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19 pages, 2322 KiB

Open AccessArticle

Expression of Doublecortin, Glial Fibrillar Acidic Protein, and Vimentin in the Intact Subpallium and after Traumatic Injury to the Pallium in Juvenile Salmon, Oncorhynchus masou

by Evgeniya V. Pushchina, Eva I. Zharikova and Anatoly A. Varaksin

Int. J. Mol. Sci. 2022, 23(3), 1334; https://doi.org/10.3390/ijms23031334 - 25 Jan 2022

Cited by 1 | Viewed by 2416

Abstract

Fetalization associated with a delay in development and the preservation of the features of the embryonic structure of the brain dominates the ontogeny of salmonids. The aim of the present study was to comparatively analyze the distribution of the glial-type aNSC markers such [...] Read more.

Fetalization associated with a delay in development and the preservation of the features of the embryonic structure of the brain dominates the ontogeny of salmonids. The aim of the present study was to comparatively analyze the distribution of the glial-type aNSC markers such as vimentin and glial fibrillar acidic protein (GFAP) and the migratory neuronal precursors such as doublecortin in the telencephalon subpallium of juvenile masu salmon, Oncorhynchus masou, in normal conditions and at 1 week after an injury to the dorsal pallium. Immunohistochemical labeling of vimentin, GFAP, and doublecortin in the pallium of intact juvenile masu salmon revealed single cells with similar morphologies corresponding to a persistent pool of neuronal and/or glial progenitors. The study of the posttraumatic process showed the presence of intensely GFAP-labeled cells of the neuroepithelial type that form reactive neurogenic zones in all areas of the subpallial zone of juvenile masu salmon. A comparative analysis of the distribution of radial glia in the dorsal, ventral, and lateral zones of the subpallium showed a maximum concentration of cells in the dorsal part of subpallium (VD) and a minimum concentration in the lateral part of subpallium VL. An essential feature of posttraumatic immunolabeling in the masu salmon subpallium is the GFAP distribution patterns that are granular intracellular in the apical periventricular zone (PVZ) and fibrillar extracellular in the subventricular (SVZ) and parenchymal zones (PZ). In contrast to those in intact animals, most of the GFAP+ granules and constitutive neurogenic niches in injured fish were localized in the basal part of the PVZ. With the traumatic injury to the subpallium, the number of Vim+ cells in the lateral and ventral regions significantly increased. At 1 week post-injury, the total immunolabeling of vimentin cells in the PVZ was replaced by the granular pattern of Vim immunodistribution spreading from the PVZ to the SVZ and deeper parenchymal layers of the brain in all areas of the subpallium. A significant increase in the number of DC+ cells was observed also in all areas of the subpallium. The number of cells increased both in the PVZ and in the SVZ, as well as in the deeper PZ. Thus, at 1 week after the injury to the dorsal pallium, the number of DC, Vim, and GFAP expressing cells of the neuroepithelial type in the subpallium of juvenile masu salmon increased, and additionally GFAP+ radial glia appeared in VD, which was absent from intact animals. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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16 pages, 6266 KiB

Open AccessArticle

Hippocampal Expression of Cytochrome P450 1B1 in Penetrating Traumatic Brain Injury

by Erik Lidin, Mattias K. Sköld, Maria Angéria, Johan Davidsson and Mårten Risling

Int. J. Mol. Sci. 2022, 23(2), 722; https://doi.org/10.3390/ijms23020722 - 10 Jan 2022

Cited by 6 | Viewed by 1644

Abstract

Hippocampal dysfunction contributes to multiple traumatic brain injury sequala. Female rodents’ outcome is superior to male which has been ascribed the neuroprotective sex hormones 17β-estradiol and progesterone. Cytochrome P450 1B1 (CYP1B1) is an oxidative enzyme influencing the neuroinflammatory response by creating inflammatory mediators [...] Read more.

Hippocampal dysfunction contributes to multiple traumatic brain injury sequala. Female rodents’ outcome is superior to male which has been ascribed the neuroprotective sex hormones 17β-estradiol and progesterone. Cytochrome P450 1B1 (CYP1B1) is an oxidative enzyme influencing the neuroinflammatory response by creating inflammatory mediators and metabolizing neuroprotective 17β-estradiol and progesterone. In this study, we aimed to describe hippocampal CYP1B1 mRNA expression, protein presence of CYP1B1 and its key redox partner Cytochrome P450 reductase (CPR) in both sexes, as well as the effect of penetrating traumatic brain injury (pTBI). A total 64 adult Sprague Dawley rats divided by sex received pTBI or sham-surgery and were assigned survival times of 1-, 3-, 5- or 7 days. CYP1B1 mRNA was quantified using in-situ hybridization and immunohistochemistry performed to verify protein colocalization. CYP1B1 mRNA expression was present in all subregions but greatest in CA2 irrespective of sex, survival time or intervention. At 3-, 5- and 7 days post-injury, expression in CA2 was reduced in male rats subjected to pTBI compared to sham-surgery. Females subjected to pTBI instead exhibited increased expression in all CA subregions 3 days post-injury, the only time point expression in CA2 was greater in females than in males. Immunohistochemical analysis confirmed neuronal CYP1B1 protein in all hippocampal subregions, while CPR was limited to CA1 and CA2. CYP1B1 mRNA is constitutively expressed in both sexes. In response to pTBI, females displayed a more urgent but brief regulatory response than males. This indicates there may be sex-dependent differences in CYP1B1 activity, possibly influencing inflammation and neuroprotection in pTBI. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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21 pages, 3239 KiB

Open AccessArticle

Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers

by Marzieh Hajiaghamemar, Todd Kilbaugh, Kristy B. Arbogast, Christina L. Master and Susan S. Margulies

Int. J. Mol. Sci. 2020, 21(5), 1786; https://doi.org/10.3390/ijms21051786 - 05 Mar 2020

Cited by 13 | Viewed by 3204

Abstract

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as [...] Read more.

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse (n = 13) or focal (n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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17 pages, 1698 KiB

Open AccessArticle

Integrative Analysis of Circulating Metabolite Profiles and Magnetic Resonance Imaging Metrics in Patients with Traumatic Brain Injury

by Ilias Thomas, Alex M. Dickens, Jussi P. Posti, Mehrbod Mohammadian, Christian Ledig, Riikka S. K. Takala, Tuulia Hyötyläinen, Olli Tenovuo and Matej Orešič

Int. J. Mol. Sci. 2020, 21(4), 1395; https://doi.org/10.3390/ijms21041395 - 19 Feb 2020

Cited by 10 | Viewed by 3522

Abstract

Recent evidence suggests that patients with traumatic brain injuries (TBIs) have a distinct circulating metabolic profile. However, it is unclear if this metabolomic profile corresponds to changes in brain morphology as observed by magnetic resonance imaging (MRI). The aim of this study was [...] Read more.

Recent evidence suggests that patients with traumatic brain injuries (TBIs) have a distinct circulating metabolic profile. However, it is unclear if this metabolomic profile corresponds to changes in brain morphology as observed by magnetic resonance imaging (MRI). The aim of this study was to explore how circulating serum metabolites, following TBI, relate to structural MRI (sMRI) findings. Serum samples were collected upon admission to the emergency department from patients suffering from acute TBI and metabolites were measured using mass spectrometry-based metabolomics. Most of these patients sustained a mild TBI. In the same patients, sMRIs were taken and volumetric data were extracted (138 metrics). From a pool of 203 eligible screened patients, 96 met the inclusion criteria for this study. Metabolites were summarized as eight clusters and sMRI data were reduced to 15 independent components (ICs). Partial correlation analysis showed that four metabolite clusters had significant associations with specific ICs, reflecting both the grey and white matter brain injury. Multiple machine learning approaches were then applied in order to investigate if circulating metabolites could distinguish between positive and negative sMRI findings. A logistic regression model was developed, comprised of two metabolic predictors (erythronic acid and myo-inositol), which, together with neurofilament light polypeptide (NF-L), discriminated positive and negative sMRI findings with an area under the curve of the receiver-operating characteristic of 0.85 (specificity = 0.89, sensitivity = 0.65). The results of this study show that metabolomic analysis of blood samples upon admission, either alone or in combination with protein biomarkers, can provide valuable information about the impact of TBI on brain structural changes. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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17 pages, 2746 KiB

Open AccessArticle

Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion

by Meghan Blaya, Jessie Truettner, Weizhao Zhao, Helen Bramlett and William Dalton Dietrich

Int. J. Mol. Sci. 2020, 21(2), 609; https://doi.org/10.3390/ijms21020609 - 17 Jan 2020

Cited by 4 | Viewed by 2598

Abstract

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes [...] Read more.

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes and other active individuals who may sustain repetitive concussive injury during periods of exercise and exertion when core temperatures are elevated. Previous studies have emphasized the impact that increased brain temperature has on adverse neurological outcomes. A lack of diagnostic tools to assess concussive mTBI limits the ability to effectively identify the post-concussive period during which the brain is uniquely susceptible to damage upon sustaining additional injury. Studies have suggested that a temporal window of increased vulnerability that exists corresponds to a period of injury-induced depression of cerebral glucose metabolism. In the current study, we sought to evaluate the relationship between repetitive concussion, local cerebral glucose metabolism, and brain temperature using the Marmarou weight drop model to generate mTBI. Animals were injured three consecutive times over a period of 7 days while exposed to either normothermic or hyperthermic temperatures for 15 min prior to and 1 h post each injury. A ¹⁴C-2-deoxy-d-glucose (2DG) autoradiography was used to measure local cerebral metabolic rate of glucose (lCMR_Glc) in 10 diverse brain regions across nine bregma levels 8 days after the initial insult. We found that repetitive mTBI significantly decreased glucose utilization bilaterally in several cortical areas, such as the cingulate, visual, motor, and retrosplenial cortices, as well as in subcortical areas, including the caudate putamen and striatum, compared to sham control animals. lCMR_Glc was significant in both normothermic and hyperthermic repetitive mTBI animals relative to the sham group, but to a greater degree when exposed to hyperthermic conditions. Taken together, we report significant injury-induced glucose hypometabolism after repetitive concussion in the brain, and additionally highlight the importance of temperature management in the acute period after brain injury. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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12 pages, 1518 KiB

Open AccessArticle

Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus

by Ilknur Ozen, Karsten Ruscher, Robert Nilsson, Johanna Flygt, Fredrik Clausen and Niklas Marklund

Int. J. Mol. Sci. 2020, 21(2), 387; https://doi.org/10.3390/ijms21020387 - 08 Jan 2020

Cited by 21 | Viewed by 3591

Abstract

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson’s disease (PD). Interleukin-1beta (IL-1β), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1β was found to improve functional recovery following experimental TBI. However, the mechanisms [...] Read more.

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson’s disease (PD). Interleukin-1beta (IL-1β), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1β was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1β neutralization are still poorly understood. The present study investigated the role of IL-1β on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1β neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1β attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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22 pages, 8065 KiB

Open AccessArticle

Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement

by Giacomo Lazzarino, Angela Maria Amorini, Stefano Signoretti, Giuseppe Musumeci, Giuseppe Lazzarino, Giuseppe Caruso, Francesco Saverio Pastore, Valentina Di Pietro, Barbara Tavazzi and Antonio Belli

Int. J. Mol. Sci. 2019, 20(22), 5774; https://doi.org/10.3390/ijms20225774 - 16 Nov 2019

Cited by 33 | Viewed by 4327

Abstract

Using a closed-head impact acceleration model of mild or severe traumatic brain injury (mTBI or sTBI, respectively) in rats, we evaluated the effects of graded head impacts on the gene and protein expressions of pyruvate dehydrogenase (PDH), as well as major enzymes of [...] Read more.

Using a closed-head impact acceleration model of mild or severe traumatic brain injury (mTBI or sTBI, respectively) in rats, we evaluated the effects of graded head impacts on the gene and protein expressions of pyruvate dehydrogenase (PDH), as well as major enzymes of mitochondrial tricarboxylic acid cycle (TCA). TBI was induced in anaesthetized rats by dropping 450 g from 1 (mTBI) or 2 m height (sTBI). After 6 h, 12 h, 24 h, 48 h, and 120 h gene expressions of enzymes and subunits of PDH. PDH kinases and phosphatases (PDK1-4 and PDP1-2, respectively), citrate synthase (CS), isocitrate dehydrogenase (IDH), oxoglutarate dehydrogenase (OGDH), succinate dehydrogenase (SDH), succinyl-CoA synthase (SUCLG), and malate dehydrogenase (MDH) were determined in whole brain extracts (n = 6 rats at each time for both TBI levels). In the same samples, the high performance liquid chromatographic (HPLC) determination of acetyl-coenzyme A (acetyl-CoA) and free coenzyme A (CoA-SH) was performed. Sham-operated animals (n = 6) were used as controls. After mTBI, the results indicated a general transient decrease, followed by significant increases, in PDH and TCA gene expressions. Conversely, permanent PDH and TCA downregulation occurred following sTBI. The inhibitory conditions of PDH (caused by PDP1-2 downregulations and PDK1-4 overexpression) and SDH appeared to operate only after sTBI. This produced almost no change in acetyl-CoA and free CoA-SH following mTBI and a remarkable depletion of both compounds after sTBI. These results again demonstrated temporary or steady mitochondrial malfunctioning, causing minimal or profound modifications to energy-related metabolites, following mTBI or sTBI, respectively. Additionally, PDH and SDH appeared to be highly sensitive to traumatic insults and are deeply involved in mitochondrial-related energy metabolism imbalance. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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31 pages, 2601 KiB

Open AccessArticle

In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury—Lessons Learned

by Anssi Lipponen, Teemu Natunen, Mika Hujo, Robert Ciszek, Elina Hämäläinen, Jussi Tohka, Mikko Hiltunen, Jussi Paananen, David Poulsen, Emilia Kansanen, Xavier Ekolle Ndode-Ekane, Anna-Liisa Levonen and Asla Pitkänen

Int. J. Mol. Sci. 2019, 20(21), 5395; https://doi.org/10.3390/ijms20215395 - 29 Oct 2019

Cited by 10 | Viewed by 4884

Abstract

We developed a pipeline for the discovery of transcriptomics-derived disease-modifying therapies and used it to validate treatments in vitro and in vivo that could be repurposed for TBI treatment. Desmethylclomipramine, ionomycin, sirolimus and trimipramine, identified by in silico LINCS analysis as candidate treatments [...] Read more.

We developed a pipeline for the discovery of transcriptomics-derived disease-modifying therapies and used it to validate treatments in vitro and in vivo that could be repurposed for TBI treatment. Desmethylclomipramine, ionomycin, sirolimus and trimipramine, identified by in silico LINCS analysis as candidate treatments modulating the TBI-induced transcriptomics networks, were tested in neuron-BV2 microglial co-cultures, using tumour necrosis factor α as a monitoring biomarker for neuroinflammation, nitrite for nitric oxide-mediated neurotoxicity and microtubule associated protein 2-based immunostaining for neuronal survival. Based on (a) therapeutic time window in silico, (b) blood-brain barrier penetration and water solubility, (c) anti-inflammatory and neuroprotective effects in vitro (p < 0.05) and (d) target engagement of Nrf2 target genes (p < 0.05), desmethylclomipramine was validated in a lateral fluid-percussion model of TBI in rats. Despite the favourable in silico and in vitro outcomes, in vivo assessment of clomipramine, which metabolizes to desmethylclomipramine, failed to demonstrate favourable effects on motor and memory tests. In fact, clomipramine treatment worsened the composite neuroscore (p < 0.05). Weight loss (p < 0.05) and prolonged upregulation of plasma cytokines (p < 0.05) may have contributed to the worsened somatomotor outcome. Our pipeline provides a rational stepwise procedure for evaluating favourable and unfavourable effects of systems-biology discovered compounds that modulate post-TBI transcriptomics. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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10 pages, 698 KiB

Open AccessCommunication

Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats

by Nikolett Szarka, Luca Toth, Andras Czigler, Zoltan Kellermayer, Zoltan Ungvari, Krisztina Amrein, Endre Czeiter, Zsolt Kristof Bali, Sai Ambika Tadepalli, Matyas Wahr, Istvan Hernadi, Akos Koller, Andras Buki and Peter Toth

Int. J. Mol. Sci. 2019, 20(13), 3223; https://doi.org/10.3390/ijms20133223 - 30 Jun 2019

Cited by 19 | Viewed by 4420

Abstract

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid [...] Read more.

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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Review

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15 pages, 1373 KiB

Open AccessReview

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

by Alexander Fletcher-Sandersjöö, Marc Maegele and Bo-Michael Bellander

Int. J. Mol. Sci. 2020, 21(5), 1596; https://doi.org/10.3390/ijms21051596 - 26 Feb 2020

Cited by 18 | Viewed by 4414

Abstract

Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which [...] Read more.

Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which is abundant in the healthy brain, undergoes significant intra- and extracranial amplification following TBI. Previously considered to be structurally similar but separate systems, evidence of an interaction between the complement and coagulation systems in non-TBI cohorts has accumulated, with the activation of one system amplifying the activation of the other, independent of their established pathways. However, it is not known whether this interaction exists in TBI. In this review we summarize the available literature on complement activation following TBI, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system interacts with the coagulation cascade by activating the intrinsic coagulation pathway and by bypassing the initial cascade and directly producing thrombin as well. This crosstalk also effects platelets, where evidence points to a relationship with the complement system on multiple levels, with complement anaphylatoxins being able to induce disproportionate platelet activation and adhesion. The complement system also stimulates thrombosis by inhibiting fibrinolysis and stimulating endothelial cells to release prothrombotic microparticles. These interactions see clinical relevance in several disorders where a deficiency in complement regulation seems to result in a prothrombotic clinical presentation. Finally, based on these observations, we present the outline of an observational cohort study that is currently under preparation and aimed at assessing how complement influences coagulation in patients with isolated TBI. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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11 pages, 880 KiB

Open AccessReview

The Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury

by Denes Toth, Andrea Tamas and Dora Reglodi

Int. J. Mol. Sci. 2020, 21(3), 827; https://doi.org/10.3390/ijms21030827 - 28 Jan 2020

Cited by 22 | Viewed by 4522

Abstract

Traumatic brain injury remains a growing public health concern and represents the greatest contributor to death and disability globally among all trauma-related injuries. There are limited clinical data regarding biomarkers in the diagnosis and outcome prediction of TBI. The lack of real effective [...] Read more.

Traumatic brain injury remains a growing public health concern and represents the greatest contributor to death and disability globally among all trauma-related injuries. There are limited clinical data regarding biomarkers in the diagnosis and outcome prediction of TBI. The lack of real effective treatment for recovery calls for research of TBI to be shifted into the area of prevention, treatment of secondary brain injury and neurorehabilitation. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been reported to act as a hormone, a neuromodulator, a neurotransmitter and a trophic factor, and has been implicated in a variety of developmental and regenerative processes. The importance of PACAP in neuronal regeneration lies in the upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central nervous system injury. The aim of this minireview is to summarize both the therapeutic and biomarker potential of the neuropeptide PACAP, as a novel possible target molecule presently being investigated in several human conditions including TBI, and with encouraging results in animal models of TBI. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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27 pages, 844 KiB

Open AccessReview

Approaches to Monitor Circuit Disruption after Traumatic Brain Injury: Frontiers in Preclinical Research

by Gokul Krishna, Joshua A. Beitchman, Caitlin E. Bromberg and Theresa Currier Thomas

Int. J. Mol. Sci. 2020, 21(2), 588; https://doi.org/10.3390/ijms21020588 - 16 Jan 2020

Cited by 20 | Viewed by 5091

Abstract

Mild traumatic brain injury (TBI) often results in pathophysiological damage that can manifest as both acute and chronic neurological deficits. In an attempt to repair and reconnect disrupted circuits to compensate for loss of afferent and efferent connections, maladaptive circuitry is created and [...] Read more.

Mild traumatic brain injury (TBI) often results in pathophysiological damage that can manifest as both acute and chronic neurological deficits. In an attempt to repair and reconnect disrupted circuits to compensate for loss of afferent and efferent connections, maladaptive circuitry is created and contributes to neurological deficits, including post-concussive symptoms. The TBI-induced pathology physically and metabolically changes the structure and function of neurons associated with behaviorally relevant circuit function. Complex neurological processing is governed, in part, by circuitry mediated by primary and modulatory neurotransmitter systems, where signaling is disrupted acutely and chronically after injury, and therefore serves as a primary target for treatment. Monitoring of neurotransmitter signaling in experimental models with technology empowered with improved temporal and spatial resolution is capable of recording in vivo extracellular neurotransmitter signaling in behaviorally relevant circuits. Here, we review preclinical evidence in TBI literature that implicates the role of neurotransmitter changes mediating circuit function that contributes to neurological deficits in the post-acute and chronic phases and methods developed for in vivo neurochemical monitoring. Coupling TBI models demonstrating chronic behavioral deficits with in vivo technologies capable of real-time monitoring of neurotransmitters provides an innovative approach to directly quantify and characterize neurotransmitter signaling as a universal consequence of TBI and the direct influence of pharmacological approaches on both behavior and signaling. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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30 pages, 6064 KiB

Open AccessReview

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

by Ruchira M. Jha, Josh Bell, Giuseppe Citerio, J. Claude Hemphill, W. Taylor Kimberly, Raj K. Narayan, Juan Sahuquillo, Kevin N. Sheth and J. Marc Simard

Int. J. Mol. Sci. 2020, 21(2), 409; https://doi.org/10.3390/ijms21020409 - 09 Jan 2020

Cited by 37 | Viewed by 5735

Abstract

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 [...] Read more.

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)—Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease. Full article

(This article belongs to the Special Issue Understanding Traumatic Brain Injury: Mechanisms and Therapeutic Targets)

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