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Pharmaceutics
Special Issues
Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies
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Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 16657

Special Issue Editor

Dr. Maria Tikhonova

E-Mail Website
Guest Editor
Research Institute for Neurosciences & Medicine, 630117 Novosibirsk, Russia
Interests: neuroscience; neuropharmacology; neurodegenerative disorders; traumatic brain injury; animal models; behavior; neurogenomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue for Pharmaceutics entitled “Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies”.

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality all over the world. Four overlapping stages are distinguished in the pathogenesis of TBI: a primary lesion, the development of its consequences, secondary damage, and regeneration. Secondary lesions are associated with the combined effects of neurotransmitter excitotoxicity, electrolyte imbalance, neuroinflammation, and intracellular stress. Of the factors of secondary damage to brain cells in TBI, cerebral edema is the most frequent and dangerous. There are two major types of edema: cytotoxic edema and vasogenic edema. Cytotoxic edema is induced by hypoxia or ischemia, which leads to the upregulation of various ion channels, such as Na-K-2Cl channels, or failure of sodium–potassium pumps in the astrocytic or neuronal membrane. The most important characteristic of vasogenic edema is blood–brain barrier (BBB) rupture, which directly results from the breakdown of tight junctions between vascular endothelial cells. A tight junction is composed of a series of interacting transmembrane proteins, including zona occludens-1 (ZO-1), claudin-1, claudin-3, and occludin. Thus, these ion channels and transmembrane proteins attract certain attention as potential targets for TBI treatment.

This Special Issue is meant to highlight recent progress in the field. We welcome all types of articles providing new insights from experimental models and human studies about TBI mechanisms, with a focus on targets for pharmacological intervention and novel approaches to TBI treatment.

Dr. Maria Tikhonova
Guest Editor

Manuscript Submission Information

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

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

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • traumatic brain injury
  • cytotoxic brain edema
  • vasogenic brain edema
  • neuroinflammation
  • neurogenesis
  • oxidative stress
  • heat shock proteins
  • neurodegeneration
  • excitotoxicity
  • neuroregenerative therapy
  • traumatic brain injury (TBI) mechanisms and novel therapies

Published Papers (6 papers)

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Research

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27 pages, 5569 KiB  
Article
Post-Injury Buprenorphine Administration Is Associated with Long-Term Region-Specific Glial Alterations in Rats
by Jane Ryu, Pantea Jeizan, Saira Ahmed, Sareena Ehsan, Jefin Jose, Sean Regan, Karen Gorse, Corrina Kelliher and Audrey Lafrenaye
Pharmaceutics 2022, 14(10), 2068; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14102068 - 28 Sep 2022
Cited by 1 | Viewed by 1830
Abstract
Traumatic brain injury (TBI) is a major leading cause of death and disability. While previous studies regarding focal pathologies following TBI have been done, there is a lack of information concerning the role of analgesics and their influences on injury pathology. Buprenorphine (Bup), [...] Read more.
Traumatic brain injury (TBI) is a major leading cause of death and disability. While previous studies regarding focal pathologies following TBI have been done, there is a lack of information concerning the role of analgesics and their influences on injury pathology. Buprenorphine (Bup), an opioid analgesic, is a commonly used analgesic in experimental TBI models. Our previous studies investigated the acute effects of Buprenorphine-sustained release-Lab (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. The current study investigated the longer-term chronic outcomes of Bup-SR-Lab treatment at 4 weeks following TBI utilizing a central fluid percussion injury (cFPI) model in adult male rats. Histological assessments of physiological changes, neuronal damage, cortical and thalamic cytokine expression, microglial and astrocyte morphological changes, and myelin alterations were done, as we had done in our acute study. In the current study the Whisker Nuisance Task (WNT) was also performed pre- and 4w post-injury to assess changes in somatosensory sensitivity following saline or Bup-SR-Lab treatment. Bup-SR-Lab treatment had no impact on overall physiology or neuronal damage at 4w post-injury regardless of region or injury, nor did it have any significant effects on somatosensory sensitivity. However, greater IL-4 cytokine expression with Bup-SR-Lab treatment was observed compared to saline treated animals. Microglia and astrocytes also demonstrated region-specific morphological alterations associated with Bup-SR-Lab treatment, in which cortical microglia and thalamic astrocytes were particularly vulnerable to Bup-mediated changes. There were discernable injury-specific and region-specific differences regarding myelin integrity and changes in specific myelin basic protein (MBP) isoform expression following Bup-SR-Lab treatment. This study indicates that use of Bup-SR-Lab could impact TBI-induced glial alterations in a region-specific manner 4w following diffuse brain injury. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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21 pages, 27124 KiB  
Article
A Novel Laser-Based Zebrafish Model for Studying Traumatic Brain Injury and Its Molecular Targets
by Maria A. Tikhonova, Nikolai A. Maslov, Alim A. Bashirzade, Eugenyi V. Nehoroshev, Vladislav Y. Babchenko, Nadezhda D. Chizhova, Elena O. Tsibulskaya, Anna A. Akopyan, Evgeniya V. Markova, Yi-Ling Yang, Kwok-Tung Lu, Allan V. Kalueff, Lyubomir I. Aftanas and Tamara G. Amstislavskaya
Pharmaceutics 2022, 14(8), 1751; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14081751 - 22 Aug 2022
Cited by 3 | Viewed by 2716
Abstract
Traumatic brain injury (TBI) is a major public health problem. Here, we developed a novel model of non-invasive TBI induced by laser irradiation in the telencephalon of adult zebrafish (Danio rerio) and assessed their behavior and neuromorphology to validate the model and evaluate [...] Read more.
Traumatic brain injury (TBI) is a major public health problem. Here, we developed a novel model of non-invasive TBI induced by laser irradiation in the telencephalon of adult zebrafish (Danio rerio) and assessed their behavior and neuromorphology to validate the model and evaluate potential targets for neuroreparative treatment. Overall, TBI induced hypolocomotion and anxiety-like behavior in the novel tank test, strikingly recapitulating responses in mammalian TBI models, hence supporting the face validity of our model. NeuN-positive cell staining was markedly reduced one day, but not seven days, after TBI, suggesting increased neuronal damage immediately after the injury, and its fast recovery. The brain-derived neurotrophic factor (Bdnf) level in the brain dropped immediately after the trauma, but fully recovered seven days later. A marker of microglial activation, Iba1, was elevated in the TBI brain, albeit decreasing from Day 3. The levels of hypoxia-inducible factor 1-alpha (Hif1a) increased 30 min after the injury, and recovered by Day 7, further supporting the construct validity of the model. Collectively, these findings suggest that our model of laser-induced brain injury in zebrafish reproduces mild TBI and can be a useful tool for TBI research and preclinical neuroprotective drug screening. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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17 pages, 2532 KiB  
Article
Activation of NLRP3 Is Required for a Functional and Beneficial Microglia Response after Brain Trauma
by Ana Belen Lopez-Rodriguez, Céline Decouty-Perez, Victor Farré-Alins, Alejandra Palomino-Antolín, Paloma Narros-Fernández and Javier Egea
Pharmaceutics 2022, 14(8), 1550; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14081550 - 26 Jul 2022
Cited by 7 | Viewed by 1652
Abstract
Despite the numerous research studies on traumatic brain injury (TBI), many physiopathologic mechanisms remain unknown. TBI is a complex process, in which neuroinflammation and glial cells play an important role in exerting a functional immune and damage-repair response. The activation of the NLRP3 [...] Read more.
Despite the numerous research studies on traumatic brain injury (TBI), many physiopathologic mechanisms remain unknown. TBI is a complex process, in which neuroinflammation and glial cells play an important role in exerting a functional immune and damage-repair response. The activation of the NLRP3 inflammasome is one of the first steps to initiate neuroinflammation and so its regulation is essential. Using a closed-head injury model and a pharmacological (MCC950; 3 mg/kg, pre- and post-injury) and genetical approach (NLRP3 knockout (KO) mice), we defined the transcriptional and behavioral profiles 24 h after TBI. Wild-type (WT) mice showed a strong pro-inflammatory response, with increased expression of inflammasome components, microglia and astrocytes markers, and cytokines. There was no difference in the IL1β production between WT and KO, nor compensatory mechanisms of other inflammasomes. However, some microglia and astrocyte markers were overexpressed in KO mice, resulting in an exacerbated cytokine expression. Pretreatment with MCC950 replicated the behavioral and blood–brain barrier results observed in KO mice and its administration 1 h after the lesion improved the damage. These findings highlight the importance of NLRP3 time-dependent activation and its role in the fine regulation of glial response. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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16 pages, 1962 KiB  
Article
Chronic Administration of 7,8-DHF Lessens the Depression-like Behavior of Juvenile Mild Traumatic Brain Injury Treated Rats at Their Adult Age
by Shih-Te Yang, Hsiu-Yi Hung, Long-Sun Ro, Ming-Feng Liao, Tamara G. Amstislavskaya, Maria A. Tikhonova, Yi-Ling Yang and Kwok-Tung Lu
Pharmaceutics 2021, 13(12), 2169; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122169 - 16 Dec 2021
Cited by 3 | Viewed by 2238
Abstract
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among the global youth and commonly results in long-lasting sequelae, including paralysis, epilepsy, and a host of mental disorders such as major depressive disorder. Previous studies were mainly focused on severe [...] Read more.
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among the global youth and commonly results in long-lasting sequelae, including paralysis, epilepsy, and a host of mental disorders such as major depressive disorder. Previous studies were mainly focused on severe TBI as it occurs in adults. This study explored the long-term adverse effect of mild TBI in juvenile animals (mTBI-J). Male Sprague Dawley rats received mTBI-J or sham treatment at six weeks old, then underwent behavioral, biochemical, and histological experiments three weeks later (at nine weeks old). TTC staining, H&E staining, and brain edema measurement were applied to evaluate the mTBI-J induced cerebral damage. The forced swimming test (FST) and sucrose preference test (SPT) were applied for measuring depression-like behavior. The locomotor activity test (LAT) was performed to examine mTBI-J treatment effects on motor function. After the behavioral experiments, the dorsal hippocampus (dHip) and ventral hippocampus (vHip) were dissected out for western blotting to examine the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB). Finally, a TrkB agonist 7,8-DHF was injected intraperitoneally to evaluate its therapeutic effect on the mTBI-J induced behavioral abnormalities at the early adult age. Results showed that a mild brain edema occurred, but no significant neural damage was found in the mTBI-J treated animals. In addition, a significant increase of depression-like behaviors was observed in the mTBI-J treated animals; the FST revealed an increase in immobility, and a decrease in sucrose consumption was found in the mTBI-J treated animals. There were no differences observed in the total distance traveled of the LAT and the fall latency of the rotarod test. The hippocampal BDNF expression, but not the TrkB, were significantly reduced in mTBI-J, and the mTBI-J treatment-induced depression-like behavior was lessened after four weeks of 7,8-DHF administration. Collectively, these results indicate that even a mild juvenile TBI treatment that did not produce motor deficits or significant histological damage could have a long-term adverse effect that could be sustained to adulthood, which raises the depression-like behavior in the adult age. In addition, chronic administration of 7,8-DHF lessens the mTBI-J treatment-induced depression-like behaviors in adult rats. We suggest the potential usage of 7,8-DHF as a therapeutic agent for preventing the long-term adverse effect of mTBI-J. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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Review

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26 pages, 904 KiB  
Review
Revisiting Excitotoxicity in Traumatic Brain Injury: From Bench to Bedside
by Daniela Baracaldo-Santamaría, Daniel Felipe Ariza-Salamanca, María Gabriela Corrales-Hernández, Maria José Pachón-Londoño, Isabella Hernandez-Duarte and Carlos-Alberto Calderon-Ospina
Pharmaceutics 2022, 14(1), 152; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010152 - 08 Jan 2022
Cited by 26 | Viewed by 3646
Abstract
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality. Consequences vary from mild cognitive impairment to death and, no matter the severity of subsequent sequelae, it represents a high burden for affected patients and for the health care [...] Read more.
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality. Consequences vary from mild cognitive impairment to death and, no matter the severity of subsequent sequelae, it represents a high burden for affected patients and for the health care system. Brain trauma can cause neuronal death through mechanical forces that disrupt cell architecture, and other secondary consequences through mechanisms such as inflammation, oxidative stress, programmed cell death, and, most importantly, excitotoxicity. This review aims to provide a comprehensive understanding of the many classical and novel pathways implicated in tissue damage following TBI. We summarize the preclinical evidence of potential therapeutic interventions and describe the available clinical evaluation of novel drug targets such as vitamin B12 and ifenprodil, among others. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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47 pages, 1090 KiB  
Review
Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment
by Clément Delage, Toufik Taib, Célia Mamma, Dominique Lerouet and Valérie C. Besson
Pharmaceutics 2021, 13(10), 1624; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101624 - 06 Oct 2021
Cited by 25 | Viewed by 3696
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability all over the world. TBI leads to (1) an inflammatory response, (2) white matter injuries and (3) neurodegenerative pathologies in the long term. In humans, TBI occurs most often in children [...] Read more.
Traumatic brain injury (TBI) is a leading cause of death and disability all over the world. TBI leads to (1) an inflammatory response, (2) white matter injuries and (3) neurodegenerative pathologies in the long term. In humans, TBI occurs most often in children and adolescents or in the elderly, and it is well known that immune responses and the neuroregenerative capacities of the brain, among other factors, vary over a lifetime. Thus, age-at-injury can influence the consequences of TBI. Furthermore, age-at-injury also influences the pharmacological effects of drugs. However, the post-TBI inflammatory, neuronal and functional consequences have been mostly studied in experimental young adult animal models. The specificity and the mechanisms underlying the consequences of TBI and pharmacological responses are poorly understood in extreme ages. In this review, we detail the variations of these age-dependent inflammatory responses and consequences after TBI, from an experimental point of view. We investigate the evolution of microglial, astrocyte and other immune cells responses, and the consequences in terms of neuronal death and functional deficits in neonates, juvenile, adolescent and aged male animals, following a single TBI. We also describe the pharmacological responses to anti-inflammatory or neuroprotective agents, highlighting the need for an age-specific approach to the development of therapies of TBI. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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