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18 pages, 4068 KiB

Open AccessArticle

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

by K. Bergen, M. Frödin, C. Von Gertten, A. -C. Sandberg-Nordqvist and M. K. Sköld

Brain Sci. 2018, 8(8), 151; https://doi.org/10.3390/brainsci8080151 - 11 Aug 2018

Cited by 3 | Viewed by 3890

Following traumatic brain injuries (TBI), insulin-like growth factor (IGF) is cortically widely upregulated. This upregulation has a potential role in the recovery of neuronal tissue, plasticity, and neurotrophic activity, though the molecular mechanisms involved in IGF regulation and the exact role of IGF [...] Read more.

Following traumatic brain injuries (TBI), insulin-like growth factor (IGF) is cortically widely upregulated. This upregulation has a potential role in the recovery of neuronal tissue, plasticity, and neurotrophic activity, though the molecular mechanisms involved in IGF regulation and the exact role of IGF after TBI remain unclear. Vitronectin (VN), an extracellular matrix (ECM) molecule, has recently been shown to be of importance for IGF-mediated cellular growth and migration. Since VN is downregulated after TBI, we hypothesized that insufficient VN levels after TBI impairs the potential beneficial activity of IGF. To test if vitronectin and IGF-1/IGFBP-2 could contribute to neurite growth, we cultured hippocampal neurons on ± vitronectin-coated coverslips and them treated with ± IGF-1/IGF binding protein 2 (IGFBP-2). Under same conditions, cell cultures were also subjected to in vitro trauma to investigate differences in the posttraumatic regenerative capacity with ± vitronectin-coated coverslips and with ± IGF-1/IGFBP-2 treatment. In both the control and trauma situations, hippocampal neurons showed a stronger growth pattern on vitronectin than on the control substrate. Surprisingly, the addition of IGF-1/IGFBP-2 showed a decrease in neurite growth. Since neurite growth was measured as the number of neurites per area, we hypothesized that IGF-1/IGFBP-2 contributes to the polarization of neurons and thus induced a less dense neurite network after IGF-1/IGFBP-2 treatment. This hypothesis could not be confirmed and we therefore conclude that vitronectin has a positive effect on neurite growth in vitro both under normal conditions and after trauma, but that addition of IGF-1/IGFBP-2 does not have a positive additive effect. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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22 pages, 64992 KiB

Open AccessArticle

The Effect of Axon Resealing on Retrograde Neuronal Death after Spinal Cord Injury in Lamprey

by Guixin Zhang, William Rodemer, Taemin Lee, Jianli Hu and Michael E. Selzer

Brain Sci. 2018, 8(4), 65; https://doi.org/10.3390/brainsci8040065 - 14 Apr 2018

Cited by 11 | Viewed by 5610

Abstract

Failure of axon regeneration in the central nervous system (CNS) of mammals is due to both extrinsic inhibitory factors and to neuron-intrinsic factors. The importance of intrinsic factors is illustrated in the sea lamprey by the 18 pairs of large, individually identified reticulospinal [...] Read more.

Failure of axon regeneration in the central nervous system (CNS) of mammals is due to both extrinsic inhibitory factors and to neuron-intrinsic factors. The importance of intrinsic factors is illustrated in the sea lamprey by the 18 pairs of large, individually identified reticulospinal (RS) neurons, whose axons are located in the same spinal cord tracts but vary greatly in their ability to regenerate after spinal cord transection (TX). The neurons that are bad regenerators also undergo very delayed apoptosis, signaled early by activation of caspases. We noticed that the neurons with a low probability of axon regeneration tend to be larger than the good regenerators. We postulate that the poorly regenerating larger neurons have larger caliber axons, which reseal more slowly, allowing more prolonged entry of toxic signals (e.g., Ca⁺⁺) into the axon at the injury site. To test this hypothesis, we used a dye-exclusion assay, applying membrane-impermeable dyes to the cut ends of spinal cords at progressively longer post-TX intervals. Axons belonging to the very small neurons (not individually identified) of the medial inferior RS nucleus resealed within 15 min post-TX. Almost 75% of axons belonging to the medium-sized identified RS neurons resealed within 3 h. At this time, only 36% of the largest axons had resealed, often taking more than 24 h to exclude the dye. There was an inverse relationship between an RS neuron’s size and the probability that its axon would regenerate (r = −0.92) and that the neuron would undergo delayed apoptosis, as indicated by staining with a fluorescently labeled inhibitor of caspases (FLICA; r = 0.73). The artificial acceleration of resealing with polyethylene glycol (PEG) reduced retrograde neuronal apoptosis by 69.5% at 2 weeks after spinal cord injury (SCI), suggesting that axon resealing is a critical determinant of cell survival. Ca⁺⁺-free Ringer’s solution with EGTA prolonged the sealing time and increased apoptotic signaling, suggesting that factors other than Ca⁺⁺ diffusion into the injured tip contribute to retrograde death signaling. A longer distance of the lesion from the cell body reduced apoptotic signaling independent of the axon sealing time. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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11 pages, 2235 KiB

Open AccessArticle

Neurodegeneration and Sensorimotor Deficits in the Mouse Model of Traumatic Brain Injury

by Saurav Bhowmick, Veera D‘Mello, Nizmi Ponery and P. M. Abdul-Muneer

Brain Sci. 2018, 8(1), 11; https://doi.org/10.3390/brainsci8010011 - 06 Jan 2018

Cited by 31 | Viewed by 6975

Abstract

Traumatic brain injury (TBI) can result in persistent sensorimotor and cognitive deficits, which occur through a cascade of deleterious pathophysiological events over time. In this study, we investigated the hypothesis that neurodegeneration caused by TBI leads to impairments in sensorimotor function. TBI induces [...] Read more.

Traumatic brain injury (TBI) can result in persistent sensorimotor and cognitive deficits, which occur through a cascade of deleterious pathophysiological events over time. In this study, we investigated the hypothesis that neurodegeneration caused by TBI leads to impairments in sensorimotor function. TBI induces the activation of the caspase-3 enzyme, which triggers cell apoptosis in an in vivo model of fluid percussion injury (FPI). We analyzed caspase-3 mediated apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and poly (ADP-ribose) polymerase (PARP) and annexin V western blotting. We correlated the neurodegeneration with sensorimotor deficits by conducting the animal behavioral tests including grid walk, balance beam, the inverted screen test, and the climb test. Our study demonstrated that the excess cell death or neurodegeneration correlated with the neuronal dysfunction and sensorimotor impairments associated with TBI. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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2612 KiB

Open AccessArticle

A Proposed Mechanism for Development of CTE Following Concussive Events: Head Impact, Water Hammer Injury, Neurofilament Release, and Autoimmune Processes

by Steven Kornguth, Neal Rutledge, Gabe Perlaza, James Bray and Allen Hardin

Brain Sci. 2017, 7(12), 164; https://doi.org/10.3390/brainsci7120164 - 19 Dec 2017

Cited by 27 | Viewed by 8062

Abstract

During the past decade, there has been an increasing interest in early diagnosis and treatment of traumatic brain injuries (TBI) that lead to chronic traumatic encephalopathy (CTE). The subjects involved range from soldiers exposed to concussive injuries from improvised explosive devices (IEDs) to [...] Read more.

During the past decade, there has been an increasing interest in early diagnosis and treatment of traumatic brain injuries (TBI) that lead to chronic traumatic encephalopathy (CTE). The subjects involved range from soldiers exposed to concussive injuries from improvised explosive devices (IEDs) to a significant number of athletes involved in repetitive high force impacts. Although the forces from IEDs are much greater by a magnitude than those from contact sports, the higher frequency associated with contact sports allows for more controlled assessment of the mechanism of action. In our study, we report findings in university-level women soccer athletes followed over a period of four and a half years from accession to graduation. Parameters investigated included T1-, T2-, and susceptibility-weighted magnetic resonance images (SWI), IMPACT (Immediate Post-Concussion Assessment and Cognitive Testing), and C3 Logix behavioral and physiological assessment measures. The MRI Studies show several significant findings: first, a marked increase in the width of sulci in the frontal to occipital cortices; second, an appearance of subtle hemorrhagic changes at the base of the sulci; third was a sustained reduction in total brain volume in several soccer players at a developmental time when brain growth is generally seen. Although all of the athletes successfully completed their college degree and none exhibited long term clinical deficits at the time of graduation, the changes documented by MRI represent a clue to the pathological mechanism following an injury paradigm. The authors propose that our findings and those of prior publications support a mechanism of injury in CTE caused by an autoimmune process associated with the release of neural proteins from nerve cells at the base of the sulcus from a water hammer injury effect. As evidence accumulates to support this hypothesis, there are pharmacological treatment strategies that may be able to mitigate the development of long-term disability from TBI. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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Review

Jump to: Research

12 pages, 616 KiB

Open AccessReview

NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease

by Ryan Thompson and Christina Chan

Brain Sci. 2018, 8(12), 226; https://doi.org/10.3390/brainsci8120226 - 19 Dec 2018

Cited by 18 | Viewed by 5250

Abstract

The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural [...] Read more.

The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF’s ability to recruit chromatin remodelers. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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13 pages, 233 KiB

Open AccessReview

A Review of Traumatic Brain Injury and the Gut Microbiome: Insights into Novel Mechanisms of Secondary Brain Injury and Promising Targets for Neuroprotection

by Caroline S. Zhu, Ramesh Grandhi, Thomas Tyler Patterson and Susannah E. Nicholson

Brain Sci. 2018, 8(6), 113; https://doi.org/10.3390/brainsci8060113 - 19 Jun 2018

Cited by 68 | Viewed by 9916

Abstract

The gut microbiome and its role in health and disease have recently been major focus areas of research. In this review, we summarize the different ways in which the gut microbiome interacts with the rest of the body, with focus areas on its [...] Read more.

The gut microbiome and its role in health and disease have recently been major focus areas of research. In this review, we summarize the different ways in which the gut microbiome interacts with the rest of the body, with focus areas on its relationships with immunity, the brain, and injury. The gut–brain axis, a communication network linking together the central and enteric nervous systems, represents a key bidirectional pathway with feed-forward and feedback mechanisms. The gut microbiota has a central role in this pathway and is significantly altered following injury, leading to a pro-inflammatory state within the central nervous system (CNS). Herein, we examine traumatic brain injury (TBI) in relation to this axis and explore potential interventions, which may serve as targets for improving clinical outcomes and preventing secondary brain injury. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

19 pages, 1108 KiB

Open AccessReview

Emerging Cellular and Molecular Strategies for Enhancing Central Nervous System (CNS) Remyelination

by Mohammad Abu-Rub and Robert H. Miller

Brain Sci. 2018, 8(6), 111; https://doi.org/10.3390/brainsci8060111 - 15 Jun 2018

Cited by 26 | Viewed by 6231

Abstract

Myelination is critical for the normal functioning of the central nervous system (CNS) in vertebrates. Conditions in which the development of myelin is perturbed result in severely compromised individuals often with shorter lifespans, while loss of myelin in the adult results in a [...] Read more.

Myelination is critical for the normal functioning of the central nervous system (CNS) in vertebrates. Conditions in which the development of myelin is perturbed result in severely compromised individuals often with shorter lifespans, while loss of myelin in the adult results in a variety of functional deficits. Although some form of spontaneous remyelination often takes place, the repair process as a whole often fails. Several lines of evidence suggest it is feasible to develop strategies that enhance the capacity of the CNS to undergo remyelination and potentially reverse functional deficits. Such strategies include cellular therapies using either neural or mesenchymal stem cells as well as molecular regulators of oligodendrocyte development and differentiation. Given the prevalence of demyelinating diseases and their effects on the quality of life for affected individuals it is imperative that effective therapies are developed. Here we discuss some of the new approaches to CNS myelin repair that hold promise for reducing the burden of diseases characterized by myelin loss. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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10 pages, 499 KiB

Open AccessReview

History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair

by Melissa J. Walker and Xiao-Ming Xu

Brain Sci. 2018, 8(6), 109; https://doi.org/10.3390/brainsci8060109 - 13 Jun 2018

Cited by 37 | Viewed by 5423

Abstract

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, in combination with [...] Read more.

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, in combination with other factors and cell transplantations, for repairing the injured spinal cord. As studies of recent decades strongly suggest that combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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Graphical abstract

12 pages, 576 KiB

Open AccessReview

New Insights into the Role of Neuron-Specific Enolase in Neuro-Inflammation, Neurodegeneration, and Neuroprotection

by Azizul Haque, Rachel Polcyn, Denise Matzelle and Naren L. Banik

Brain Sci. 2018, 8(2), 33; https://doi.org/10.3390/brainsci8020033 - 18 Feb 2018

Cited by 143 | Viewed by 14289

Abstract

Neurodegeneration is a complex process that leads to irreversible neuronal damage and death in spinal cord injury (SCI) and various neurodegenerative diseases, which are serious, debilitating conditions. Despite exhaustive research, the cause of neuronal damage in these degenerative disorders is not completely understood. [...] Read more.

Neurodegeneration is a complex process that leads to irreversible neuronal damage and death in spinal cord injury (SCI) and various neurodegenerative diseases, which are serious, debilitating conditions. Despite exhaustive research, the cause of neuronal damage in these degenerative disorders is not completely understood. Elevation of cell surface α-enolase activates various inflammatory pathways, including the production of pro-inflammatory cytokines, chemokines, and some growth factors that are detrimental to neuronal cells. While α-enolase is present in all neurological tissues, it can also be converted to neuron specific enolase (NSE). NSE is a glycolytic enzyme found in neuronal and neuroendocrine tissues that may play a dual role in promoting both neuroinflammation and neuroprotection in SCI and other neurodegenerative events. Elevated NSE can promote ECM degradation, inflammatory glial cell proliferation, and actin remodeling, thereby affecting migration of activated macrophages and microglia to the injury site and promoting neuronal cell death. Thus, NSE could be a reliable, quantitative, and specific marker of neuronal injury. Depending on the injury, disease, and microenvironment, NSE may also show neurotrophic function as it controls neuronal survival, differentiation, and neurite regeneration via activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. This review discusses possible implications of NSE expression and activity in neuroinflammation, neurodegeneration, and neuroprotection in SCI and various neurodegenerative diseases for prognostic and therapeutic potential. Full article

(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)

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