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Biomedicines
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Molecular Mechanisms and Novel Therapies for Brain Injury
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Molecular Mechanisms and Novel Therapies for Brain Injury

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 9983

Special Issue Editor

Dr. Arjun Sapkota

E-Mail Website
Guest Editor
Neuroscience Lab, San Diego Biomedical Research Institute, San Diego, CA 92121, USA
Interests: ischemic stroke; multiple sclerosis; vascular dementia; neuroinflammation; hypoxia; vascular remodeling; drug discovery

Special Issue Information

Dear Colleagues,

Brain injury—whether that be stroke, spinal cord injury, traumatic brain injury, seizure, brain tumors—is the leading cause of death and disability globally. To date, numerous efforts have been made to develop new therapeutics that modulate the pathogenesis of brain injury. Unfortunately, these studies have not led to the successful development and discovery of new drug targets, biomarkers, and therapeutics that tackle brain injury. Therefore, uncovering the molecular mechanisms of injury, recovery, and neuroprotection is important for the development of novel, effective therapies.

This Special Issue aims to collect up-to-date overviews of the current understandings of brain injury, molecular mechanisms, and novel therapies, as well as the possible clinical translations and therapeutic strategies to treat brain injury. We invite authors to submit of original research articles, reviews, and short notes focusing on molecular mechanisms and novel therapies. These should highlight, but are not limited to, molecular or genetic manipulation affecting protective or detrimental outcomes, the mechanisms of action of various pharmacological agents, innovative therapeutic strategies for treatment, and neuroinflammation.

Dr. Arjun Sapkota
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. Biomedicines 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 2600 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

  • stroke
  • spinal cord injury
  • traumatic brain injury
  • seizure
  • brain tumors
  • neurodegeneration
  • neuroinflammation
  • blood–brain barrier disruption
  • neuroprotection
  • drug discover
  • mechanism of action
  • target validation

Published Papers (6 papers)

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Research

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15 pages, 1696 KiB  
Article
Brain Plasticity Modulator p75 Neurotrophin Receptor in Human Urine after Different Acute Brain Injuries—A Prospective Cohort Study
by Santtu Hellström, Antti Sajanti, Abhinav Srinath, Carolyn Bennett, Romuald Girard, Ying Cao, Janek Frantzén, Fredrika Koskimäki, Johannes Falter, Seán B. Lyne, Tomi Rantamäki, Riikka Takala, Jussi P. Posti, Susanna Roine, Jukka Puolitaival, Miro Jänkälä, Sulo Kolehmainen, Melissa Rahi, Jaakko Rinne, Eero Castrén and Janne Koskimäkiadd Show full author list remove Hide full author list
Biomedicines 2024, 12(1), 112; https://doi.org/10.3390/biomedicines12010112 - 05 Jan 2024
Viewed by 919
Abstract
Acute brain injuries (ABIs) pose a substantial global burden, demanding effective prognostic indicators for outcomes. This study explores the potential of urinary p75 neurotrophin receptor (p75NTR) concentration as a prognostic biomarker, particularly in relation to unfavorable outcomes. The study involved 46 ABI patients, [...] Read more.
Acute brain injuries (ABIs) pose a substantial global burden, demanding effective prognostic indicators for outcomes. This study explores the potential of urinary p75 neurotrophin receptor (p75NTR) concentration as a prognostic biomarker, particularly in relation to unfavorable outcomes. The study involved 46 ABI patients, comprising sub-cohorts of aneurysmal subarachnoid hemorrhage, ischemic stroke, and traumatic brain injury. Furthermore, we had four healthy controls. Samples were systematically collected from patients treated at the University Hospital of Turku between 2017 and 2019, at early (1.50 ± 0.70 days) and late (9.17 ± 3.40 days) post-admission time points. Urinary p75NTR levels, measured by ELISA and normalized to creatinine, were compared against patients’ outcomes using the modified Rankin Scale (mRS). Early urine samples showed no significant p75NTR concentration difference between favorable and unfavorable mRS groups. In contrast, late samples exhibited a statistically significant increase in p75NTR concentrations in the unfavorable group (p = 0.033), demonstrating good prognostic accuracy (AUC = 70.9%, 95% CI = 53–89%, p = 0.03). Assessment of p75NTR concentration changes over time revealed no significant variation in the favorable group (p = 0.992) but a significant increase in the unfavorable group (p = 0.009). Moreover, p75NTR concentration was significantly higher in ABI patients (mean ± SD 40.49 ± 28.83–65.85 ± 35.04 ng/mg) compared to healthy controls (mean ± SD 0.54 ± 0.44 ng/mg), irrespective of sampling time or outcome (p < 0.0001). In conclusion, late urinary p75NTR concentrations emerged as a potential prognostic biomarker for ABIs, showing increased levels associated with unfavorable outcomes regardless of the specific type of brain injury. While early samples exhibited no significant differences, the observed late increases emphasize the time-dependent nature of this potential biomarker. Further validation in larger patient cohorts is crucial, highlighting the need for additional research to establish p75NTR as a reliable prognostic biomarker across various ABIs. Additionally, its potential role as a diagnostic biomarker warrants exploration. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
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14 pages, 2318 KiB  
Article
Maternal Caffeine Consumption during Gestation and Lactation Abolishes Cortical Oxidative Stress and Restores Na+/K+-ATPase Activity in Neonates Exposed to Hyperthermia-Induced Seizures
by María Crespo, David Agustín León-Navarro and Mairena Martín
Biomedicines 2023, 11(12), 3292; https://doi.org/10.3390/biomedicines11123292 - 12 Dec 2023
Viewed by 886
Abstract
Caffeine is a psychoactive substance that is widely consumed by individuals of various demographics, including pregnant women. It can readily cross the blood–brain and placental barriers, easily reaching the fetal brain. In addition, caffeine has also shown antioxidant properties, as its consumption reduces [...] Read more.
Caffeine is a psychoactive substance that is widely consumed by individuals of various demographics, including pregnant women. It can readily cross the blood–brain and placental barriers, easily reaching the fetal brain. In addition, caffeine has also shown antioxidant properties, as its consumption reduces oxidative stress in various pathologies, including epilepsy. Febrile seizures (FS) are among the most common convulsive disorders in infants and young children. Here, we used an animal model of FS to learn whether maternal caffeine (1 g/L) intake consumption during gestation and lactation could exert beneficial effects on the rat cortex. Neonatal development was analyzed by measuring pinna opening, eye opening, righting reflex on the surface, and geotaxis reflex. Five and twenty days after HIS, the rats were euthanized, and plasma membranes and cytosolic fractions were isolated from their cortex brain. The enzymatic activities of glutathione reductase, glutathione S-transferase, Na+/K+-ATPase, and Mg2+-ATPase, as well as the levels of thiobarbituric acid reacting substances, were quantified. Results showed that maternal caffeine intake eliminates oxidative stress and normalizes Na+/K+-ATPase activity disrupted by HIS and also affects some parameters relating to the neurodevelopment of neonates. As FS in infants has been related to epilepsy in adults, the antioxidant properties of caffeine could prevent potential damage from hyperthermia. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
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12 pages, 4641 KiB  
Article
Isoflurane Conditioning Provides Protection against Subarachnoid Hemorrhage Induced Delayed Cerebral Ischemia through NF-kB Inhibition
by Meizi Liu, Keshav Jayaraman, Jogender Mehla, Deepti Diwan, James W. Nelson, Ahmed E. Hussein, Ananth K. Vellimana, Yousef Abu-Amer, Gregory J. Zipfel and Umeshkumar Athiraman
Biomedicines 2023, 11(4), 1163; https://doi.org/10.3390/biomedicines11041163 - 12 Apr 2023
Cited by 2 | Viewed by 1456
Abstract
Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is [...] Read more.
Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is pathologically associated with vasospasm. We previously showed that a brief exposure to isoflurane, an inhalational anesthetic, provided multifaceted protection against DCI after SAH. The aim of our current study is to investigate the role of NF-kB in isoflurane-conditioning-induced neurovascular protection against SAH-induced DCI. Twelve-week-old wild type male mice (C57BL/6) were divided into five groups: sham, SAH, SAH + Pyrrolidine dithiocarbamate (PDTC, a selective NF-kB inhibitor), SAH + isoflurane conditioning, and SAH + PDTC with isoflurane conditioning. Experimental SAH was performed via endovascular perforation. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. Three doses of PDTC (100 mg/kg) were injected intraperitoneally. NF-kB and microglial activation and the cellular source of NF-kB after SAH were assessed by immunofluorescence staining. Vasospasm, microvessel thrombosis, and neuroscore were assessed. NF-kB was activated after SAH; it was attenuated by isoflurane conditioning. Microglia was activated and found to be a major source of NF-kB expression after SAH. Isoflurane conditioning attenuated microglial activation and NF-kB expression in microglia after SAH. Isoflurane conditioning and PDTC individually attenuated large artery vasospasm and microvessel thrombosis, leading to improved neurological deficits after SAH. The addition of isoflurane to the PDTC group did not provide any additional DCI protection. These data indicate isoflurane-conditioning-induced DCI protection after SAH is mediated, at least in part, via downregulating the NF-kB pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
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21 pages, 11519 KiB  
Article
The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation
by Rika Bajorat, Lena Danckert, Florian Ebert, Theresa Bancken, Stefan Bergt, Felix Klawitter, Brigitte Vollmar, Daniel A. Reuter, Tobias Schürholz and Johannes Ehler
Biomedicines 2023, 11(3), 855; https://doi.org/10.3390/biomedicines11030855 - 11 Mar 2023
Viewed by 1390
Abstract
The synthetic antimicrobial peptides (sAMPs) Pep19-2.5 and Pep19-4LF have been shown in vitro and in vivo to reduce the release of pro-inflammatory cytokines, leading to the suppression of inflammation and immunomodulation. We hypothesized that intervention with Pep19-2.5 and Pep19-4LF immediately after cardiac arrest [...] Read more.
The synthetic antimicrobial peptides (sAMPs) Pep19-2.5 and Pep19-4LF have been shown in vitro and in vivo to reduce the release of pro-inflammatory cytokines, leading to the suppression of inflammation and immunomodulation. We hypothesized that intervention with Pep19-2.5 and Pep19-4LF immediately after cardiac arrest and resuscitation (CA-CPR) might attenuate immediate systemic inflammation, survival, and long-term outcomes in a standardized mouse model of CA-CPR. Long-term outcomes up to 28 days were assessed between a control group (saline) and two peptide intervention groups. Primarily, survival as well as neurological and cognitive parameters were assessed. In addition, systemic inflammatory molecules and specific biomarkers were analyzed in plasma as well as in brain tissue. Treatment with sAMPs did not provide any short- or long-term benefits for either survival or neurological outcomes, and no significant benefit on inflammation in the CA-CPR animal model. While no difference was found in the plasma analysis of early cytokines between the intervention groups four hours after resuscitation, a significant increase in UCH-L1, a biomarker of neuronal damage and blood–brain barrier rupture, was measured in the Pep19-4LF-treated group. The theoretical benefit of both sAMPs tested here for the treatment of post-cardiac arrest syndrome could not be proven. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
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Review

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22 pages, 401 KiB  
Review
Clinical Management in Traumatic Brain Injury
by Amy Yan, Andrew Torpey, Erin Morrisroe, Wesam Andraous, Ana Costa and Sergio Bergese
Biomedicines 2024, 12(4), 781; https://doi.org/10.3390/biomedicines12040781 - 02 Apr 2024
Viewed by 879
Abstract
Traumatic brain injury is one of the leading causes of morbidity and mortality worldwide and is one of the major public healthcare burdens in the US, with millions of patients suffering from the traumatic brain injury itself (approximately 1.6 million/year) or its repercussions [...] Read more.
Traumatic brain injury is one of the leading causes of morbidity and mortality worldwide and is one of the major public healthcare burdens in the US, with millions of patients suffering from the traumatic brain injury itself (approximately 1.6 million/year) or its repercussions (2–6 million patients with disabilities). The severity of traumatic brain injury can range from mild transient neurological dysfunction or impairment to severe profound disability that leaves patients completely non-functional. Indications for treatment differ based on the injury’s severity, but one of the goals of early treatment is to prevent secondary brain injury. Hemodynamic stability, monitoring and treatment of intracranial pressure, maintenance of cerebral perfusion pressure, support of adequate oxygenation and ventilation, administration of hyperosmolar agents and/or sedatives, nutritional support, and seizure prophylaxis are the mainstays of medical treatment for severe traumatic brain injury. Surgical management options include decompressive craniectomy or cerebrospinal fluid drainage via the insertion of an external ventricular drain. Several emerging treatment modalities are being investigated, such as anti-excitotoxic agents, anti-ischemic and cerebral dysregulation agents, S100B protein, erythropoietin, endogenous neuroprotectors, anti-inflammatory agents, and stem cell and neuronal restoration agents, among others. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
25 pages, 1100 KiB  
Review
Optimization of Nutrition after Brain Injury: Mechanistic and Therapeutic Considerations
by Roy A. Poblete, Shelby Yaceczko, Raya Aliakbar, Pravesh Saini, Saman Hazany, Hannah Breit, Stan G. Louie, Patrick D. Lyden and Arthur Partikian
Biomedicines 2023, 11(9), 2551; https://doi.org/10.3390/biomedicines11092551 - 17 Sep 2023
Cited by 1 | Viewed by 3242
Abstract
Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, [...] Read more.
Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Brain Injury)
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