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    15 August 2019, Volume 14 Issue 8 Previous Issue    Next Issue
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    Tandem pore TWIK-related potassium channels and neuroprotection
    J. Antonio Lamas,Diego Fernández-Fernández
    2019, 14 (8):  1293-1308.  doi: 10.4103/1673-5374.253506
    Abstract ( 125 )   PDF (618KB) ( 284 )   Save

    TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notwithstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications.

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    Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system
    Florian Simon,Nicolaos Floros, Wiebke Ibing, Hubert Schelzig, Artis Knapsis
    2019, 14 (8):  1309-1312.  doi: 10.4103/1673-5374.253507
    Abstract ( 100 )   PDF (172KB) ( 132 )   Save

    Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.

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    Dendritic shrinkage after injury: a cellular killer or a necessity for axonal regeneration?
    An Beckers, Lieve Moons
    2019, 14 (8):  1313-1316.  doi: 10.4103/1673-5374.253505
    Abstract ( 134 )   PDF (1393KB) ( 167 )   Save

    Dendrites form an essential component of the neuronal circuit, yet have been largely overlooked in regenerative research. Nevertheless, subtle changes in the dendritic arbors of neurons are one of the first stages of various neurodegenerative diseases, leading to dysfunctional neuronal networks and ultimately cellular death. Maintaining dendrites is therefore considered an essential neuroprotective strategy. This mini-review aims to discuss an intriguing hypothesis, which postulates that dendritic shrinkage is an important stimulant to boost axonal regeneration, and thus that preserving dendrites might not be the ideal therapeutic method to regain a full functional network upon central nervous system damage. Indeed, our study in zebrafish, a versatile animal model with robust regenerative capacity recently unraveled that dendritic retraction is evoked prior to axonal regrowth after optic nerve injury. Strikingly, inhibiting dendritic pruning upon damage perturbed axonal regeneration. This constraining effect of dendrites on axonal regrowth has sporadically been proposed in literature, as summarized in this short narrative. In addition, the review discusses a plausible underlying mechanism for the observed antagonistic axon-dendrite interplay, which is based on energy restriction inside neurons. Axonal injury indeed leads to a high local energy demand in which efficient axonal energy supply is fundamental to ensure regrowth. At the same time, axonal lesion is known to induce mitochondrial depolarization, causing energy depletion in the axonal compartment of damaged neurons. Mitochondria, however, become mostly stationary after development, which has been proposed as a potential underlying reason for the low regenerative capacity of adult mammals. Per contra, upon reduced neuronal activity, mitochondrial mobility enhances. In this view, dendritic shrinkage after axonal injury in zebrafish could result in less synaptic input and hence, a release of mitochondria within the soma-dendrite compartment that then translocate to the axonal growth cone to stimulate axonal regeneration. If this hypothesis proofs to be correct, i.e. dendritic remodeling serving as fuel for axonal regeneration, we envision a major shift in the research focus within the neuroregenerative field and in the potential uncovering of various novel therapeutic targets.

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    Regenerative biomarkers for Duchenne muscular dystrophy
    Simon Guiraud,Kay E. Davies
    2019, 14 (8):  1317-1320.  doi: 10.4103/1673-5374.253534
    Abstract ( 98 )   PDF (1157KB) ( 162 )   Save

    Skeletal muscle has an extraordinary capacity to regenerate after injury and trauma. The muscle repair mechanism is a complex process orchestrated by multiple steps. In neuromuscular disorders such as Duchenne muscular dystrophy (DMD), the pathological consequences of the lack of dystrophin and the loss of the dystrophin-associated protein complex are dramatic, with a progressive cascade of events, such as continual influx of inflammation, repeated cycles of degeneration and impaired regeneration. Thus, muscle regeneration is a hallmark of the disease and careful monitoring of regenerative processes with robust markers should provide useful information to the field. Since decades, several indices of regeneration such as centronucleation and fibre size have been commonly used. In the present review, we discuss the impaired regenerative process in DMD, the common and new indices of regeneration and their associated methodologies. We notably highlight the regenerative marker embryonic myosin as a robust indicator of muscle regeneration. We also describe new quantitative methodologies offering the possibility of using a panel of translational regenerative biomarkers to obtain a more complete view of the regeneration processes. Upregulation of utrophin, an autosomal and functional paralogue of dystrophin, is one of the most promising therapeutic strategies as it targets the primary cause of the disease and is applicable to all DMD patients regardless their genetic defects. As utrophin is a regeneration associated protein increased in dystrophic muscle, we discuss the correlation of utrophin levels after drug treatment with regeneration markers. The recent advances in technologies and complementary markers of muscle regeneration described in this review, provide an unprecedented opportunity to develop more robust utrophin DMD based strategies for all DMD patients.

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    Exploring the efficacy of natural products in alleviating Alzheimer’s disease
    Prajakta Deshpande,Neha Gogia,Amit Singh
    2019, 14 (8):  1321-1329.  doi: 10.4103/1673-5374.253509
    Abstract ( 124 )   PDF (1225KB) ( 208 )   Save

    Alzheimer’s disease (hereafter AD) is a progressive neurodegenerative disorder that affects the central nervous system. There are multiple factors that cause AD, viz., accumulation of extracellular Amyloid-beta 42 plaques, intracellular hyper-phosphorylated Tau tangles, generation of reactive oxygen species due to mitochondrial dysfunction and genetic mutations. The plaques and tau tangles triggers aberrant signaling, which eventually cause cell death of the neurons. As a result, there is shrinkage of brain, cognitive defects, behavioral and psychological problems. To date, there is no direct cure for AD. Thus, scientists have been testing various strategies like screening for the small inhibitor molecule library or natural products that may block or prevent onset of AD. Historically, natural products have been used in many cultures for the treatment of various diseases. The research on natural products have gained importance as the active compounds extracted from them have medicinal values with reduced side effects, and they are bioavailable. The natural products may target the proteins or members of signaling pathways that get altered in specific diseases. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target for AD, and to address questions about how these natural products can rescue AD or other neurodegenerative disorders. Some of these products are in clinical trials and results are promising because of their neuroprotective, anti-inflammatory, antioxidant, anti-amyloidogenic, anticholinesterase activities and easy availability. This review summarizes the use of animal model systems to identify natural products, which may serve as potential therapeutic targets for AD.

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    Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease
    Daisuke Tanokashira,Wataru Fukuokaya,Akiko Taguchi
    2019, 14 (8):  1330-1334.  doi: 10.4103/1673-5374.253535
    Abstract ( 101 )   PDF (435KB) ( 120 )   Save

    Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased hosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

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    Role of macrophages in peripheral nerve injury and repair
    Ping Liu,Jiang Peng,Gong-Hai Han,Xiao Ding,Shuai Wei,Gang Gao,Kun Huang,Feng Chang,Yu Wang
    2019, 14 (8):  1335-1342.  doi: 10.4103/1673-5374.253510
    Abstract ( 288 )   PDF (840KB) ( 178 )   Save

    Resident and inflammatory macrophages are essential effectors of the innate immune system. These cells provide innate immune defenses and regulate tissue and organ homeostasis. In addition to their roles in diseases such as cancer, obesity and osteoarthritis, they play vital roles in tissue repair and disease rehabil¬itation. Macrophages and other inflammatory cells are recruited to tissue injury sites where they promote changes in the microenvironment. Among the inflammatory cell types, only macrophages have both pro-inflammatory (M1) and anti-inflammatory (M2) actions, and M2 macrophages have four subtypes. The co-action of M1 and M2 subtypes can create a favorable microenvironment, releasing cytokines for damaged tissue repair. In this review, we discuss the activation of macrophages and their roles in severe pe¬ripheral nerve injury. We also describe the therapeutic potential of macrophages in nerve tissue engineering treatment and highlight approaches for enhancing M2 cell-mediated nerve repair and regeneration.

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    Therapeutic strategies for peripheral nerve injury:decellularized nerve conduits and Schwann cell transplantation
    Gong-Hai Han 1, 2,Jiang Peng 2,Ping Liu 3,Xiao Ding 4,Shuai Wei 4,Sheng Lu 5,Yu Wang
    2019, 14 (8):  1343-1351.  doi: 10.4103/1673-5374.253511
    Abstract ( 183 )   PDF (1898KB) ( 236 )   Save

    In recent years, the use of Schwann cell transplantation to repair peripheral nerve injury has attracted much attention. Animal-based studies show that the transplantation of Schwann cells in combination with nerve scaffolds promotes the repair of injured peripheral nerves. Autologous Schwann cell transplantation in humans has been reported recently. This article reviews current methods for removing the extracellular matrix and analyzes its composition and function. The development and secretory products of Schwann cells are also reviewed. The methods for the repair of peripheral nerve injuries that use myelin and Schwann cell transplantation are assessed. This survey of the literature data shows that using a decellularized nerve conduit combined with Schwann cells represents an effective strategy for the treatment of peripheral nerve injury. This analysis provides a comprehensive basis on which to make clinical decisions for the repair of peripheral nerve injury.

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    Role and prospects of regenerative biomaterials in the repair of spinal cord injury
    Shuo Liu, Yuan-Yuan Xie, Bin Wang
    2019, 14 (8):  1352-1363.  doi: 10.4103/1673-5374.253512
    Abstract ( 169 )   PDF (1252KB) ( 174 )   Save

    Axonal junction defects and an inhibitory environment after spinal cord injury seriously hinder the regener¬ation of damaged tissues and neuronal functions. At the site of spinal cord injury, regenerative biomaterials can fill cavities, deliver curative drugs, and provide adsorption sites for transplanted or host cells. Some re¬generative biomaterials can also inhibit apoptosis, inflammation and glial scar formation, or further promote neurogenesis, axonal growth and angiogenesis. This review summarized a variety of biomaterial scaffolds made of natural, synthetic, and combined materials applied to spinal cord injury repair. Although these biomaterial scaffolds have shown a certain therapeutic effect in spinal cord injury repair, there are still many problems to be resolved, such as product standards and material safety and effectiveness.

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    The “Brain Stress Timing” phenomenon and other misinterpretations of randomized clinical trial on aneurysmal subarachnoid hemorrhage
    Rafael Martínez-Pérez,Natalia Rayo,Agustín Montivero,Jorge Marcelo Mura
    2019, 14 (8):  1364-1366.  doi: 10.4103/1673-5374.253513
    Abstract ( 120 )   PDF (957KB) ( 251 )   Save

    Clipping and coiling are currently the two alternatives in treatment of ruptured cerebral aneurysms. In spite of some meritorious analysis, further discussion is helpful to understand the actual state of art. Retreatment and rebleeding rates clearly favors clipping, although short-term functional outcome seems to be beneficial for clipping, while this different is not such if we perform the comparison at a longer follow up. Long-term follow ups and cost analysis are mandatory to have a clear view of the current picture in treatment of subarachnoid hemorrhage. Treatment strategy should be made by a multi-disciplinary team in accredited centers with proficient experience in both techniques.

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    Rac GTPases: domain-specific functions in neuronal development
    Steffen Nørgaard, Roger Pocock
    2019, 14 (8):  1367-1368.  doi: 10.4103/1673-5374.253515
    Abstract ( 91 )   PDF (644KB) ( 143 )   Save

    Understanding fundamental mechanisms governing axon outgrowth and guidance can inform the development of therapeutic strategies to restore neuronal function damaged though injury or disease. Axons navigate the extracellular environment by responding to guidance cues that bind to cell surface receptors to relay information intracellularly via Rho GTPase family members, including the Rac GTPases. Rac GTPases act as master switches to regulate diverse signalling pathways to control the actin cytoskeleton-a major driver of axon outgrowth. However, scant evidence exists concerning how different domains within Rac GTPases regulate specific neurodevelopmental events, such as axon outgrowth and guidance.

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    Insights into ligand expression heterogeneity across multiple cell types in the adult forebrain that regulates neural stem cell behavior
    Rainer Akkermann, Kasum Azim
    2019, 14 (8):  1369-1371.  doi: 10.4103/1673-5374.251304
    Abstract ( 85 )   PDF (1952KB) ( 124 )   Save

    In the adult mammalian central nervous system (CNS), neural cell generation is restricted to two highly specialized germinal niches. These are the subventricular zone (SVZ) that borders the forebrain lateral ventricles and the subgranular zone of the hippocampus. In the case of the former niche, the SVZ gives rise daily to thousands of migratory neuroblasts that travel long distances to the olfactory bulb via the rostral migratory stream. Neural stem cells (NSCs) first engage through a sequence of activation phenotypes and give rise to transiently amplifying progenitors (TAPs) that subsequently differentiate into neuroblasts. Once in the olfactory bulb, they generate phenotypically distinct neurons. Most of these constitute the interneuron class that is preferentially derived from the lateral portion of the SVZ, whilst a small proportion of projection neurons are also formed from the dorsal SVZ. Similarly, although fractional in number, oligodendrocyte lineage cells and astrocytes are additionally generated from this germinal zone. Lesser is known regarding the differentiation steps regarding adult astrogenesis from the SVZ. Oligodendrocyte lineage cells diverge from TAPs and remain relatively close within the periventricular forebrain corresponding to their site generation. Oligodendrocytes generated from the SVZ will also pass through phenotypically distinct stages until they form mature oligodendrocytes. Adult NG2 glia (oligodendrocyte precursor cells) are the main proliferative population of the adult CNS outside of neurogenic niches and are supported in their capacity to restore oligodendrocyte populations following injury by SVZ derived early oligodendroglial populations.

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    Translational perspective: is cinnamon a suitable agent for cognitive impairment and Alzheimer’s disease associated with brain trauma?
    Burak Yulug, Seyda Cankaya
    2019, 14 (8):  1372-1373.  doi: 10.4103/1673-5374.253518
    Abstract ( 115 )   PDF (351KB) ( 153 )   Save

    Cinnamon, is an exotic spice and a major constituent of our food which is commonly used in different areas of the world for the treatment of various diseases. Besides its anti-inflammatory, anti-diabetic and anti-cancer properties, cinnamon also exerts strong brain protective and pro-cognitive effects in various models of neurodegeneration. Traumatic brain injury (TBI) is characterized with significant vascular, neuronal and axonal damage that is associated with critical oxidative injury and neuroinflammation. Clinical studies have already conferred that pre and post-injury systemic inflammation could modify the subsequent prognosis of brain injury. Moreover, many pharmacological agents were failed to show a clinical neuroprotective effect after TBI suggesting that there is an emergency need for novel brain protective therapeutic strategies to improve the clinical outcomes. However, although there are increasing promising experimental data, many clinical trials were failed to change the clinical endpoint after TBI. Additionally, studies have already indicated that drug-drug interactions play an essential role in the development of pharmacotoxic side effects. Taken together, these findings might further indicate that a single agent which is acting on multiple cell death pathways may exert a higher neuroprotective activity. Here, cinnamon might be a novel clinical candidate agent for TBI with its multifaceted neuroprotective and procognitive effects, and its superior safety profile. Interestingly, it has been recently revealed that brain trauma has been not only associated with cognitive impairment but also increase the risk of the development of Alzheimer’s disease.

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    Soluble Neuregulin1 (WRG1): a factor promoting peripheral nerve regeneration by affecting Schwann cell activity immediately after injury
    Marwa El Soury, Giovanna Gambarotta
    2019, 14 (8):  1374-1375.  doi: 10.4103/1673-5374.253516
    Abstract ( 194 )   PDF (521KB) ( 417 )   Save

    Neuregulin-1 (NRG1) is a well known growth factor playing contradictory roles in myelination depending on the existing isoform. Transmembrane NRG1 acts as a promyelinating factor, while the soluble isoform inhibits myelination. In this perspective, we would like to emphasize this conflicting role played by NRG1 isoforms regarding their roles in myelination, remyelination and the entire process of peripheral nerve regeneration.

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    Detrimental and synergistic role of epilepsy-Alzheimer’s disease risk factors
    Mikhail A. Filippov, Vasily V. Vorobyov
    2019, 14 (8):  1376-1377.  doi: 10.4103/1673-5374.253519
    Abstract ( 114 )   PDF (338KB) ( 127 )   Save

    Identification of individuals at risk for developing Alzheimer’s disease (AD) is an important issue for its pretreatment. Perspective studies predicting the disease are based on the genetic approaches emerging from the nucleotide polymorphism analysis in different loci through the entire genome in AD patients. Considerable diversity of genes located in these regions raise the question of this diversity’s peculiar role in the disease development. The mechanisms of AD have been shown to be associated with the gene variation, increased beta-amyloid production and concomitant epileptiform activity/epilepsy in particular. In this perspective, the roles of various genes linked to epileptogenic mechanisms and the risk of AD development are analyzed. We propose that genotyping of apolipoprotein E (APOE) alleles combined with recording of electroencephalogram (EEG) can identify the early-onset AD that will allow highlighting a cohort of individuals at the risk of AD patients.

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    ADAM17/TACE: a key molecule in brain injury regeneration
    Samuel Domínguez-García, Carmen Castro, Noelia Geribaldi-Doldán
    2019, 14 (8):  1378-1379.  doi: 10.4103/1673-5374.253517
    Abstract ( 98 )   PDF (398KB) ( 140 )   Save

    It has been many years since “the tumor necrosis factor-α-converting enzyme”, also known as ADAM17/TACE, was described as “the enzyme that does it all” because of its role in neurodegenerative diseases and in several physiological processes including proteolysis, adhesion, intracellular signaling, migration and proliferation. ADAM17/TACE is an integral membrane protein that belongs to the disintegrin and metalloprotease (ADAM)family. Several years ago, Romero-Grimaldi et al. discovered that ADAM17 was involved in the glial/neuronal fate decision of neural progenitor cells (NPCs) in vitro, and this was mediated at least in part, by its capacity to facilitate the release of the epidermal growth factor receptor (EGFR) ligand, transforming growth factor alpha (TGFα), thus regulating EGFR activation. EGFR, also referred to as ErbB1, belongs to a family of transmembrane receptors, which activate intracellular signaling cascades leading to the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinase or phosphoinositide 3-kinase/protein kinase B. and regulate cell cycle through cyclin expression.

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    Galectin-3 prospects as a therapeutic agent for multiple sclerosis
    Laura Thomas, Laura Andrea Pasquini
    2019, 14 (8):  1380-1382.  doi: 10.4103/1673-5374.253521
    Abstract ( 116 )   PDF (1073KB) ( 112 )   Save

    Galectin-3 (Gal-3) in oligodendrocyte (OLG) differentiation: OLGs are the cells in charge of myelination in the central nervous system (CNS), allowing rapid conduction of the neural action potential and giving trophic support to axons. OLGs undergo a series of changes throughout their life cycle: first, upon neural stem cell commitment to the OLG lineage, cells referred to as OLG precur sor cells (OPC) present a bipolar morphology, have proliferative and migratory capacity and express molecular markers like platelet-derived growth factor receptor alpha and neural/glial antigen 2;  next, in an intermediate stage called preOLG, OLGs are more ramified and express CNPase, Olig1 and O4, among others; finally, cells develop into myelin forming cells which express molecular markers like myelin basic protein (MBP), adenomatous polyposis polyposis and proteolipid protein. Worth pointing out, the actin cytoskeleton plays an important role in OLG maturation, as it evolves from pro-polymerization to pro-depolymerization dynamics, which allows axon ensheathing. These mechanisms are controlled in part by the relationship between MBP and actin disassembly proteins such as cofilin-1 and gelsolin. The latter are normally sequestered and inactivated by phosphatidylinositol 4,5-bisphosphate present in the plasma membrane. When MBP is expressed in mature OLG, it competes with gelsolin and cofilin-1 for phosphatidylinositol 4,5-bisphosphate binding, displacing and hence activating them, to trigger the disassembly of actin filaments.

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    Cell-free therapy: a neuroregenerative approach to sensory neuropathy?
    Afrânio Ferreira Evangelista,Milena Botelho Pereira Soares,Cristiane Flora Villarreal
    2019, 14 (8):  1383-1384.  doi: 10.4103/1673-5374.253522
    Abstract ( 121 )   PDF (120KB) ( 91 )   Save

    Stem cells are considered as key therapeutic tools in the field of regenerative medicine. In the last decade, based on a growing body of knowledge about their mechanisms of action, a new way of exploring the therapeutic potential of stem cells without the need for cell transplantation has been evidenced. This approach, called cell-free therapy, uses stem cells as a source of therapeutic molecules rather than the therapeutic agent per se, and several studies have shown relevant therapeutic effects under a variety of experimental conditions, including nervous system disorders.

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    Compartmentalized necroptosis activation in excitotoxicity-induced axonal degeneration: a novel mechanism implicated in neurodegenerative disease pathology
    Macarena S. Arrázola,Felipe A. Court
    2019, 14 (8):  1385-1386.  doi: 10.4103/1673-5374.253520
    Abstract ( 107 )   PDF (443KB) ( 155 )   Save

    Excitotoxicity and neuronal cell death: Glutamate is the main excitatory neurotransmitter of the central nervous system and functionally involved in most brain activities, including brain development, synaptic plasticity, learning and memory. Excitatory synaptic transmission is primarily mediated by ligand-gated ion channels, including α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate receptors. Activation of glutamate receptors, particularly NMDA receptors, usually leads to calcium influx, which can act as a second messenger for several processes to mediate synaptic activity and brain function. Nevertheless, excessive release of glutamate neurotransmitter may produce intracellular calcium overload, leading to a cascade of events mediating cytoskeleton damage accompanied with reactive oxygen species (ROS) generation, mitochondrial dysfunction and ultimately neuronal cell death. These toxic effects of glutamate are known as excitotoxicity. Neuronal excitotoxicity has been linked to several acute and chronic brain diseases, such as stroke/ischemia, epilepsy and a range of neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD), contributing to the neuronal lost in different brain regions. Unfortunately, treating nervous system disorders with general glutamate receptor blockers has been associated with undesirable side effects, becoming increasingly necessary to unravel downstream effectors in the excitotoxicity-dependent cell death pathway in order to develop novel therapeutic strategies.

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    Treadmill training improves neurological deficits and suppresses neuronal apoptosis in cerebral ischemic stroke rats
    Li-Mei Cao, Zhi-Qiang Dong, Qiang Li, Xu Chen
    2019, 14 (8):  1387-1393.  doi: 10.4103/1673-5374.253523
    Abstract ( 120 )   PDF (1874KB) ( 108 )   Save

    Rehabilitation training is believed to be beneficial to patients with stroke, but its molecular mechanism is still unclear. Rat models of ce¬rebral ischemic stroke were established by middle cerebral artery occlusion/reperfusion, and then received treadmill training of different intensities, twice a day for 30 minutes for 1 week. Low-intensity training was conducted at 5 m/min, with a 10-minute running, 10-minute rest, and 10-minute running cycle. In the moderate-intensity training, the intensity gradually increased from 5 m/min to 10 m/min in 5 minutes, with the same rest cycle as above. In high-intensity training, the intensity gradually increased from 5 m/min to 25 m/min in 5 minutes, with the same rest cycle as above. The Bederson scale was used to evaluate the improvement of motor function. Infarct volume was detected using 2,3,5-triphenyltetrazolium chloride staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining was applied to detect the apoptosis of nerve cells in brain tissue. Western blot assay was employed to analyze the activation of cyclic adenosine monophosphate (cAMP)/protein kinase A and Akt/glycogen synthase kinase-3β signaling pathways in rat brain tissue. All training intensities reduced the neurological deficit score, infarct volume, and apoptosis in nerve cells in brain tissue of stroke rats. Training intensities activated the cAMP/protein kinase A and Akt/glycogen synthase kinase-3 beta signaling pathways. This activation was more obvious with higher training intensities. These changes were reversed by intracerebroventricular injection of protein kinase A inhibitor Rp-cAMP. Our findings indicate that the neuroprotective effect of rehabilitation training is achieved via activation of the cAMP/ protein kinase A and Akt/glycogen synthase kinase-3 beta signaling pathways.

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    Time-course pattern of neuronal loss and gliosis in gerbil hippocampi following mild, severe, or lethal transient global cerebral ischemia
    Tae-Kyeong Lee,Hyunjung Kim,Minah Song,Jae-Chul Lee,Joon Ha Park,Ji Hyeon Ahn,Go Eun Yang,Hyeyoung Kim,Taek Geun Ohk,Myoung Cheol Shin,Jun Hwi Cho,Moo-Ho Won
    2019, 14 (8):  1394-1403.  doi: 10.4103/1673-5374.253524
    Abstract ( 154 )   PDF (13625KB) ( 86 )   Save

    Transient ischemia in the whole brain leads to neuronal loss/death in vulnerable brain regions. The striatum, neocortex and hippocampus selectively loose specific neurons after transient ischemia. Just 5 minutes of transient ischemia can cause pyramidal neuronal death in the hippocampal cornu ammonis (CA) 1 field at 4 days after transient ischemia. In this study, we investigated the effects of 5-minute (mild), 15-minute (severe), and 20-minute (lethal) transient ischemia by bilateral common carotid artery occlusion (BCCAO) on behavioral change and neuronal death and gliosis (astrocytosis and microgliosis) in gerbil hippocampal subregions (CA1–3 region and dentate gyrus). We performed spontaneous motor activity test to evaluate gerbil locomotor activity, cresyl violet staining to detect cellular distribution, neuronal nuclei immunohistochemistry to detect neuronal distribution, and Fluoro-Jade B histofluorescence to evaluate neuronal death. We also conducted immunohistochemical staining for glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 (Iba1) to evaluate astrocytosis and microgliosis, respectively. Animals subjected to 20-minute BCCAO died in at least 2 days. BCCAO for 15 minutes led to pyramidal cell death in hippocampal CA1–3 region 2 days later and granule cell death in hippocampal dentate gyrus 5 days later. Similar results were not found in animals subjected to 5-minute BCCAO. Gliosis was much more rapidly and severely progressed in animals subjected to 15-minute BCCAO than in those subjected to 5-minute BCCAO. Our results indicate that neuronal loss in the hippocampal formation following transient ischemia is significantly different according to regions and severity of transient ischemia. The experimental protocol was approved by Institutional Animal Care and Use Committee (AICUC) of Kangwon National University (approval No., KW-180124-1) on May 22, 2018.

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    Differences in brain-derived neurotrophic factor gene polymorphisms between acute ischemic stroke patients and healthy controls in the Han population of southwest China
    Jie Zhou,Meng-Meng Ma,Jing-Huan Fang, Lei Zhao, Mu-Ke Zhou, Jian Guo,Li He
    2019, 14 (8):  1404-1411.  doi: 10.4103/1673-5374.253525
    Abstract ( 109 )   PDF (358KB) ( 149 )   Save

    Single-nucleotide polymorphisms in the brain-derived neurotrophic factor gene may affect the secretion and function of brain-derived neurotrophic factor, thereby affecting the occurrence, severity and prognosis of ischemic stroke. This case-control study included 778 pa¬tients (475 males and 303 females, mean age of 64.0 ± 12.6 years) in the acute phase of ischemic stroke and 865 control subjects (438 males and 427 females, mean age of 51.7 ± 14.7 years) from the Department of Neurology, West China Hospital, Sichuan University, China between September 2011 and December 2014. The patients’ severities of neurological deficits in the acute phase were assessed using the National Institutes of Health Stroke Scale immediately after admission to hospital. The ischemic stroke patients were divided into different subtypes according to the Trial of Org 10172 in Acute Stroke Treatment classification. Early prognosis was evaluated using the Modified Rankin Scale when the patients were discharged. Genomic DNA was extracted from peripheral blood of participants. Genotyping of rs7124442 and rs6265 was performed using Kompetitive Allele Specific polymerase chain reaction genotyping technology. Our results demonstrated that patients who carried the C allele of the rs7124442 locus had a lower risk of poor prognosis than the T allele carriers (odds ratio [OR] = 0.67; 95% confidence interval [CI]: 0.45–1.00; P = 0.048). The patients with the CC or TC genotype also exhibited lower risk than TT carriers (OR = 0.65; 95% CI: 0.42–1.00; P = 0.049). The AA genotype at the rs6265 locus was associated with the occurrence of ischemic stroke in patients with large-artery atherosclerosis (OR = 0.58; 95% CI: 0.37–0.90; P = 0.015). We found that the C allele (CC and TC genotypes) at the rs7124442 locus may be protective for the prognosis of ischemic stroke. The AA genotype at the rs6265 locus is likely a protective factor against the occurrence of ischemic stroke in patients with large-artery atherosclerosis. The study protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China (approval ID number 2008[4], on July 25, 2008.

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    Assessment of cerebrovascular reserve impairment using the breath-holding index in patients with leukoaraiosis
    Ying Bian,Jin-Chun Wang,Feng Sun,Zi-Yi Sun,Yu-Jiao Lin,Yang Liu,Bin Zhao,Li Liu,Xiao-Guang Luo
    2019, 14 (8):  1412-1418.  doi: 10.4103/1637-5374.251332
    Abstract ( 175 )   PDF (255KB) ( 154 )   Save

    Many studies have demonstrated that leukoaraiosis is associated with impaired cerebrovascular reserve function. However, the definitive hemodynamic changes that occur in leukoaraiosis are not clear, and there are many controversies. This study aimed to investigate he¬modynamic changes in symptomatic leukoaraiosis using transcranial Doppler ultrasonography and the breath-holding test in a Chinese Han population, from northern China. A total of 203 patients who were diagnosed with ischemic stroke or clinical chronic progressive ischemic symptoms were enrolled in this study, including 97 males and 106 females, with an age range of 43–93 years. The severity of leukoaraiosis was evaluated according to the Fazekas grading scale, and patients were divided into four groups accordingly. Grade 0 was no leukoaraiosis, and grades I, II, and III were mild, moderate, and severe leukoaraiosis, respectively, with 44, 79, 44, and 36 cases in each group. Transcranial Doppler ultrasonography and the breath-holding test were performed. The mean blood flow velocity of the bilateral middle cerebral artery was measured and the breath-holding index was calculated. The breath holding index was correlated with leukoara¬iosis severity and cognitive impairment. Patients with a low breath holding index presented poor performance in the Montreal Cognitive Assessment (MoCA) and executive function tests. That is, the lower the breath holding index, the lower the scores for the MoCA and the higher for the trail-making test Parts A and B. These results indicate that the breath-holding index is a useful parameter for the evaluation of cerebrovascular reserve impairment in patients with leukoaraiosis. In addition, the breath-holding index can reflect cognitive dysfunc¬tion, providing a new insight into the pathophysiology of leukoaraiosis. This study was approved by the Ethics Committee of the Fifth People’s Hospital of China (approval No. 20160301). Written informed consent was obtained from each participant.  This trial has been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800014421).

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    The development of brain functional connectivity networks revealed by resting-state functional magnetic resonance imaging
    Chao-Lin Li,Yan-Jun Deng,Yu-Hui He,Hong-Chang Zhai,Fu-Cang Jia
    2019, 14 (8):  1419-1429.  doi: 10.4103/1673-5374.253526
    Abstract ( 203 )   PDF (3078KB) ( 202 )   Save

    Previous studies on brain functional connectivity networks in children have mainly focused on changes in function in specific brain re¬gions, as opposed to whole brain connectivity in healthy children. By analyzing the independent components of activation and network connectivity between brain regions, we examined brain activity status and development trends in children aged 3 and 5 years. These data could provide a reference for brain function rehabilitation in children with illness or abnormal function. We acquired functional magnetic resonance images from 15 3-year-old children and 15 5-year-old children under natural sleep conditions. The participants were recruited from five kindergartens in the Nanshan District of Shenzhen City, China. The parents of the participants signed an informed consent form with the premise that they had been fully informed regarding the experimental protocol. We used masked independent component analy¬sis and BrainNet Viewer software to explore the independent components of the brain and correlation connections between brain regions. We identified seven independent components in the two groups of children, including the executive control network, the dorsal attention network, the default mode network, the left frontoparietal network, the right frontoparietal network, the salience network, and the motor network. In the default mode network, the posterior cingulate cortex, medial frontal gyrus, and inferior parietal lobule were activated in both 3- and 5-year-old children, supporting the “three-brain region theory” of the default mode network. In the frontoparietal network, the frontal and parietal gyri were activated in the two groups of children, and functional connectivity was strengthened in 5-year-olds compared with 3-year-olds, although the nodes and network connections were not yet mature. The high-correlation network connections in the default mode networks and dorsal attention networks had been significantly strengthened in 5-year-olds vs. 3-year-olds. Further, the salience network in the 3-year-old children included an activated insula/inferior frontal gyrus-anterior cingulate cortex network circuit and an activated thalamus-parahippocampal-posterior cingulate cortex-subcortical regions network circuit. By the age of 5 years, nodes and high-correlation network connections (edges) were reduced in the salience network. Overall, activation of the dorsal attention net¬work, default mode network, left frontoparietal network, and right frontoparietal network increased (the volume of activation increased, the signals strengthened, and the high-correlation connections increased and strengthened) in 5-year-olds compared with 3-year-olds, but activation in some brain nodes weakened or disappeared in the salience network, and the network connections (edges) were reduced. Between the ages of 3 and 5 years, we observed a tendency for function in some brain regions to be strengthened and for the generaliza¬tion of activation to be reduced, indicating that specialization begins to develop at this time. The study protocol was approved by the local ethics committee of the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences in China on November 15, 2013 with approval No. SIAT-IRB-131115-H0075.

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    Hydrogen peroxide mediates pro-inflammatory cell-to-cell signaling: a new therapeutic target for inflammation?
    Dhanushka Gunawardena, Ritesh Raju, Gerald Münch
    2019, 14 (8):  1430-1437.  doi: 10.4103/1673-5374.253529
    Abstract ( 491 )   PDF (1619KB) ( 194 )   Save

    Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide – like nitric oxide – acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration-dependent manner. The experiment showed concentration-dependent inhibition of nitric oxide and tumor necrosis factor-α production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-α production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates adjacent cells. Like nitric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-α. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.

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    Mechanisms by which fibroblast growth factor 20 improves motor performance in a mouse model of Parkinson’s disease
    Ai-Qin Wang, Li-Na Kong, Ming-Zhu Meng, Xiu-He Zhao,Si Chen, Xiao-Tang Wang
    2019, 14 (8):  1438-1444.  doi: 10.4103/1673-5374.253527
    Abstract ( 114 )   PDF (931KB) ( 160 )   Save

    Genome-wide studies have reported that Parkinson’s disease is associated with abnormal expression of various growth factors. In this study, male C57BL/6 mice aged 10 weeks were used to establish Parkinson’s disease models using an intraperitoneal injection of 60 mg/kg 1-meth¬yl-4-phenyl-1,2,3,6-tetrahydropyridine. 28 days later, 10 or 100 ng fibroblast growth factor 20 was injected intracerebroventricularly. The electrophysiological changes in the mouse hippocampus were recorded using a full-cell patch clamp. Expression of Kv4.2 in the substantia nigra was analyzed using a western blot assay. Serum malondialdehyde levels were analyzed by enzyme-linked immunosorbent assay. The motor coor¬dination of mice was evaluated using the rotarod test. The results showed that fibroblast growth factor 20 decreased A-type potassium current in neurons of the substantia nigra, increased long-term potentiation amplitude in the hippocampus, and downregulated Kv4.2 expression. A high dose of fibroblast growth factor 20 reduced serum malondialdehyde levels and enhanced the motor coordination of mice. These findings confirm that fibroblast growth factor 20 has a therapeutic effect on the toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and its mecha¬nism of action is associated with the inhibition of A-type K+ currents and Kv4.2 expression. All animal procedures were approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University, China in 2017 (approval No. KYLL-2017-0012).

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    Diabetic retinopathy and age-related macular degeneration: a survey of pharmacoutilization and cost in Calabria, Italy
    Damiana Scuteri,Ada Vero,Mariacristina Zito,Maria Diana Naturale,Giacinto Bagetta,Carlo Nucci,Paolo Tonin,Maria Tiziana Corasaniti
    2019, 14 (8):  1445-1448.  doi: 10.4103/1673-5374.253528
    Abstract ( 124 )   PDF (527KB) ( 123 )   Save

    The aged population is constantly growing, thus fostering an increase in age-dependent diseases. Among these, diabetic retinopathy (DR) along with age-related macular degeneration entails progressive vision loss. Since such conditions are associated with the proliferation of novel vessels, their pharmacotherapeutic management consists of the intravitreal injection of anti-vascular endothelial growth factor drugs, able to hinder the driving of vascular proliferation prompted by vascular endothelial growth factor. The humanized anti-vascular endothelial growth factor monoclonal antibody ranibizumab provided evidence for efficacy in several trials, hence earning approval by the US Food and Drug Administration for therapeutic use in all the stages of DR. Due to the lack of epidemiologic and pharmacoeconomic evaluation in the local Calabria Region context, the present retrospective observational study focused on prevalence of DR and age-related macular degeneration, treatment and cost of therapy with ranibizumab in 870 patients arriving to clinical observation at the “Mater Domini” University Hospital in Calabria, Italy from January 2014 to June 2017. Data were extracted from the database of ophthalmology ward and subjected to statistical analysis. The results suggest that the most frequent retinal diseases are age-related macular degeneration and DR and that the use of ranibizumab has been decreasing over the 4-year study period together with the associated cost per patient which was similar for both disorders. Therefore, appropriateness of treatment with drugs other than ranibizumab needs to be assessed in this setting and deep monitoring of pharmacologic treatment for retinal diseases is necessary to prevent or delay visual acuity decrease and complete vision loss. Study procedures were performed in accordance with the “Mater Domini” University Hospital ethical standards of the responsible committee on human experimentation

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    Modified contralateral C7 nerve transfer: the possibility of permitting ulnar nerve recovery is confirmed by 10 cases of autopsy
    Guang-Hui Hong,Jing-Bo Liu,Yu-Zhou Liu,Kai-Ming Gao,Xin Zhao,Jie Lao
    2019, 14 (8):  1449-1454.  doi: 10.4103/1673-5374.253530
    Abstract ( 151 )   PDF (3568KB) ( 143 )   Save

    Contralateral C7 nerve transfer surgery is one of the most important surgical techniques for treating total brachial plexus nerve injury. In the traditional contralateral C7 nerve transfer surgery, the whole ulnar nerve on the paralyzed side is harvested for transfer, which com¬pletely sacrifices its potential of recovery. In the present, novel study, we report on the anatomical feasibility of a modified contralateral C7 nerve transfer surgery. Ten fresh cadavers (4 males and 6 females) provided by the Department of Anatomy, Histology, and Embryology at the Medical College of Fudan University, China were used in modified contralateral C7 nerve transfer surgery. In this surgical model, only the dorsal and superficial branches of the ulnar nerve and the medial antebrachial cutaneous nerve on the paralyzed side (left) were har¬vested for grafting the contralateral (right) C7 nerve and the recipient nerves. Both the median nerve and deep branch of the ulnar nerve on the paralyzed (left) side were recipient nerves. To verify the feasibility of this surgery, the distances between each pair of coaptating nerve ends were measured by a vernier caliper. The results validated that starting point of the deep branch of ulnar nerve and the starting point of the medial antebrachial cutaneous nerve at the elbow were close to each other and could be readily anastomosed. We investigat¬ed whether the fiber number of donor and recipient nerves matched one another. The axons were counted in sections of nerve segments distal and proximal to the coaptation sites after silver impregnation. Averaged axon number of the ulnar nerve at the upper arm level was approximately equal to the sum of the median nerve and proximal end of medial antebrachial cutaneous nerve (left: 0.94:1; right: 0.93:1). In conclusion, the contralateral C7 nerve could be transferred to the median nerve but also to the deep branch of the ulnar nerve via grafts of the ulnar nerve without deep branch and the medial antebrachial cutaneous nerve. The advantage over traditional surgery was that the recovery potential of the deep branch of ulnar nerve was preserved. The study was approved by the Ethics Committee of Fudan University (approval number: 2015-064) in July, 2015.

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    Variation in expression of small ubiquitin-like modifiers in injured sciatic nerve of mice
    Dian-Ying Zhang,Kai Yu,Zhong Yang,Xiao-Zhi Liu,Xiao-Fang Ma,Yan-Xia Li
    2019, 14 (8):  1455-1461.  doi: 10.4103/1673-5374.253531
    Abstract ( 109 )   PDF (1612KB) ( 176 )   Save

    Small ubiquitin-like modifiers (SUMOs) have been shown to regulate axonal regeneration, signal transduction, neuronal migration, and myelination, by covalently and reversibly attaching to the protein substrates during neuronal cell growth, development, and differenti¬ation. It has not been reported whether SUMOs play a role in peripheral nerve injury and regeneration. To investigate any association between SUMOylation and potential neuroprotective effects during peripheral nerve injury and regeneration, C57/BL mice were ran¬domly divided into sham and experimental groups. The sciatic nerve was exposed only in the sham group. The experimental group underwent neurotomy and epineurial neurorrhaphy. Real-time quantitative polymerase chain reaction and western blot assay results revealed different mRNA and protein expression levels of SUMO1, SUMO2, SUMO3 and UBC9 in sciatic nerve tissue (containing both 5 mm of proximal and distal stumps at the injury site) at various time points after injury. Compared with the sham group, protein levels of SUMO1 and SUMO2/3 increased in both their covalent and free states after sciatic nerve injury in the experimental group, especially in the covalent state. UBC9 protein levels showed similar changes to those of SUMO1 and SUMO2/3 in the covalent states. Immunohisto¬chemical staining demonstrated that SUMO1 and SUMO2/3 immunopositivities were higher in the experimental group than in the sham group. Our results verified that during the repair of sciatic nerve injury, the mRNA and protein expression of SUMO1, SUMO2, SUMO3 and UBC9 in injured nerve tissues changed in varying patterns and there were clear changes in the expression of SUMO-related proteins. These findings reveal that SUMOs possibly play an important role in the repair of peripheral nerve injury. All animal protocols were ap¬proved by the Institutional Animal Care and Use Committee of Tianjin Fifth Central Hospital, China (approval No. TJWZXLL2018041) on November 8, 2018.

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    MicroRNA changes of bone marrow-derived mesenchymal stem cells differentiated into neuronal-like cells by Schwann cell-conditioned medium
    Zhi-Jian Wei,Bao-You Fan,Yang Liu,Han Ding,Hao-Shuai Tang,Da-Yu Pan,Jia-Xiao Shi,Peng-Yuan Zheng,Hong-Yu Shi,Heng Wu,Ang Li,Shi-Qing Feng
    2019, 14 (8):  1462-1469.  doi: 10.4103/1673-5374.253532
    Abstract ( 144 )   PDF (1864KB) ( 149 )   Save

    Bone marrow-derived mesenchymal stem cells differentiate into neurons under the induction of Schwann cells. However, key microRNAs and related pathways for differentiation remain unclear. This study screened and identified differentially expressed microRNAs in bone mar¬row-derived mesenchymal stem cells induced by Schwann cell-conditioned medium, and explored targets and related pathways involved in their differentiation into neuronal-like cells. Primary bone marrow-derived mesenchymal stem cells were isolated from femoral and tibial bones, while primary Schwann cells were isolated from bilateral saphenous nerves. Bone marrow-derived mesenchymal stem cells were cul¬tured in unconditioned (control group) and Schwann cell-conditioned medium (bone marrow-derived mesenchymal stem cell + Schwann cell group). Neuronal differentiation of bone marrow-derived mesenchymal stem cells induced by Schwann cell-conditioned medium was ob¬served by time-lapse imaging. Upon induction, the morphology of bone marrow-derived mesenchymal stem cells changed into a neural shape with neurites. Results of quantitative reverse transcription-polymerase chain reaction revealed that nestin mRNA expression was upregulated from 1 to 3 days and downregulated from 3 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. Compared with the control group, microtubule-associated protein 2 mRNA expression gradually increased from 1 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. After 7 days of induction, microRNA analysis identified 83 significantly differentially expressed microRNAs between the two groups. Gene Ontology analysis indicated enrichment of microRNA target genes for neuronal projection devel¬opment, regulation of axonogenesis, and positive regulation of cell proliferation. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that Hippo, Wnt, transforming growth factor-beta, and Hedgehog signaling pathways were potentially associated with neural differentiation of bone marrow-derived mesenchymal stem cells. This study, which carried out successful microRNA analysis of neuronal-like cells differentiated from bone marrow-derived mesenchymal stem cells by Schwann cell induction, revealed key microRNAs and pathways involved in neural differentiation of bone marrow-derived mesenchymal stem cells. All protocols were approved by the Animal Ethics Com¬mittee of Institute of Radiation Medicine, Chinese Academy of Medical Sciences on March 12, 2017 (approval number: DWLI-20170311).

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    Improvement of ataxia in a patient with cerebellar infarction by recovery of injured cortico-ponto-cerebellar tract and dentato-rubro-thalamic tract: a diffusion tensor tractography study
    Sung Ho Jang,Hyeok Gyu Kwon
    2019, 14 (8):  1470-1472.  doi: 10.4103/1673-5374.253533
    Abstract ( 156 )   PDF (972KB) ( 146 )   Save

    Coordinated movement is generated by communication between the cerebrum and cerebellum via the cerebellar peduncles (CPs). The CPs are classified into three types (superior, middle, and inferior), and each includes a variety of neural tracts. Among those tracts, the cortico-ponto-cerebellar tract (CPCT), a middle CP, is involved in motor planning and initiation of movement, while the dentato-rubro-thalamic tract (DRTT), a superior CP, is involved in motor coordination, movement timing, verbal fluency, and working memory . Injuries of these two neural tracts in various brain pathologies are commonly accompanied by ataxia. In particular, cerebellar infarction results in inevitable injuries of the CPCT and the DRTT, and over 50% of patients with cerebellar infarction experience ataxia.

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