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Brain Injury: New Insights into Mechanisms and Future Promising Treatments

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 5844

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Special Issue Editors

Dr. Kristina Pilipović

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Guest Editor

Faculty of Medicine, University of Rijeka, Rijeka, Croatia
Interests: traumatic brain injury; stroke; neurodegeneration; neuroinflammation; glia; nanotechnology; vesicles

Dr. Petra Dolenec

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Guest Editor

Faculty of Medicine, University of Rijeka, Rijeka, Croatia
Interests: traumatic brain injury; microglia; neurodegeneration; neuroinflammation; pharmacology

Special Issue Information

Dear Colleagues,

Every year, more than 85 million people suffer from acquired brain injuries, with traumatic injury and stroke being their most common causes. Compared to other tissues in the human body, the central nervous system, with its complexity of structure and function, and its slow regeneration rate, remains to be challenging to treat. Most of the therapeutic approaches in brain injury management used thus far in preclinical and clinical studies have been focused on attempts to reduce the sequelae of the injury and enhance the function of the remaining brain tissue. However, this approach does not address the need to regenerate or replace damaged or necrotic tissue. One of the promising approaches for the repair of traumatically injured brains involves using nanotechnology and tissue engineering approaches, techniques that focus on bridging the structural gaps and allowing the reconnection of the severed neuronal processes.

This Special Issue aims to cover the current research from preclinical and clinical studies, as well as reviews, and to identify the current knowledge and opportunities for future tailored research concerning the field of brain injury mechanisms and treatment, with an emphasis on regenerative and restoration techniques. Submissions that focus on the neuropathological molecular mechanisms involved in brain injury pathophysiology are also encouraged.

Dr. Kristina Pilipović
Dr. Petra Dolenec
Guest Editors

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

acquired brain injury
nanomedicine
nanotechnology
neuroregenerative therapy
neurorepair
new and emerging treatments
pharmacotherapy
stroke
tissue engineering
traumatic brain injury

Published Papers (6 papers)

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Research

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9 pages, 1240 KiB

Open AccessArticle

Electrophysiological Screening to Assess Foot Drop Syndrome in Severe Acquired Brain Injury in Rehabilitative Settings

by Francesco Piccione, Antonio Cerasa, Paolo Tonin, Simone Carozzo, Rocco Salvatore Calabrò, Stefano Masiero and Lucia Francesca Lucca

Biomedicines 2024, 12(4), 878; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12040878 - 16 Apr 2024

Viewed by 324

Abstract

Background: Foot drop syndrome (FDS), characterized by severe weakness and atrophy of the dorsiflexion muscles of the feet, is commonly found in patients with severe acquired brain injury (ABI). If the syndrome is unilateral, the cause is often a peroneal neuropathy (PN), due to compression of the nervous trunk on the neck of the fibula at the knee level; less frequently, the cause is a previous or concomitant lumbar radiculopathy. Bilateral syndromes are caused by polyneuropathies and myopathies. Central causes, due to brain or spinal injury, mimic this syndrome but are usually accompanied by other symptoms, such as spasticity. Critical illness polyneuropathy (CIP) and myopathy (CIM), isolated or in combination (critical illness polyneuromyopathy, CIPNM), have been shown to constitute an important cause of FDS in patients with ABI. Assessing the causes of FDS in the intensive rehabilitation unit (IRU) has several limitations, which include the complexity of the electrophysiological tests, limited availability of neurophysiology consultants, and the severe disturbance in consciousness and lack of cooperation from patients. Objectives: We sought to propose a simplified electrophysiological screening that identifies FDS causes, particularly PN and CIPNM, to help clinicians to recognize the significant clinical predictors of poor outcomes in severe ABI at admission to IRU. Methods: This prospective, single-center study included 20 severe ABI patients with FDS (11 females/9 males, mean age 55.10 + 16.26; CRS-R= 11.90 + 6.32; LCF: 3.30 + 1.30; DRS: 21.45 + 3.33), with prolonged rehabilitation treatment (≥2 months). We applied direct tibialis anterior muscle stimulation (DMS) associated with peroneal nerve motor conduction evaluation, across the fibular head (NCS), to identify CIP and/or CIM and to exclude demyelinating or compressive unilateral PN. Results: At admission to IRU, simplified electrophysiological screening reported four unilateral PN, four CIP and six CIM with a CIPNM overall prevalence estimate of about 50%. After 2 months, the CIPNM group showed significantly poorer outcomes compared to other ABI patients without CIPNM, as demonstrated by the lower probability of achieving endotracheal-tube weaning (20% versus 90%) and lower CRS-R and DRS scores. Due to the subacute rehabilitation setting of our study, it was not possible to evaluate the motor results of recovery of the standing position, functional walking and balance, impaired by the presence of unilateral PN. Conclusions: The implementation of the proposed simplified electrophysiological screening may enable the early identification of unilateral PN or CIPNM in severe ABI patients, thereby contributing to better functional prognosis in rehabilitative settings. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

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13 pages, 6813 KiB

Open AccessArticle

Neuroprotective Effects of Krypton Inhalation on Photothrombotic Ischemic Stroke

by Viktoriya V. Antonova, Denis N. Silachev, Egor Y. Plotnikov, Irina B. Pevzner, Elmira I. Yakupova, Mikhail V. Pisarev, Ekaterina A. Boeva, Zoya I. Tsokolaeva, Maxim A. Lyubomudrov, Igor V. Shumov, Andrey V. Grechko and Oleg A. Grebenchikov

Biomedicines 2024, 12(3), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030635 - 13 Mar 2024

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Abstract

This is the first in vivo study to investigate the neuroprotective effects of krypton on focal cerebral ischemia. The aim of the study was to analyze the effect of 2 h of inhalation of a krypton–oxygen mixture (Kr 70%/O₂ 30%) on the recovery of neurological functions and the degree of brain damage in rats after photoinduced ischemic stroke (PIS) and to investigate the possible mechanisms responsible for this neuroprotection. Experiments were performed on male Wistar rats weighing 250–300 g (n = 32). Animals were randomized into four groups. Two groups (n = 20) underwent photoinduced ischemic stroke, followed by 2 h of inhalation of krypton–oxygen mixture consisting of Kr 70%/O₂ 30% or a nitrogen–oxygen breathing mixture consisting of N₂ 70%/O₂ 30%, followed by neurological examinations on days 3 and 7. The other two groups (n = 12) received only gas mixtures of the same concentration and exposure duration as in those in the PIS groups, then Western blot analysis of the potential molecular mechanisms was performed. The results of the study show that treatment with the krypton–oxygen mixture consisting of Kr 70%/O₂ 30% improves the neurological status on day 7 of observation, reduces the lesion volume according to the MRI examination and the number of Iba-1- and caspase-3-positive cells in the damaged area, promotes the activation of neoangiogenesis (an increase in the von Willebrand factor), and reduces the penumbra area and the number of NeuN-positive cells in it on day 14 of observation. Inhalation of the krypton–oxygen mixture also significantly increases the levels of phosphorylated AKT kinase (protein kinase B) and glycogen synthase kinase 3b (pGSK3b) and promotes the expression of transcription factor Nrf2, which was accompanied by the lowered expression of transcription factor NFkB (p50). Thus, we showed pronounced neuroprotection induced by krypton inhalation after stroke and identified the signaling pathways that may be responsible for restoring neurological functions and reducing damage. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

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11 pages, 1409 KiB

Open AccessArticle

Noradrenergic Pathways Involved in Micturition in an Animal Model of Hydrocephalus—Implications for Urinary Dysfunction

by Marta Louçano, Ana Coelho, Sílvia Sousa Chambel, Cristina Prudêncio, Célia Duarte Cruz and Isaura Tavares

Biomedicines 2024, 12(1), 215; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12010215 - 18 Jan 2024

Viewed by 851

Abstract

Hydrocephalus is characterized by enlargement of the cerebral ventricles, accompanied by distortion of the periventricular tissue. Patients with hydrocephalus usually experience urinary impairments. Although the underlying etiology is not fully described, the effects of hydrocephalus in the neuronal network responsible for the control of urination, which involves periventricular areas, including the periaqueductal gray (PAG) and the noradrenergic locus coeruleus (LC). In this study, we aimed to investigate the mechanisms behind urinary dysfunction in rats with kaolin-induced hydrocephalus. For that purpose, we used a validated model of hydrocephalus—the rat injected with kaolin in the cisterna magna—also presents urinary impairments in order to investigate the putative involvement of noradrenergic control from the brain to the spinal cord Onuf’s nucleus, a key area in the motor control of micturition. We first evaluated bladder contraction capacity using cystometry. Since our previous characterization of the LC in hydrocephalic animals showed increased levels of noradrenaline, we then evaluated the noradrenergic innervation of the spinal cord’s Onuf’s nucleus by measuring levels of dopamine β-hydroxylase (DBH). We also evaluated the expression of the c-Fos protooncogene, the most widely used marker of neuronal activation, in the ventrolateral PAG (vlPAG), an area that plays a major role in the control of urination by its indirect control of the LC via pontine micturition center. Hydrocephalic rats showed an increased frequency of bladder contractions and lower minimum pressure. These animals also presented increased DBH levels at the Onuf´s nucleus, along with decreased c-Fos expression in the vlPAG. The present findings suggest that impairments in urinary function during hydrocephalus may be due to alterations in descending noradrenergic modulation. We propose that the effects of hydrocephalus in the decrease of vlPAG neuronal activation lead to a decrease in the control over the LC. The increased availability of noradrenaline production at the LC probably causes an exaggerated micturition reflex due to the increased innervation of the Onuf´s nucleus, accounting for the urinary impairments detected in hydrocephalic animals. The results of the study provide new insights into the neuronal underlying mechanisms of urinary dysfunction in hydrocephalus. Further research is needed to fully evaluate the translational perspectives of the current findings. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

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12 pages, 253 KiB

Open AccessArticle

The Association of Different Genetic Variants with the Development of Hypoxic–Ischemic Encephalopathy

by Vesna Pavlov, Anet Papazovska Cherepnalkovski, Marino Marcic, Ljiljana Marcic and Radenka Kuzmanic Samija

Biomedicines 2023, 11(10), 2795; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102795 - 15 Oct 2023

Viewed by 1046

Abstract

The aim of this study is to investigate the frequency of six tag SNPs (single nucleotide polymorphisms) within specific genes (F2, F5, F7, MTHFR, NOS2A, PAI 2-1, PAI 2-2, and PAI 3-3): F2 (rs1799963), F5 (rs6025), F7 (rs6046), NOS 2 (rs1137933), PAI 2 (SERPINB2) (rs6103), MTHFR (rs1801133). The study also investigates their association with the development and severity of HIE. The genes F2, F5, and F7 code for proteins involved in blood clotting. MTHFR is a gene that plays a significant role in processing amino acids, the fundamental building blocks of proteins. NOS2A, PAI 2-1, PAI 2-2, and PAI 3-3 are genes involved in the regulation of various physiological processes, such as the relaxation of smooth muscle, regulation of central blood pressure, vasodilatation, and synaptic plasticity. Changes in these genes may be associated with brain injury. This retrospective study included 279 participants, of which 132 participants had Hypoxic–Ischemic Encephalopathy (HIE) and 147 subjects were in the control group. Our study found that certain genetic variants in the rs61103 and rs1137933 polymorphisms were associated with hypoxic–ischemic encephalopathy (HIE) and the findings of the magnetic resonance imaging. There was a correlation between Apgar scores and the degree of damage according to the ultrasound findings. These results highlight the complex relationship between genetic factors, clinical parameters, and the severity of HIE. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

14 pages, 3474 KiB

Open AccessArticle

Novel Insights into Pathophysiology of Delayed Cerebral Ischemia: Effects of Current Rescue Therapy on Microvascular Perfusion Heterogeneity

by Björn B. Hofmann, Cihat Karadag, Christian Rubbert, Simon Schieferdecker, Milad Neyazi, Yousef Abusabha, Igor Fischer, Hieronymus D. Boogaarts, Sajjad Muhammad, Kerim Beseoglu, Daniel Hänggi, Bernd Turowski, Marcel A. Kamp and Jan F. Cornelius

Biomedicines 2023, 11(10), 2624; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102624 - 24 Sep 2023

Viewed by 1103

Abstract

General microvascular perfusion and its heterogeneity are pathophysiological features of delayed cerebral ischemia (DCI) that are gaining increasing attention. Recently, CT perfusion (CTP) imaging has made it possible to evaluate them radiologically using mean transit time (MTT) and its heterogeneity (measured by cvMTT). This study evaluates the effect of multimodal rescue therapy (intra-arterial nimodipine administration and elevation of blood pressure) on MTT and cvMTT during DCI in aneurysmal subarachnoid haemorrhage (aSAH) patients. A total of seventy-nine aSAH patients who underwent multimodal rescue therapy between May 2012 and December 2019 were retrospectively included in this study. CTP-based perfusion impairment (MTT and cvMTT) on the day of DCI diagnosis was compared with follow-up CTP after initiation of combined multimodal therapy. The mean MTT was significantly reduced in the follow-up CTP compared to the first CTP (3.7 ± 0.7 s vs. 3.3 ± 0.6 s; p < 0.0001). However, no significant reduction of cvMTT was observed (0.16 ± 0.06 vs. 0.15 ± 0.06; p = 0.44). Mean arterial pressure was significantly increased between follow-up and first CTP (98 ± 17 mmHg vs. 104 ± 15 mmHg; p < 0.0001). The combined multimodal rescue therapy was effective in addressing the general microvascular perfusion impairment but did not affect the mechanisms underlying microvascular perfusion heterogeneity. This highlights the need for research into new therapeutic approaches that also target these pathophysiological mechanisms of DCI. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

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Review

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15 pages, 1939 KiB

Open AccessReview

Neurologic Injury-Related Predisposing Factors of Post-Traumatic Stress Disorder: A Critical Examination

by Wiley Gillam, Nikhil Godbole, Shourya Sangam, Alyssa DeTommaso, Marco Foreman and Brandon Lucke-Wold

Biomedicines 2023, 11(10), 2732; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102732 - 09 Oct 2023

Cited by 1 | Viewed by 1182

Abstract

The present review aimed to identify the means through which neurologic injury can predispose individuals to Post-Traumatic Stress Disorder (PTSD). In recent years, comprehensive studies have helped to clarify which structures in the central nervous system can lead to distinct PTSD symptoms—namely, dissociative reactions or flashbacks—when damaged. Our review narrowed its focus to three common neurologic injuries, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and stroke. We found that in each of the three cases, individuals may be at an increased risk of developing PTSD symptoms. Beyond discussing the potential mechanisms by which neurotrauma may lead to PTSD, we summarized our current understanding of the pathophysiology of the disorder and discussed predicted associations between the limbic system and PTSD. In particular, the effect of noradrenergic neuromodulatory signaling on the hypothalamic pituitary adrenal (HPA) axis as it pertains to fear memory recall needs to be further explored to better understand its effects on limbic structures in PTSD patients. At present, altered limbic activity can be found in both neurotrauma and PTSD patients, suggesting a potential causative link. Particularly, changes in the function of the limbic system may be associated with characteristic symptoms of PTSD such as intrusive memories and acute psychological distress. Despite evidence demonstrating the correlation between neurotrauma and PTSD, a lack of PTSD prognosis exists in TBI, SAH, and stroke patients who could benefit from early treatment. It should be noted that PTSD symptoms often compound with pre-existing issues, further deteriorating health outcomes for these patients. It is ultimately our goal to clarify the relationship between neurotrauma and PTSD so that earlier diagnoses and appropriate treatment are observed in clinic. Full article

(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)

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