2: Intrapartum deaths, Group_3: Post-partum deaths, Control group sudden neonatal death); all groups were further divided into two subgroups (Subgroup_B [brain] and Subgroup_P [placenta]), and the study was conducted through the immunohistochemical investigations of markers of oxidative stress (NOX2, 8-OHdG, NT, iNOS), IL-6, and only on the brain samples, AQP4. The results for the brain samples suggest that NOX2, 8-OHdG, NT, iNOS, and IL-6 were statistically significantly expressed above the controls. iNOS was more expressed in the fetal intrauterine death (Group_1) and less expressed in post-partum death (Group_3), while in intrapartum death (Group_2), the immunoreactivity was very low. IL-6 showed the highest expression in the brain cortex of the fetal intrauterine death (Group_1), while intrapartum death (Group_2) and post-partum death (Group_3) showed weak immunoreactivity. Post-partum death (Group_3) placentas showed the highest immunoreactivity to NOX2, which was almost double that of the fetal intrauterine death (Group_1) and intrapartum death (Group_2) placentas. Placental tissues of fetal intrauterine death (Group_1) and intrapartum death (Group_2) showed higher expression of iNOS than post-partum death (Group_3), while the IL-6 expression was higher in the fetal intrauterine death (Group_1) than the post-partum death (Group_3). The AQP4 was discarded as a possible marker because the immunohistochemical reaction in the three groups of cases and the control group was negative. The goal of this study, from the point of view of forensic pathology, is to provide scientific evidence in cases of medical liability in the Obstetric field to support the clinical data of the timing of HIE. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury)

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15 pages, 4010 KiB

Open AccessArticle

Comparative Study of Terminal Cortical Potentials Using Iridium and Ag/AgCl Electrodes

by Bulat Mingazov, Daria Vinokurova, Andrei Zakharov and Roustem Khazipov

Int. J. Mol. Sci. 2023, 24(13), 10769; https://doi.org/10.3390/ijms241310769 - 28 Jun 2023

Viewed by 950

Abstract

Brain ischemia induces slow voltage shifts in the cerebral cortex, including waves of spreading depolarization (SD) and negative ultraslow potentials (NUPs), which are considered as brain injury markers. However, different electrode materials and locations yield variable SD and NUP features. Here, we compared terminal cortical events during isoflurane or sevoflurane euthanasia using intracortical linear iridium electrode arrays and Ag/AgCl-based electrodes in the rat somatosensory cortex. Inhalation of anesthetics caused respiratory arrest, associated with hyperpolarization and followed by SD and NUP on both Ir and Ag electrodes. Ag-NUPs were bell shaped and waned within half an hour after death. Ir-NUPs were biphasic, with the early fast phase corresponding to Ag-NUP, and the late absent on Ag electrodes, phase of a progressive depolarizing voltage shift reaching −100 mV by two hours after death. In addition, late Ir-NUPs were more ample in the deep layers than at the cortical surface. Thus, intracortical Ag and Ir electrodes reliably assess early manifestations of terminal brain injury including hyperpolarization, SD and the early phase of NUP, while the late, giant amplitude phase of NUP, which is present only on Ir electrodes, is probably related to the sensitivity of Ir electrodes to a yet unidentified factor related to brain death. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury)

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19 pages, 1578 KiB

Open AccessArticle

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice

by Simon Klepper, Susan Jung, Lara Dittmann, Carol I. Geppert, Arnd Hartmann, Nicole Beier and Regina Trollmann

Int. J. Mol. Sci. 2022, 23(15), 8693; https://doi.org/10.3390/ijms23158693 - 4 Aug 2022

Cited by 3 | Viewed by 1852

Abstract

Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood–brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 µg/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln⁺ fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury)

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Review

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15 pages, 1358 KiB

Open AccessReview

Cerebral Glucose Metabolism following TBI: Changes in Plasma Glucose, Glucose Transport and Alternative Pathways of Glycolysis—A Translational Narrative Review

by Annerixt Gribnau, Mark L. van Zuylen, Jonathan P. Coles, Mark P. Plummer, Henning Hermanns and Jeroen Hermanides

Int. J. Mol. Sci. 2024, 25(5), 2513; https://doi.org/10.3390/ijms25052513 - 21 Feb 2024

Viewed by 1249

Abstract

Traumatic brain injury (TBI) is a major public health concern with significant consequences across various domains. Following the primary event, secondary injuries compound the outcome after TBI, with disrupted glucose metabolism emerging as a relevant factor. This narrative review summarises the existing literature on post-TBI alterations in glucose metabolism. After TBI, the brain undergoes dynamic changes in brain glucose transport, including alterations in glucose transporters and kinetics, and disruptions in the blood–brain barrier (BBB). In addition, cerebral glucose metabolism transitions from a phase of hyperglycolysis to hypometabolism, with upregulation of alternative pathways of glycolysis. Future research should further explore optimal, and possibly personalised, glycaemic control targets in TBI patients, with GLP-1 analogues as promising therapeutic candidates. Furthermore, a more fundamental understanding of alterations in the activation of various pathways, such as the polyol and lactate pathway, could hold the key to improving outcomes following TBI. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Extracerebral Factors Affecting Brain Injury)

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