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Neurological Injuries’ Monitoring, Tracking and Treatment

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

Deadline for manuscript submissions: closed (30 June 2015) | Viewed by 265542

Special Issue Editor

1. Department of Neurosurgery, Orthopaedics, Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
2. Department of Biomedical Engineering, Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Interests: brain monitoring and therapeutic hypothermia; peripheral nerve injury and regeneration; translational therapeutic model for neurological injuries; development and characterization of biomaterials for bone and peripheral nerve regeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite recent advancements, the monitoring and tracking of neurological injuries are still major hindrances in the development of neurological injury therapies. Current monitoring methodologies have been largely limited to post-injury evaluation and prognostication. Induced hypothermia improves both survival and neurological outcome in cardiac arrest survivors. However, the monitoring methodologies to guide hypothermia therapy and improve its efficiency are not currently satisfying. Among the most exciting research areas, stem cell biology recently burst out and holds significant promise in the repair of neurological injuries. However, the role and effect of stem cell therapy still remain un-elucidated.

The goal of this Special Issue is to provide a summary of the field, describe its impact as well as introduce the recent advances in the Neurological Injuries' Monitoring, Tracking and Treatment. We invite authors to submit original research and review articles related with neurological injury; mainly brain injury after cardiac arrest, stroke and traumatic brain injury, but spinal cord injury as well. We are interested in articles that explore the advances in neuroengineering and latest technologies in monitoring and tracking neurological injury from translational model to clinical evaluation, such as electrophysiological monitoring and the optogenesis technique. This issue will address novel therapeutic intervention in humans and also in animal models, including therapeutic hypothermia and stem cell therapy.

Dr. Xiaofeng Jia
Guest Editor

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Keywords

  • brain injury
  • cardiac arrest
  • stroke
  • traumatic brain injury
  • spinal cord injury
  • brain monitoring
  • electrophysiology
  • therapeutic hypothermia
  • stem cell
  • optogenesis
  • translational model
  • functional outcome
  • neuroengineering
  • clinical evaluation

Published Papers (30 papers)

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6345 KiB  
Article
Temporal Genetic Modifications after Controlled Cortical Impact—Understanding Traumatic Brain Injury through a Systematic Network Approach
by Yung-Hao Wong, Chia-Chou Wu, John Chung-Che Wu, Hsien-Yong Lai, Kai-Yun Chen, Bo-Ren Jheng, Mien-Cheng Chen, Tzu-Hao Chang and Bor-Sen Chen
Int. J. Mol. Sci. 2016, 17(2), 216; https://doi.org/10.3390/ijms17020216 - 06 Feb 2016
Cited by 6 | Viewed by 5221
Abstract
Traumatic brain injury (TBI) is a primary injury caused by external physical force and also a secondary injury caused by biological processes such as metabolic, cellular, and other molecular events that eventually lead to brain cell death, tissue and nerve damage, and atrophy. [...] Read more.
Traumatic brain injury (TBI) is a primary injury caused by external physical force and also a secondary injury caused by biological processes such as metabolic, cellular, and other molecular events that eventually lead to brain cell death, tissue and nerve damage, and atrophy. It is a common disease process (as opposed to an event) that causes disabilities and high death rates. In order to treat all the repercussions of this injury, treatment becomes increasingly complex and difficult throughout the evolution of a TBI. Using high-throughput microarray data, we developed a systems biology approach to explore potential molecular mechanisms at four time points post-TBI (4, 8, 24, and 72 h), using a controlled cortical impact (CCI) model. We identified 27, 50, 48, and 59 significant proteins as network biomarkers at these four time points, respectively. We present their network structures to illustrate the protein–protein interactions (PPIs). We also identified UBC (Ubiquitin C), SUMO1, CDKN1A (cyclindependent kinase inhibitor 1A), and MYC as the core network biomarkers at the four time points, respectively. Using the functional analytical tool MetaCore™, we explored regulatory mechanisms and biological processes and conducted a statistical analysis of the four networks. The analytical results support some recent findings regarding TBI and provide additional guidance and directions for future research. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
The Development of Neuroendocrine Disturbances over Time: Longitudinal Findings in Patients after Traumatic Brain Injury and Subarachnoid Hemorrhage
by Anna Kopczak, Carmen Krewer, Manfred Schneider, Ilonka Kreitschmann-Andermahr, Harald Jörn Schneider and Günter Karl Stalla
Int. J. Mol. Sci. 2016, 17(1), 2; https://doi.org/10.3390/ijms17010002 - 22 Dec 2015
Cited by 7 | Viewed by 5757
Abstract
Previous reports suggest that neuroendocrine disturbances in patients with traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) may still develop or resolve months or even years after the trauma. We investigated a cohort of n = 168 patients (81 patients after TBI [...] Read more.
Previous reports suggest that neuroendocrine disturbances in patients with traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) may still develop or resolve months or even years after the trauma. We investigated a cohort of n = 168 patients (81 patients after TBI and 87 patients after SAH) in whom hormone levels had been determined at various time points to assess the course and pattern of hormonal insufficiencies. Data were analyzed using three different criteria: (1) patients with lowered basal laboratory values; (2) patients with lowered basal laboratory values or the need for hormone replacement therapy; (3) diagnosis of the treating physician. The first hormonal assessment after a median time of three months after the injury showed lowered hormone laboratory test results in 35% of cases. Lowered testosterone (23.1% of male patients), lowered estradiol (14.3% of female patients) and lowered insulin-like growth factor I (IGF-I) values (12.1%) were most common. Using Criterion 2, a higher prevalence rate of 55.6% of cases was determined, which correlated well with the prevalence rate of 54% of cases using the physicians’ diagnosis as the criterion. Intraindividual changes (new onset insufficiency or recovery) were predominantly observed for the somatotropic axis (12.5%), the gonadotropic axis in women (11.1%) and the corticotropic axis (10.6%). Patients after TBI showed more often lowered IGF-I values at first testing, but normal values at follow-up (p < 0.0004). In general, most patients remained stable. Stable hormone results at follow-up were obtained in 78% (free thyroxine (fT4) values) to 94.6% (prolactin values). Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Evaluation of Injured Axons Using Two-Photon Excited Fluorescence Microscopy after Spinal Cord Contusion Injury in YFP-H Line Mice
by Hideki Horiuchi, Yusuke Oshima, Tadanori Ogata, Tadao Morino, Seiji Matsuda, Hiromasa Miura and Takeshi Imamura
Int. J. Mol. Sci. 2015, 16(7), 15785-15799; https://doi.org/10.3390/ijms160715785 - 13 Jul 2015
Cited by 13 | Viewed by 6656
Abstract
Elucidation of the process of degeneration of injured axons is important for the development of therapeutic modules for the treatment of spinal cord injuries. The aim of this study was to establish a method for time-lapse observation of injured axons in living animals [...] Read more.
Elucidation of the process of degeneration of injured axons is important for the development of therapeutic modules for the treatment of spinal cord injuries. The aim of this study was to establish a method for time-lapse observation of injured axons in living animals after spinal cord contusion injury. YFP (yellow fluorescent protein)-H transgenic mice, which we used in this study, express fluorescence in their nerve fibers. Contusion damage to the spinal cord at the 11th vertebra was performed by IH (Infinite Horizon) impactor, which applied a pressure of 50 kdyn. The damaged spinal cords were re-exposed during the observation period under anesthesia, and then observed by two-photon excited fluorescence microscopy, which can observe deep regions of tissues including spinal cord axons. No significant morphological change of injured axons was observed immediately after injury. Three days after injury, the number of axons decreased, and residual axons were fragmented. Seven days after injury, only fragments were present in the damaged tissue. No hind-limb movement was observed during the observation period after injury. Despite the immediate paresis of hind-limbs following the contusion injury, the morphological degeneration of injured axons was delayed. This method may help clarification of pathophysiology of axon degeneration and development of therapeutic modules for the treatment of spinal cord injury. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Memantine Attenuates Delayed Vasospasm after Experimental Subarachnoid Hemorrhage via Modulating Endothelial Nitric Oxide Synthase
by Chih-Yuan Huang, Liang-Chao Wang, Yan-Shen Shan, Chia-Hsin Pan and Kuen-Jer Tsai
Int. J. Mol. Sci. 2015, 16(6), 14171-14180; https://doi.org/10.3390/ijms160614171 - 23 Jun 2015
Cited by 18 | Viewed by 5966
Abstract
Delayed cerebral vasospasm is an important pathological feature of subarachnoid hemorrhage (SAH). The cause of vasospasm is multifactorial. Impairs nitric oxide availability and endothelial nitric oxide synthase (eNOS) dysfunction has been reported to underlie vasospasm. Memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) blocker [...] Read more.
Delayed cerebral vasospasm is an important pathological feature of subarachnoid hemorrhage (SAH). The cause of vasospasm is multifactorial. Impairs nitric oxide availability and endothelial nitric oxide synthase (eNOS) dysfunction has been reported to underlie vasospasm. Memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) blocker has been proven to reduce early brain injury after SAH. This study investigated the effect of memantine on attenuation of vasospasm and restoring eNOS functionality. Male Sprague-Dawley rats weighing 350–450 g were randomly divided into three weight-matched groups, sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the severity of vasospasm and the expression of eNOS. Memantine effectively ameliorated cerebral vasospasm by restoring eNOS functionality. Memantine can prevent vasospasm in experimental SAH. Treatment strategies may help combat SAH-induced vasospasm in the future. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Potential Natural Products for Alzheimer’s Disease: Targeted Search Using the Internal Ribosome Entry Site of Tau and Amyloid-β Precursor Protein
by Yun-Chieh Tasi, Ting-Yu Chin, Ying-Ju Chen, Chun-Chih Huang, Shou-Lun Lee and Tzong-Yuan Wu
Int. J. Mol. Sci. 2015, 16(4), 8789-8810; https://doi.org/10.3390/ijms16048789 - 20 Apr 2015
Cited by 10 | Viewed by 7869
Abstract
Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer’s disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach [...] Read more.
Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer’s disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by β-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 μM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the β-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE−/−) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Posttraumatic Inflammation as a Key to Neuroregeneration after Traumatic Spinal Cord Injury
by Arash Moghaddam, Christopher Child, Thomas Bruckner, Hans Jürgen Gerner, Volker Daniel and Bahram Biglari
Int. J. Mol. Sci. 2015, 16(4), 7900-7916; https://doi.org/10.3390/ijms16047900 - 09 Apr 2015
Cited by 49 | Viewed by 7330
Abstract
Pro- and anti-inflammatory cytokines might have a large impact on the secondary phase and on the neurological outcome of patients with acute spinal cord injury (SCI). We measured the serum levels of different cytokines (Interferon-γ, Tumor Necrosis Factor-α, Interleukin-1β, IL-6, IL-8, IL-10, and [...] Read more.
Pro- and anti-inflammatory cytokines might have a large impact on the secondary phase and on the neurological outcome of patients with acute spinal cord injury (SCI). We measured the serum levels of different cytokines (Interferon-γ, Tumor Necrosis Factor-α, Interleukin-1β, IL-6, IL-8, IL-10, and Vascular Endothelial Growth Factor) over a 12-week period in 40 acute traumatic SCI patients: at admission on average one hour after initial trauma; at four, nine, 12, and 24 h; Three, and seven days after admission; and two, four, eight, and twelve weeks after admission. This was done using a Luminex Performance Human High Sensitivity Cytokine Panel. SCI was classified using the American Spinal Injury Association (ASIA) Impairment Scale (AIS) at time of admission and after 12 weeks. TNFα, IL-1β, IL-6, IL-8, and IL-10 concentrations were significantly higher in patients without neurological remission and in patients with an initial AIS A (p < 0.05). This study shows significant differences in cytokine concentrations shown in traumatic SCI patients with different neurological impairments and within a 12-week period. IL-8 and IL-10 are potential peripheral markers for neurological remission and rehabilitation after traumatic SCI. Furthermore our cytokine expression pattern of the acute, subacute, and intermediate phase of SCI establishes a possible basis for future studies to develop standardized monitoring, prognostic, and tracking techniques. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage
by Min Seong Kwon, Seung Kyoon Woo, David B. Kurland, Sung Hwan Yoon, Andre F. Palmer, Uddyalok Banerjee, Sana Iqbal, Svetlana Ivanova, Volodymyr Gerzanich and J. Marc Simard
Int. J. Mol. Sci. 2015, 16(3), 5028-5046; https://doi.org/10.3390/ijms16035028 - 05 Mar 2015
Cited by 90 | Viewed by 8782
Abstract
Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from [...] Read more.
Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb), heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS) contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα), from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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1519 KiB  
Communication
MRS of Brain Metabolite Levels Demonstrates the Ability of Scavenging of Excess Brain Glutamate to Protect against Nerve Agent Induced Seizures
by Angela Ruban, Inbal E. Biton, Arik Markovich and David Mirelman
Int. J. Mol. Sci. 2015, 16(2), 3226-3236; https://doi.org/10.3390/ijms16023226 - 02 Feb 2015
Cited by 12 | Viewed by 5322
Abstract
This study describes the use of in vivo magnetic resonance spectrocopy (MRS) to monitor brain glutamate and lactate levels in a paraoxon (PO) intoxication model. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces [...] Read more.
This study describes the use of in vivo magnetic resonance spectrocopy (MRS) to monitor brain glutamate and lactate levels in a paraoxon (PO) intoxication model. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces the brain-accumulated levels of glutamate. Previously we have shown that the treatment causes a rapid decrease of blood glutamate levels and creates a gradient between the brain and blood glutamate levels which leads to the efflux of excess brain glutamate into the blood stream thereby reducing its potential to cause neurological damage. The fact that this treatment significantly decreased the brain glutamate and lactate levels following PO intoxication suggests that it could become a new effective neuroprotective agent. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Comprehensive Analysis of Neonatal versus Adult Unilateral Decortication in a Mouse Model Using Behavioral, Neuroanatomical, and DNA Microarray Approaches
by Akira Yoshikawa, Tomoya Nakamachi, Junko Shibato, Randeep Rakwal and Seiji Shioda
Int. J. Mol. Sci. 2014, 15(12), 22492-22517; https://doi.org/10.3390/ijms151222492 - 05 Dec 2014
Cited by 7 | Viewed by 7529
Abstract
Previously, studying the development, especially of corticospinal neurons, it was concluded that the main compensatory mechanism after unilateral brain injury in rat at the neonatal stage was due in part to non-lesioned ipsilateral corticospinal neurons that escaped selection by axonal elimination or neuronal [...] Read more.
Previously, studying the development, especially of corticospinal neurons, it was concluded that the main compensatory mechanism after unilateral brain injury in rat at the neonatal stage was due in part to non-lesioned ipsilateral corticospinal neurons that escaped selection by axonal elimination or neuronal apoptosis. However, previous results suggesting compensatory mechanism in neonate brain were not correlated with high functional recovery. Therefore, what is the difference among neonate and adult in the context of functional recovery and potential mechanism(s) therein? Here, we utilized a brain unilateral decortication mouse model and compared motor functional recovery mechanism post-neonatal brain hemisuction (NBH) with adult brain hemisuction (ABH). Three analyses were performed: (1) Quantitative behavioral analysis of forelimb movements using ladder walking test; (2) neuroanatomical retrograde tracing analysis of unlesioned side corticospinal neurons; and (3) differential global gene expressions profiling in unlesioned-side neocortex (rostral from bregma) in NBH and ABH on a 8 × 60 K mouse whole genome Agilent DNA chip. Behavioral data confirmed higher recovery ability in NBH over ABH is related to non-lesional frontal neocortex including rostral caudal forelimb area. A first inventory of differentially expressed genes genome-wide in the NBH and ABH mouse model is provided as a resource for the scientific community. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Communication
PACAP38 Differentially Effects Genes and CRMP2 Protein Expression in Ischemic Core and Penumbra Regions of Permanent Middle Cerebral Artery Occlusion Model Mice Brain
by Motohide Hori, Tomoya Nakamachi, Junko Shibato, Randeep Rakwal, Masachi Tsuchida, Seiji Shioda and Satoshi Numazawa
Int. J. Mol. Sci. 2014, 15(9), 17014-17034; https://doi.org/10.3390/ijms150917014 - 23 Sep 2014
Cited by 17 | Viewed by 9206
Abstract
Pituitary adenylate-cyclase activating polypeptide (PACAP) has neuroprotective and axonal guidance functions, but the mechanisms behind such actions remain unclear. Previously we examined effects of PACAP (PACAP38, 1 pmol) injection intracerebroventrically in a mouse model of permanent middle cerebral artery occlusion (PMCAO) along with [...] Read more.
Pituitary adenylate-cyclase activating polypeptide (PACAP) has neuroprotective and axonal guidance functions, but the mechanisms behind such actions remain unclear. Previously we examined effects of PACAP (PACAP38, 1 pmol) injection intracerebroventrically in a mouse model of permanent middle cerebral artery occlusion (PMCAO) along with control saline (0.9% NaCl) injection. Transcriptomic and proteomic approaches using ischemic (ipsilateral) brain hemisphere revealed differentially regulated genes and proteins by PACAP38 at 6 and 24 h post-treatment. However, as the ischemic hemisphere consisted of infarct core, penumbra, and non-ischemic regions, specificity of expression and localization of these identified molecular factors remained incomplete. This led us to devise a new experimental strategy wherein, ischemic core and penumbra were carefully sampled and compared to the corresponding contralateral (healthy) core and penumbra regions at 6 and 24 h post PACAP38 or saline injections. Both reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to examine targeted gene expressions and the collapsin response mediator protein 2 (CRMP2) protein profiles, respectively. Clear differences in expression of genes and CRMP2 protein abundance and degradation product/short isoform was observed between ischemic core and penumbra and also compared to the contralateral healthy tissues after PACAP38 or saline treatment. Results indicate the importance of region-specific analyses to further identify, localize and functionally analyse target molecular factors for clarifying the neuroprotective function of PACAP38. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Association between Toll-Like Receptor 4 Expression and Neural Stem Cell Proliferation in the Hippocampus Following Traumatic Brain Injury in Mice
by Yuqin Ye, Hongyu Xu, Xin Zhang, Ze Li, Yanfeng Jia, Xiaosheng He and Jason H. Huang
Int. J. Mol. Sci. 2014, 15(7), 12651-12664; https://doi.org/10.3390/ijms150712651 - 17 Jul 2014
Cited by 33 | Viewed by 6667
Abstract
Whether or how neural stem cells (NSCs) respond to toll-like receptor 4 (TLR4) in an inflammatory environment caused by traumatic brain injury (TBI) has not been understood. In the present study, association between TLR4 expression and NSCs proliferation in the hippocampus was investigated [...] Read more.
Whether or how neural stem cells (NSCs) respond to toll-like receptor 4 (TLR4) in an inflammatory environment caused by traumatic brain injury (TBI) has not been understood. In the present study, association between TLR4 expression and NSCs proliferation in the hippocampus was investigated in a mouse model of TBI using controlled cortical impact (CCI). Hippocampal proliferating cells were labeled with the thymidine analog 5-bromo-2-deoxyuridine (BrdU). In order to identify NSCs, the proliferating cells were further co-labeled with BrdU/sex determination region of Y chromosome related high mobility group box gene 2 (SOX2). Morphological observation on the expression of BrdU, SOX2, and TLR4 in the hippocampus was performed by inmmunofluorescence (IF). Relative quantification of TLR4 expression at the protein and mRNA level was performed using Western blotting and real-time polymerase chain reaction (PCR). It was observed that BrdU+/SOX2+cells accounted for 95.80% ± 7.91% among BrdU+ cells; several BrdU+ cells and SOX2+ cells in the hippocampus were also TLR4-positive post injury, and that BrdU+ cell numbers, together with TLR4 expression at either protein or mRNA level, increased significantly in TBI mice over 1, 3, 7, 14, and 21 days survivals and changed in a similar temporal pattern with a peak at 3 day post-injury. These results indicate that hippocampal proliferating cells (suggestive of NSCs) expressed TLR4, and that there was a potential association between increased expression of TLR4 and the proliferation of NSCs post TBI. It is concluded that hippocampal TLR4 may play a potential role in endogenous neurogenesis after TBI. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Value of Micro-CT for Monitoring Spinal Microvascular Changes after Chronic Spinal Cord Compression
by Hou-Qing Long, Wen-Han Xie, Wen-Li Chen, Wen-Lin Xie, Jing-Hui Xu and Yong Hu
Int. J. Mol. Sci. 2014, 15(7), 12061-12073; https://doi.org/10.3390/ijms150712061 - 07 Jul 2014
Cited by 28 | Viewed by 6273
Abstract
Neurological degeneration can occur after compression of the spinal cord. It is widely accepted that spinal cord compression leads to ischemic lesions and ultimately neurological dysfunction due to a narrowed spinal canal. Therefore, an in-depth understanding of the pathogenesis of spinal cord compression [...] Read more.
Neurological degeneration can occur after compression of the spinal cord. It is widely accepted that spinal cord compression leads to ischemic lesions and ultimately neurological dysfunction due to a narrowed spinal canal. Therefore, an in-depth understanding of the pathogenesis of spinal cord compression injury is required to help develop effective clinical interventions. In the present study, we propose a new method of quantitative 3D micro-CT to observe microvascular events in a chronic spinal cord compression rat model. A total of 36 rats were divided into two groups: sham control group (n = 12) and compressive spinal cord injury group (n = 24). Rats were scarified at four weeks after surgery. In each group, CD34 micro-vessel immunohistochemical staining was performed in half of the animals, while micro-CT scanning was performed in the other half. Microvessel density (MVD) was measured after immunohistochemical staining, while the vascular index (VI) was measured in 3D micro-CT. In comparison with sham control, abnormal somatosensory evoked potentials (SEP) can be seen in all 24 cases of the compression group, and VI shows the amount of microvessels reduced consistently and significantly (p < 0.01). A significant correlation is also found between MVD and VI (r = 0.95, p < 0.01). These data suggest that quantitative 3D micro-CT is a sensitive and promising tool for investigating microvascular changes during chronic compressive spinal cord injury. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Human Mesenchymal Stem Cells Modulate Inflammatory Cytokines after Spinal Cord Injury in Rat
by Lucia Machová Urdzíková, Jiří Růžička, Michael LaBagnara, Kristýna Kárová, Šárka Kubinová, Klára Jiráková, Raj Murali, Eva Syková, Meena Jhanwar-Uniyal and Pavla Jendelová
Int. J. Mol. Sci. 2014, 15(7), 11275-11293; https://doi.org/10.3390/ijms150711275 - 25 Jun 2014
Cited by 95 | Viewed by 9964
Abstract
Transplantation of mesenchymal stem cells (MSC) improves functional recovery in experimental models of spinal cord injury (SCI); however, the mechanisms underlying this effect are not completely understood. We investigated the effect of intrathecal implantation of human MSC on functional recovery, astrogliosis and levels [...] Read more.
Transplantation of mesenchymal stem cells (MSC) improves functional recovery in experimental models of spinal cord injury (SCI); however, the mechanisms underlying this effect are not completely understood. We investigated the effect of intrathecal implantation of human MSC on functional recovery, astrogliosis and levels of inflammatory cytokines in rats using balloon-induced spinal cord compression lesions. Transplanted cells did not survive at the lesion site of the spinal cord; however, functional recovery was enhanced in the MSC-treated group as was confirmed by the Basso, Beattie, and Bresnahan (BBB) and the flat beam test. Morphometric analysis showed a significantly higher amount of remaining white matter in the cranial part of the lesioned spinal cords. Immunohistochemical analysis of the lesions indicated the rearrangement of the glial scar in MSC-treated animals. Real-time PCR analysis revealed an increased expression of Irf5, Mrc1, Fgf2, Gap43 and Gfap. Transplantation of MSCs into a lesioned spinal cord reduced TNFα, IL-4, IL-1β, IL-2, IL-6 and IL-12 and increased the levels of MIP-1α and RANTES when compared to saline-treated controls. Intrathecal implantation of MSCs reduces the inflammatory reaction and apoptosis, improves functional recovery and modulates glial scar formation after SCI, regardless of cell survival. Therefore, repeated applications may prolong the beneficial effects induced by MSC application. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells on Laser-Induced Retinal Injury in Mice
by Yuanfeng Jiang, Yan Zhang, Lingjun Zhang, Meiyan Wang, Xiaomin Zhang and Xiaorong Li
Int. J. Mol. Sci. 2014, 15(6), 9372-9385; https://doi.org/10.3390/ijms15069372 - 27 May 2014
Cited by 35 | Viewed by 11678
Abstract
Stem cell therapy has shown encouraging results for neurodegenerative diseases. The retina provides a convenient locus to investigate stem cell functions and distribution in the nervous system. In the current study, we investigated the therapeutic potential of bone marrow mesenchymal stem cells (MSCs) [...] Read more.
Stem cell therapy has shown encouraging results for neurodegenerative diseases. The retina provides a convenient locus to investigate stem cell functions and distribution in the nervous system. In the current study, we investigated the therapeutic potential of bone marrow mesenchymal stem cells (MSCs) by systemic transplantation in a laser-induced retinal injury model. MSCs from C57BL/6 mice labeled with green fluorescent protein (GFP) were injected via the tail vein into mice after laser photocoagulation. We found that the average diameters of laser spots and retinal cell apoptosis were decreased in the MSC-treated group. Interestingly, GFP-MSCs did not migrate to the injured retina. Further examination revealed that the mRNA expression levels of glial fibrillary acidic protein and matrix metalloproteinase-2 were lower in the injured eyes after MSC transplantation. Our results suggest that intravenously injected MSCs have the ability to inhibit retinal cell apoptosis, reduce the inflammatory response and limit the spreading of damage in the laser-injured retina of mice. Systemic MSC therapy might play a role in neuroprotection, mainly by regulation of the intraocular microenvironment. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
The Reliability and Predictive Ability of a Biomarker of Oxidative DNA Damage on Functional Outcomes after Stroke Rehabilitation
by Yu-Wei Hsieh, Keh-Chung Lin, Mallikarjuna Korivi, Tsong-Hai Lee, Ching-Yi Wu and Kuen-Yuh Wu
Int. J. Mol. Sci. 2014, 15(4), 6504-6516; https://doi.org/10.3390/ijms15046504 - 16 Apr 2014
Cited by 24 | Viewed by 7266
Abstract
We evaluated the reliability of 8-hydroxy-2'-deoxyguanosine (8-OHdG), and determined its ability to predict functional outcomes in stroke survivors. The rehabilitation effect on 8-OHdG and functional outcomes were also assessed. Sixty-one stroke patients received a 4-week rehabilitation. Urinary 8-OHdG levels were determined by liquid [...] Read more.
We evaluated the reliability of 8-hydroxy-2'-deoxyguanosine (8-OHdG), and determined its ability to predict functional outcomes in stroke survivors. The rehabilitation effect on 8-OHdG and functional outcomes were also assessed. Sixty-one stroke patients received a 4-week rehabilitation. Urinary 8-OHdG levels were determined by liquid chromatography–tandem mass spectrometry. The test-retest reliability of 8-OHdG was good (interclass correlation coefficient = 0.76). Upper-limb motor function and muscle power determined by the Fugl-Meyer Assessment (FMA) and Medical Research Council (MRC) scales before rehabilitation showed significant negative correlation with 8-OHdG (r = −0.38, r = −0.30; p < 0.05). After rehabilitation, we found a fair and significant correlation between 8-OHdG and FMA (r = −0.34) and 8-OHdG and pain (r = 0.26, p < 0.05). Baseline 8-OHdG was significantly correlated with post-treatment FMA, MRC, and pain scores (r = −0.34, −0.31, and 0.25; p < 0.05), indicating its ability to predict functional outcomes. 8-OHdG levels were significantly decreased, and functional outcomes were improved after rehabilitation. The exploratory study findings conclude that 8-OHdG is a reliable and promising biomarker of oxidative stress and could be a valid predictor of functional outcomes in patients. Monitoring of behavioral indicators along with biomarkers may have crucial benefits in translational stroke research. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Expression of S100A6 in Rat Hippocampus after Traumatic Brain Injury Due to Lateral Head Acceleration
by Bo Fang, Ming Liang, Guitao Yang, Yuqin Ye, Hongyu Xu, Xiaosheng He and Jason H. Huang
Int. J. Mol. Sci. 2014, 15(4), 6378-6390; https://doi.org/10.3390/ijms15046378 - 15 Apr 2014
Cited by 13 | Viewed by 6468
Abstract
In a rat model of traumatic brain injury (TBI), we investigated changes in cognitive function and S100A6 expression in the hippocampus. TBI-associated changes in this protein have not previously been reported. Rat S100A6 was studied via immunohistochemical staining, Western blot, and reverse transcription-polymerase [...] Read more.
In a rat model of traumatic brain injury (TBI), we investigated changes in cognitive function and S100A6 expression in the hippocampus. TBI-associated changes in this protein have not previously been reported. Rat S100A6 was studied via immunohistochemical staining, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR) after either lateral head acceleration or sham. Reduced levels of S100A6 protein and mRNA were observed 1 h after TBI, followed by gradual increases over 6, 12, 24, and 72 h, and then a return to sham level at 14 day. Morris water maze (MWM) test was used to evaluate animal spatial cognition. TBI- and sham-rats showed an apparent learning curve, expressed as escape latency. Although TBI-rats displayed a relatively poorer cognitive ability than sham-rats, the disparity was not significant early post-injury. Marked cognitive deficits in TBI-rats were observed at 72 h post-injury compared with sham animals. TBI-rats showed decreased times in platform crossing in the daily MWM test; the performance at 72 h post-injury was the worst. In conclusion, a reduction in S100A6 may be one of the early events that lead to secondary cognitive decline after TBI, and its subsequent elevation is tightly linked with cognitive improvement. S100A6 may play important roles in neuronal degeneration and regeneration in TBI. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Transplanted Neural Stem Cells Modulate Regulatory T, γδ T Cells and Corresponding Cytokines after Intracerebral Hemorrhage in Rats
by Lu Gao, Qin Lu, Li-Jie Huang, Lin-Hui Ruan, Jian-Jing Yang, Wei-Long Huang, Wei-Shan ZhuGe, Yong-Liang Zhang, Biao Fu, Kun-Lin Jin and Qi-Chuan ZhuGe
Int. J. Mol. Sci. 2014, 15(3), 4431-4441; https://doi.org/10.3390/ijms15034431 - 13 Mar 2014
Cited by 40 | Viewed by 6944
Abstract
The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Although studies have shown that transplanted neural stem cells (NSCs) protect the central nervous system (CNS) from inflammatory damage, their effects on [...] Read more.
The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Although studies have shown that transplanted neural stem cells (NSCs) protect the central nervous system (CNS) from inflammatory damage, their effects on subpopulations of T lymphocytes and their corresponding cytokines are largely unexplored. Here, rats were subjected to ICH and NSCs were intracerebrally injected at 3 h after ICH. The profiles of subpopulations of T cells in the brain and peripheral blood were analyzed by flow cytometry. We found that regulatory T (Treg) cells in the brain and peripheral blood were increased, but γδT cells (gamma delta T cells) were decreased, along with increased anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) and decreased pro-inflammatory cytokines (IL-6, and IFN-γ), compared to the vehicle-treated control. Our data suggest that transplanted NSCs protect brain injury after ICH via modulation of Treg and γδT cell infiltration and anti- and pro-inflammatory cytokine release. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Article
Circulating MicroRNAs as Biomarkers of Acute Stroke
by Sugunavathi Sepramaniam, Jun-Rong Tan, Kay-Sin Tan, Deidre Ann DeSilva, Subramaniam Tavintharan, Fung-Peng Woon, Chee-Woon Wang, Fung-Lin Yong, Dwi-Setyowati Karolina, Prameet Kaur, Fu-Jia Liu, Kai-Ying Lim, Arunmozhiarasi Armugam and Kandiah Jeyaseelan
Int. J. Mol. Sci. 2014, 15(1), 1418-1432; https://doi.org/10.3390/ijms15011418 - 20 Jan 2014
Cited by 147 | Viewed by 9915
Abstract
MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. [...] Read more.
MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. Due to the complexity of the pathology, identifying stroke specific microRNAs has been a challenge. This study shows that microRNA profiles reflect not only the temporal progression of stroke but also the specific etiologies. A panel of 32 microRNAs, which could differentiate stroke etiologies during acute phase was identified and verified using a customized TaqMan Low Density Array (TLDA). Furthermore we also found 5 microRNAs, miR-125b-2*, -27a*, -422a, -488 and -627 to be consistently altered in acute stroke irrespective of age or severity or confounding metabolic complications. Differential expression of these 5 microRNAs was also observed in rat stroke models. Hence, their specificity to the stroke pathology emphasizes the possibility of developing these microRNAs into accurate and useful tools for diagnosis of stroke. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review

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482 KiB  
Review
Advances in Intracranial Pressure Monitoring and Its Significance in Managing Traumatic Brain Injury
by Usmah Kawoos, Richard M. McCarron, Charles R. Auker and Mikulas Chavko
Int. J. Mol. Sci. 2015, 16(12), 28979-28997; https://doi.org/10.3390/ijms161226146 - 04 Dec 2015
Cited by 88 | Viewed by 13112
Abstract
Intracranial pressure (ICP) measurements are essential in evaluation and treatment of neurological disorders such as subarachnoid and intracerebral hemorrhage, ischemic stroke, hydrocephalus, meningitis/encephalitis, and traumatic brain injury (TBI). The techniques of ICP monitoring have evolved from invasive to non-invasive—with both limitations and advantages. [...] Read more.
Intracranial pressure (ICP) measurements are essential in evaluation and treatment of neurological disorders such as subarachnoid and intracerebral hemorrhage, ischemic stroke, hydrocephalus, meningitis/encephalitis, and traumatic brain injury (TBI). The techniques of ICP monitoring have evolved from invasive to non-invasive—with both limitations and advantages. Some limitations of the invasive methods include short-term monitoring, risk of infection, restricted mobility of the subject, etc. The invasiveness of a method limits the frequency of ICP evaluation in neurological conditions like hydrocephalus, thus hampering the long-term care of patients with compromised ICP. Thus, there has been substantial interest in developing noninvasive techniques for assessment of ICP. Several approaches were reported, although none seem to provide a complete solution due to inaccuracy. ICP measurements are fundamental for immediate care of TBI patients in the acute stages of severe TBI injury. In severe TBI, elevated ICP is associated with mortality or poor clinical outcome. ICP monitoring in conjunction with other neurological monitoring can aid in understanding the pathophysiology of brain damage. This review article presents: (a) the significance of ICP monitoring; (b) ICP monitoring methods (invasive and non-invasive); and (c) the role of ICP monitoring in the management of brain damage, especially TBI. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Electrophysiological Monitoring of Brain Injury and Recovery after Cardiac Arrest
by Ruoxian Deng, Wei Xiong and Xiaofeng Jia
Int. J. Mol. Sci. 2015, 16(11), 25999-26018; https://doi.org/10.3390/ijms161125938 - 30 Oct 2015
Cited by 6 | Viewed by 7203
Abstract
Reliable prognostic methods for cerebral functional outcome of post cardiac-arrest (CA) patients are necessary, especially since therapeutic hypothermia (TH) as a standard treatment. Traditional neurophysiological prognostic indicators, such as clinical examination and chemical biomarkers, may result in indecisive outcome predictions and do not [...] Read more.
Reliable prognostic methods for cerebral functional outcome of post cardiac-arrest (CA) patients are necessary, especially since therapeutic hypothermia (TH) as a standard treatment. Traditional neurophysiological prognostic indicators, such as clinical examination and chemical biomarkers, may result in indecisive outcome predictions and do not directly reflect neuronal activity, though they have remained the mainstay of clinical prognosis. The most recent advances in electrophysiological methods—electroencephalography (EEG) pattern, evoked potential (EP) and cellular electrophysiological measurement—were developed to complement these deficiencies, and will be examined in this review article. EEG pattern (reactivity and continuity) provides real-time and accurate information for early-stage (particularly in the first 24 h) hypoxic-ischemic (HI) brain injury patients with high sensitivity. However, the signal is easily affected by external stimuli, thus the measurements of EP should be combined with EEG background to validate the predicted neurologic functional result. Cellular electrophysiology, such as multi-unit activity (MUA) and local field potentials (LFP), has strong potential for improving prognostication and therapy by offering additional neurophysiologic information to understand the underlying mechanisms of therapeutic methods. Electrophysiology provides reliable and precise prognostication on both global and cellular levels secondary to cerebral injury in cardiac arrest patients treated with TH. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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1002 KiB  
Review
Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy
by Gratianne Rabiller, Ji-Wei He, Yasuo Nishijima, Aaron Wong and Jialing Liu
Int. J. Mol. Sci. 2015, 16(10), 25605-25640; https://doi.org/10.3390/ijms161025605 - 26 Oct 2015
Cited by 74 | Viewed by 8927
Abstract
Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main [...] Read more.
Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main categories according to the frequency and amplitude, namely δ (1–4 Hz, 20–200 μV), θ (4–8 Hz, 10 μV), α (8–12 Hz, 20–200 μV), β (12–30 Hz, 5–10 μV), and γ (30–80 Hz, low amplitude). Emerging evidence from experimental and human studies suggests that groups of function and behavior seem to be specifically associated with the presence of each oscillation band, although the complex relationship between oscillation frequency and function, as well as the interaction between brain oscillations, are far from clear. Changes of brain oscillation patterns have long been implicated in the diseases of the central nervous system including ischemic stroke, in which the reduction of cerebral blood flow as well as the progression of tissue damage have direct spatiotemporal effects on the power of several oscillatory bands and their interactions. This review summarizes the current knowledge in behavior and function associated with each brain oscillation, and also in the specific changes in brain electrical activities that correspond to the molecular events and functional alterations observed after experimental and human stroke. We provide the basis of the generations of brain oscillations and potential cellular and molecular mechanisms underlying stroke-induced perturbation. We will also discuss the implications of using brain oscillation patterns as biomarkers for the prediction of stroke outcome and therapeutic efficacy. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy
by Brandon J. Dixon, Cesar Reis, Wing Mann Ho, Jiping Tang and John H. Zhang
Int. J. Mol. Sci. 2015, 16(9), 22368-22401; https://doi.org/10.3390/ijms160922368 - 15 Sep 2015
Cited by 134 | Viewed by 14019
Abstract
Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the [...] Read more.
Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury
by Seunghoon Lee, Sookyoung Park, Jinyoung Won, Sang-Rae Lee, Kyu-Tae Chang and Yonggeun Hong
Int. J. Mol. Sci. 2015, 16(8), 19657-19670; https://doi.org/10.3390/ijms160819657 - 19 Aug 2015
Cited by 15 | Viewed by 5619
Abstract
Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS). Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural [...] Read more.
Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS). Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural damage process is complex, involving a vast array of tissue structure, transcriptional/translational, electrochemical, metabolic, and functional events within the intact neighbors surrounding injured neural tissues. During aging, multiple changes involving physical, chemical, and biochemical processes occur from the molecular to the morphological levels in neural tissues. Among many recommended therapeutic candidates, melatonin also plays a role in protecting the nervous system from anti-inflammation and efficiently safeguards neuronal cells via antioxidants and other endogenous/exogenous beneficial factors. Therefore, given the wide range of mechanisms responsible for neuronal damage, multi-action drugs or therapies for the treatment of neural injury that make use of two or more agents and target several pathways may have greater efficacy in promoting functional recovery than a single therapy alone. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Therapeutic Hypothermia in Spinal Cord Injury: The Status of Its Use and Open Questions
by Jiaqiong Wang and Damien D. Pearse
Int. J. Mol. Sci. 2015, 16(8), 16848-16879; https://doi.org/10.3390/ijms160816848 - 24 Jul 2015
Cited by 55 | Viewed by 8038
Abstract
Spinal cord injury (SCI) is a major health problem and is associated with a diversity of neurological symptoms. Pathophysiologically, dysfunction after SCI results from the culmination of tissue damage produced both by the primary insult and a range of secondary injury mechanisms. The [...] Read more.
Spinal cord injury (SCI) is a major health problem and is associated with a diversity of neurological symptoms. Pathophysiologically, dysfunction after SCI results from the culmination of tissue damage produced both by the primary insult and a range of secondary injury mechanisms. The application of hypothermia has been demonstrated to be neuroprotective after SCI in both experimental and human studies. The myriad of protective mechanisms of hypothermia include the slowing down of metabolism, decreasing free radical generation, inhibiting excitotoxicity and apoptosis, ameliorating inflammation, preserving the blood spinal cord barrier, inhibiting astrogliosis, promoting angiogenesis, as well as decreasing axonal damage and encouraging neurogenesis. Hypothermia has also been combined with other interventions, such as antioxidants, anesthetics, alkalinization and cell transplantation for additional benefit. Although a large body of work has reported on the effectiveness of hypothermia as a neuroprotective approach after SCI and its application has been translated to the clinic, a number of questions still remain regarding its use, including the identification of hypothermia’s therapeutic window, optimal duration and the most appropriate rewarming rate. In addition, it is necessary to investigate the neuroprotective effect of combining therapeutic hypothermia with other treatment strategies for putative synergies, particularly those involving neurorepair. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
What’s New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment
by Cesar Reis, Yuechun Wang, Onat Akyol, Wing Mann Ho, Richard Applegate II, Gary Stier, Robert Martin and John H. Zhang
Int. J. Mol. Sci. 2015, 16(6), 11903-11965; https://doi.org/10.3390/ijms160611903 - 26 May 2015
Cited by 57 | Viewed by 13944
Abstract
Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI [...] Read more.
Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI with neuroimaging technologies, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and high definition fiber tracking (HDFT) show increasing sensitivity and specificity. Classical electrophysiological monitoring, together with newly established brain-on-chip, cerebral microdialysis techniques, both benefit TBI. First generation molecular biomarkers, based on genomic and proteomic changes following TBI, have proven effective and economical. It is conceivable that TBI-specific biomarkers will be developed with the combination of systems biology and bioinformation strategies. Advances in treatment of TBI include stem cell-based and nanotechnology-based therapy, physical and pharmaceutical interventions and also new use in TBI for approved drugs which all present favorable promise in preventing and reversing TBI. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs
by Shotaro Michinaga and Yutaka Koyama
Int. J. Mol. Sci. 2015, 16(5), 9949-9975; https://doi.org/10.3390/ijms16059949 - 30 Apr 2015
Cited by 209 | Viewed by 30210
Abstract
Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of [...] Read more.
Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vasogenic or cytotoxic edema. Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB) and extravasations of serum proteins, while cytotoxic edema is characterized by cell swelling caused by intracellular accumulation of fluid. Various experimental animal models are often used to investigate mechanisms underlying brain edema. Many soluble factors and functional molecules have been confirmed to induce BBB disruption or cell swelling and drugs targeted to these factors are expected to have anti-edema effects. In this review, we discuss the mechanisms and involvement of factors that induce brain edema formation, and the possibility of anti-edema drugs targeting them. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Unfolding the Unfolded Protein Response: Unique Insights into Brain Ischemia
by Thomas H. Sanderson, Molly Gallaway and Rita Kumar
Int. J. Mol. Sci. 2015, 16(4), 7133-7142; https://doi.org/10.3390/ijms16047133 - 30 Mar 2015
Cited by 40 | Viewed by 6324
Abstract
The endoplasmic reticulum (ER) is responsible for processing of proteins that are destined to be secreted, enclosed in a vesicle, or incorporated in the plasma membrane. Nascent peptides that enter the ER undergo a series of highly regulated processing steps to reach maturation [...] Read more.
The endoplasmic reticulum (ER) is responsible for processing of proteins that are destined to be secreted, enclosed in a vesicle, or incorporated in the plasma membrane. Nascent peptides that enter the ER undergo a series of highly regulated processing steps to reach maturation as they transit the ER. Alterations in the intracellular environment that induce ER stress are thought to interrupt these processing steps, and result in unfolding of proteins in the ER. Accumulation of unfolded proteins concurrently activates three transmembrane stress sensors, IRE1, ATF6 and PERK, and is referred to as the Unfolded Protein Response (UPR). Our understanding of the mechanisms of UPR induction has been assembled primarily from experiments inducing ER stress with chemical and genetic manipulations. However, physiological stress often induces activation of ER stress sensors in a distinct manner from the canonical UPR. The unique activation profiles in vivo have prompted us to examine the mechanism of UPR activation in neurons following cerebral ischemia. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke
by Nicholas Caffes, David B. Kurland, Volodymyr Gerzanich and J. Marc Simard
Int. J. Mol. Sci. 2015, 16(3), 4973-4984; https://doi.org/10.3390/ijms16034973 - 04 Mar 2015
Cited by 57 | Viewed by 8188
Abstract
Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell [...] Read more.
Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial KATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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Review
Nanostructured Guidance for Peripheral Nerve Injuries: A Review with a Perspective in the Oral and Maxillofacial Area
by Stefano Sivolella, Giulia Brunello, Nadia Ferrarese, Alessandro Della Puppa, Domenico D'Avella, Eriberto Bressan and Barbara Zavan
Int. J. Mol. Sci. 2014, 15(2), 3088-3117; https://doi.org/10.3390/ijms15023088 - 20 Feb 2014
Cited by 22 | Viewed by 7365
Abstract
Injury to peripheral nerves can occur as a result of various surgical procedures, including oral and maxillofacial surgery. In the case of nerve transaction, the gold standard treatment is the end-to-end reconnection of the two nerve stumps. When it cannot be performed, the [...] Read more.
Injury to peripheral nerves can occur as a result of various surgical procedures, including oral and maxillofacial surgery. In the case of nerve transaction, the gold standard treatment is the end-to-end reconnection of the two nerve stumps. When it cannot be performed, the actual strategies consist of the positioning of a nerve graft between the two stumps. Guided nerve regeneration using nano-structured scaffolds is a promising strategy to promote axon regeneration. Biodegradable electrospun conduits composed of aligned nanofibers is a new class of devices used to improve neurite extension and axon outgrowth. Self assembled peptide nanofibrous scaffolds (SAPNSs) demonstrated promising results in animal models for central nervous system injuries, and, more recently, for peripheral nerve injury. Aims of this work are (1) to review electrospun and self-assembled nanofibrous scaffolds use in vitro and in vivo for peripheral nerve regeneration; and (2) its application in peripheral nerve injuries treatment. The review focused on nanofibrous scaffolds with a diameter of less than approximately 250 nm. The conjugation in a nano scale of a natural bioactive factor with a resorbable synthetic or natural material may represent the best compromise providing both biological and mechanical cues for guided nerve regeneration. Injured peripheral nerves, such as trigeminal and facial, may benefit from these treatments. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

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Letter
Isolation of a Pluripotent Neural Stem Cell from the Embryonic Bovine Brain
by Yuhua Gao, Xiangchen Li, Dong Zheng, Weijun Guan and Yuehui Ma
Int. J. Mol. Sci. 2015, 16(3), 5990-5999; https://doi.org/10.3390/ijms16035990 - 13 Mar 2015
Cited by 6 | Viewed by 6200
Abstract
We recently isolated stem cells derived from the brain of a bovine fetus, utilizing a particular mechanical separation method. After improving our experimental conditions, we obtained neural stem cells using an optimized culture medium system. The cells were expanded, established in continuous cell [...] Read more.
We recently isolated stem cells derived from the brain of a bovine fetus, utilizing a particular mechanical separation method. After improving our experimental conditions, we obtained neural stem cells using an optimized culture medium system. The cells were expanded, established in continuous cell culture and used for immunofluorescence cytochemistry. RT-PCR showed that embryonic neural stem cells (NSCs) not only expresses the protein Sox2, Nestin but also Pax6, Musashi proteins and were differentiated into the three classical neuronal phenotypes (neurons, astrocytes, and oligodendrocytes). Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)
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