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   Table of Contents - Current issue
Coverpage
September 2019
Volume 14 | Issue 9
Page Nos. 1477-1656

Online since Thursday, May 9, 2019

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REVIEWS  

Remodeling dendritic spines for treatment of traumatic brain injury Highly accessed article p. 1477
Ye Xiong, Asim Mahmood, Michael Chopp
DOI:10.4103/1673-5374.255957  
Traumatic brain injury is an important global public health problem. Traumatic brain injury not only causes neural cell death, but also induces dendritic spine degeneration. Spared neurons from cell death in the injured brain may exhibit dendrite damage, dendritic spine degeneration, mature spine loss, synapse loss, and impairment of activity. Dendritic degeneration and synapse loss may significantly contribute to functional impairments and neurological disorders following traumatic brain injury. Normal function of the nervous system depends on maintenance of the functionally intact synaptic connections between the presynaptic and postsynaptic spines from neurons and their target cells. During synaptic plasticity, the numbers and shapes of dendritic spines undergo dynamic reorganization. Enlargement of spine heads and the formation and stabilization of new spines are associated with long-term potentiation, while spine shrinkage and retraction are associated with long-term depression. Consolidation of memory is associated with remodeling and growth of preexisting synapses and the formation of new synapses. To date, there is no effective treatment to prevent dendritic degeneration and synapse loss. This review outlines the current data related to treatments targeting dendritic spines that propose to enhance spine remodeling and improve functional recovery after traumatic brain injury. The mechanisms underlying proposed beneficial effects of therapy targeting dendritic spines remain elusive, possibly including blocking activation of Cofilin induced by beta amyloid, Ras activation, and inhibition of GSK-3 signaling pathway. Further understanding of the molecular and cellular mechanisms underlying synaptic degeneration/loss following traumatic brain injury will advance the understanding of the pathophysiology induced by traumatic brain injury and may lead to the development of novel treatments for traumatic brain injury.
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Acute drivers of neuroinflammation in traumatic brain injury Highly accessed article p. 1481
Kathryn L Wofford, David J Loane, D Kacy Cullen
DOI:10.4103/1673-5374.255958  
Neuroinflammation is initiated as a result of traumatic brain injury and can exacerbate evolving tissue pathology. Immune cells respond to acute signals from damaged cells, initiate neuroinflammation, and drive the pathological consequences over time. Importantly, the mechanism(s) of injury, the location of the immune cells within the brain, and the animal species all contribute to immune cell behavior following traumatic brain injury. Understanding the signals that initiate neuroinflammation and the context in which they appear may be critical for understanding immune cell contributions to pathology and regeneration. Within this paper, we review a number of factors that could affect immune cell behavior acutely following traumatic brain injury.
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Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis p. 1490
Peter William French, Russell Ian Ludowyke, Gilles J Guillemin
DOI:10.4103/1673-5374.255959  
Fungi are important infectious disease-causing agents, but are often overlooked as environmental factors in disease. We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease. Approximately 90% cases of ALS are sporadic, and the aetiology of sporadic ALS is still unknown. We have previously postulated that grass or soil-associated fungal infections may be a leading cause of sporadic ALS. Herein we extend this proposal to water-associated fungi. A wide variety of fungi have been reported in drinking water including Acremonium, Alternaria, Aspergillus, Cladosporium, Fusarium, Penicillium and Trichoderma. Some of these are known to produce neurotoxic mycotoxins. Despite this, drinking water is not routinely monitored for fungal contamination. Fungal contamination could explain the close correlation between distribution of well water and cases of sporadic ALS in the United States. We propose several mechanisms by which an opportunistic fungal infection from environmental exposure (to water, soil or plants) can lead to long term neuronal degradation resulting in the hallmarks of ALS. If confirmed, the association between fungal infection and sporadic ALS could lead to novel treatment strategies for this progressive and fatal disease.
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More than anti-malarial agents: therapeutic potential of artemisinins in neurodegeneration p. 1494
Bing-Wen Lu, Larry Baum, Kwok-Fai So, Kin Chiu, Li-Ke Xie
DOI:10.4103/1673-5374.255960  
Artemisinin, also called qinghaosu, is originally derived from the sweet wormwood plant (Artemisia annua), which is used in traditional Chinese medicine. Artemisinin and its derivatives (artemisinins) have been widely used for many years as anti-malarial agents, with few adverse side effects. Interestingly, evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders. Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions, whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders, including Alzheimer’s disease. Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation, inflammation, and amyloid beta protein (Aβ). In this review, we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities, suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.
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Why microglia kill neurons after neural disorders? The friendly fire hypothesis Highly accessed article p. 1499
Walace Gomes-Leal
DOI:10.4103/1673-5374.255359  
Neuroinflammation plays a fundamental role on the pathophysiology of acute and chronic neural disorders. Microglia activation is a major event following central nervous system inflammation displaying different phenotypes with beneficial and detrimental actions (a Janus face). The reason for this apparent duality is unknown. We have previously shown that following experimental middle cerebral artery occlusion in the rat brain, microglia seem to support and impair adult neurogenesis in the same ischemic striatum. Based on these results, we raised the hypothesis that in the same pathologic environment, gradients of different ligands distributed over different anatomical niches might contribute to both detrimental and beneficial microglial phenotypes. These ligands (“danger signals”) are released by dying cells and bind to microglial receptors in their membranes. Activation of different microglial receptors induces downstream biochemical pathways culminating in a spectrum of microglial phenotypes like M1 and M2 and others. In this paper, we first review the immune functions of microglia and the role of toll-like receptors on the fight against infections. We then briefly revise the dual role of microglia after neural disorders. We then propose a novel hypothesis to explain the Janus face of microglia during the pathophysiology of central nervous system diseases: the “friendly fire hypothesis”. According to this idea “danger signals” or danger associated molecular patterns released by stressed, damaged and/or dying cells during stroke, trauma and other diseases might activate microglial pattern-recognition receptors (i.e., toll like receptors) or other unidentified receptors normally activated by pathogens. This could activate the same genetic and biochemical machinery used by microglia to fight against pathogens even in the absence of infection. According to this notion, microglia may cause bystander neuronal damage with a kind of blind “friendly fire”, fighting against a non-existing infection during non-infectious disorders, like stroke and trauma. The “friendly fire hypothesis” is a novel proposal to explain why microglia may be detrimental and beneficial after acute and chronic neural disorders and may direct future investigations for developing of neuroprotective agents.
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Could autophagy dysregulation link neurotropic viruses to Alzheimer’s disease? p. 1503
Maria Anele Romeo, Alberto Faggioni, Mara Cirone
DOI:10.4103/1673-5374.253508  
Neurotropic herpesviruses have been associated with the onset and progression of Alzheimer’s disease, a common form of dementia that afflicts a large percentage of elderly individuals. Interestingly, among the neurotropic herpesviruses, herpes simplex virus-1, human herpesvirus-6A, and human herpesvirus-6B have been reported to infect several cell types present in the central nervous system and to dysregulate autophagy, a process required for homeostasis of cells, especially neurons. Indeed autophagosome accumulation, indicating an unbalance between autophagosome formation and autophagosome degradation, has been observed in neurons of Alzheimer’s disease patients and may play a role in the intracellular and extracellular accumulation of amyloid β and in the altered protein tau metabolism. Moreover, herpesvirus infection of central nervous system cells such as glia and microglia can increase the production of oxidant species through the alteration of mitochondrial dynamics and promote inflammation, another hallmark of Alzheimer’s disease. This evidence suggests that it is worth further investigating the role of neurotropic herpesviruses, particularly human herpesvirus-6A/B, in the etiopathogenesis of Alzheimer’s disease.
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PERSPECTIVES Top

Role of behavioral training in reducing functional impairments after stroke p. 1507
Mahira Moftah, Nafisa M Jadavji
DOI:10.4103/1673-5374.255967  
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Neuromodulation and ablation with focused ultrasound – toward the future of noninvasive brain therapy p. 1509
Anton Fomenko, Andres M Lozano
DOI:10.4103/1673-5374.255961  
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Strategies to promote the maturation of ALS-associated SOD1 mutants: small molecules return to the fold p. 1511
Luke McAlary, Justin J Yerbury
DOI:10.4103/1673-5374.255962  
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Cell signaling associated with internalization of 67 kDa laminin receptor (67LR) by soluble laminin and its implication for protection against neurodegenerative diseases p. 1513
Rayudu Gopalakrishna, Narayan R Bhat, Sarah Zhou, William J Mack
DOI:10.4103/1673-5374.255965  
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Spinal cord organoids add an extra dimension to traditional motor neuron cultures p. 1515
Winanto , Zi-Jian Khong, Jin-Hui Hor, Shi-Yan Ng
DOI:10.4103/1673-5374.255966  
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Preclinical concepts and results with the GABAA antagonist S44819 in a mouse model of middle cerebral artery occlusion p. 1517
Dirk M Hermann, Barbara Saba, Aurore Sors, Claudio L Bassetti
DOI:10.4103/1673-5374.255963  
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Neuroprotective effect of Neuro-EPO in neurodegenerative diseases: “Alea jacta est” p. 1519
Ramón Rama, Fernando Garzón, Yamila Rodríguez-Cruz, Tangui Maurice, Julio-César García-Rodríguez
DOI:10.4103/1673-5374.255968  
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Adipose-derived stem cell conditioned medium for the treatment of amyotrophic lateral sclerosis: pre-clinical evidence and potential for clinical application p. 1522
Chandler L Walker
DOI:10.4103/1673-5374.253514  
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Therapeutic potential of AMPA receptor antagonist perampanel against cerebral ischemia: beyond epileptic disorder p. 1525
Satoshi Suda, Kazumi Kimura
DOI:10.4103/1673-5374.255964  
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CONFERENCE MINUTES Top

What does “Disruptive” mean? Thoughts on the NIH SCI 2020 meeting p. 1527
Vance P Lemmon
DOI:10.4103/1673-5374.255969  
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RESEARCH ARTICLES: BRAIN INJURY AND NEURAL REGENERATION Top

Sodium butyrate prevents radiation-induced cognitive impairment by restoring pCREB/BDNF expression p. 1530
Hae June Lee, Yeonghoon Son, Minyoung Lee, Changjong Moon, Sung Ho Kim, In Sik Shin, Miyoung Yang, Sangwoo Bae, Joong Sun Kim
DOI:10.4103/1673-5374.255974  
Sodium butyrate is a histone deacetylase inhibitor that affects various types of brain damages. To investigate the effects of sodium butyrate on hippocampal dysfunction that occurs after whole-brain irradiation in animal models and the effect of sodium butyrate on radiation exposure-induced cognitive impairments, adult C57BL/6 mice were intraperitoneally treated with 0.6 g/kg sodium butyrate before exposure to 10 Gy cranial irradiation. Cognitive impairment in adult C57BL/6 mice was evaluated via an object recognition test 30 days after irradiation. We also detected the expression levels of neurogenic cell markers (doublecortin) and phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor. Radiation-exposed mice had decreased cognitive function and hippocampal doublecortin and phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor expression. Sodium butyrate pretreatment reversed these changes. These findings suggest that sodium butyrate can improve radiation-induced cognitive dysfunction through inhibiting the decrease in hippocampal phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor expression. The study procedures were approved by the Institutional Animal Care and Use Committee of Korea Institute of Radiological Medical Sciences (approval No. KIRAMS16-0002) on December 30, 2016.
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Pretreated Oenanthe Javanica extract increases anti-inflammatory cytokines, attenuates gliosis, and protects hippocampal neurons following transient global cerebral ischemia in gerbils p. 1536
Joon Ha Park, In Hye Kim, Ji Hyeon Ahn, Yoo Hun Noh, Sung-Su Kim, Tae-Kyeong Lee, Jae-Chul Lee, Bich-Na Shin, Tae Heung Sim, Hyun Sam Lee, Jeong Hwi Cho, In Koo Hwang, Il Jun Kang, Jong Dai Kim, Moo-Ho Won
DOI:10.4103/1673-5374.255973  
Recently, we have reported that Oenanthe javanica extract (OJE) displays strong neuroprotective effect against ischemic damage after transient global cerebral ischemia. However, neuroprotective mechanisms of OJE have not been fully identified. Thus, this study investigated the neuroprotection of OJE in the hippocampal CA1 area and its anti-inflammatory activity in gerbils subjected to 5 minutes of transient global cerebral ischemia. We treated the animals by intragastrical injection of OJE (100 and 200 mg/kg) once daily for 1 week prior to transient global cerebral ischemia. Neuroprotection of OJE was observed by immunohistochemistry for neuronal nuclear antigen and histofluorescence staining for Fluoro-Jade B. Immunohistochemistry of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 was done for astrocytosis and microgliosis, respectively. To investigate the neuroprotective mechanisms of OJE, we performed immunohistochemistry of tumor necrosis factor-alpha and interleukin-2 for pro-inflammatory function and interleukin-4 and interleukin-13 for anti-inflammatory function. When we treated the animals by intragastrical administration of 200 mg/kg of OJE, hippocampal CA1 pyramidal neurons were protected from transient global cerebral ischemia and cerebral ischemia-induced gliosis was inhibited in the ischemic hippocampal CA1 area. We also found that interleukin-4 and -13 immunoreactivities were significantly increased in pyramidal neurons of the ischemic CA1 area after OJE pretreatment, and the increased immunoreactivities were sustained in the CA1 pyramidal neurons after transient global cerebral ischemia. However, OJE pretreatment did not increase interleukin-2 and tumor necrosis factor-alpha immunoreactivities in the CA1 pyramidal neurons. Our findings suggest that pretreatment with OJE can protect neurons and attenuate gliosis from transient global cerebral ischemia via increasing expressions of interleukin-4 and -13. The experimental plan of this study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) in Kangwon National University (approval No. KW-160802-1) on August 10, 2016.
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Age-related changes in resting-state functional connectivity in older adults p. 1544
Laia Farras-Permanyer, Núria Mancho-Fora, Marc Montalà-Flaquer, David Bartrés-Faz, Lídia Vaqué-Alcázar, Maribel Peró-Cebollero, Joan Guàrdia-Olmos
DOI:10.4103/1673-5374.255976  
Age-related changes in the brain connectivity of healthy older adults have been widely studied in recent years, with some differences in the obtained results. Most of these studies showed decreases in general functional connectivity, but they also found increases in some particular regions and areas. Frequently, these studies compared young individuals with older subjects, but few studies compared different age groups only in older populations. The purpose of this study is to analyze whole-brain functional connectivity in healthy older adult groups and its network characteristics through functional segregation. A total of 114 individuals, 48 to 89 years old, were scanned using resting-state functional magnetic resonance imaging in a resting state paradigm and were divided into six different age groups (< 60, 60–64, 65–69, 70–74, 75–79, ≥ 80 years old). A partial correlation analysis, a pooled correlation analysis and a study of 3-cycle regions with prominent connectivity were conducted. Our results showed progressive diminution in the functional connectivity among different age groups and this was particularly pronounced between 75 and 79 years old. The oldest group (≥ 80 years old) showed a slight increase in functional connectivity compared to the other groups. This occurred possibly because of compensatory mechanism in brain functioning. This study provides information on the brain functional characteristics of every age group, with more specific information on the functional progressive decline, and supplies methodological tools to study functional connectivity characteristics. Approval for the study was obtained from the ethics committee of the Comisión de Bioética de la Universidad de Barcelona (approval No. PSI2012-38257) on June 5, 2012, and from the ethics committee of the Barcelona’s Hospital Clínic (approval No. 2009-5306 and 2011-6604) on October 22, 2009 and April 7, 2011 respectively.
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Traumatic axonal injury of the cingulum in patients with mild traumatic brain injury: a diffusion tensor tractography study p. 1556
Sung Ho Jang, Seong Ho Kim, Han Do Lee
DOI:10.4103/1673-5374.255977  
The cingulum, connecting the orbitofrontal cortex to the medial temporal lobe, involves in diverse cognition functions including attention, memory, and motivation. To investigate the relationship between the cingulum injury and cognitive impairment in patients with chronic mild traumatic brain injury, we evaluated the integrity between the anterior cingulum and the basal forebrain using diffusion tensor tractography in 73 patients with chronic mild traumatic brain injury (39 males, 34 females, age 43.29 ± 11.42 years) and 40 healthy controls (22 males, 18 females, age 40.11 ± 16.81 years). The patients were divided into three subgroups based on the integrity between the anterior cingulum and the basal forebrain on diffusion tensor tractography: subgroup A (n = 19 patients) – both sides of the anterior cingulum were intact; subgroup B (n = 36 patients) – either side of the anterior cingulum was intact; and subgroup C (18 patients) – both sides of the anterior cingulum were discontinued. There were significant differences in total Memory Assessment Scale score between subgroups A and B and between subgroups A and C. There were no significant differences in diffusion tensor tractography parameters (fractional anisotropy, apparent diffusion coefficient, and fiber volume) between patients and controls. These findings suggest that the integrity between the anterior cingulum and the basal forebrain, but not diffusion tensor tractography parameter, can be used to predict the cognitive function of patients with chronic mild traumatic brain injury. This study was approved by Yeungnam University Hospital Institutional Review Board (approval No. YUMC-2014-01-425-010) on August 16, 2017.
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RESEARCH ARTICLES: NEURODEGENERATIVE DISEASES AND NEURAL REGENERATION Top

L-Norvaline, a new therapeutic agent against Alzheimer’s disease p. 1562
Baruh Polis, Kolluru D Srikanth, Vyacheslav Gurevich, Hava Gil-Henn, Abraham O Samson
DOI:10.4103/1673-5374.255980  
Growing evidence highlights the role of arginase activity in the manifestation of Alzheimer’s disease (AD). Upregulation of arginase was shown to contribute to neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD. Therefore, the enzyme represents a novel therapeutic target. In this study, we administered an arginase inhibitor, L-norvaline (250 mg/L), for 2.5 months to a triple-transgenic model (3×Tg-AD) harboring PS1M146V, APPSwe, and tauP301L transgenes. Then, the neuroprotective effects of L-norvaline were evaluated using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identified the biological pathways activated by the treatment. Remarkably, L-norvaline treatment reverses the cognitive decline in AD mice. The treatment is neuroprotective as indicated by reduced beta-amyloidosis, alleviated microgliosis, and reduced tumor necrosis factor transcription levels. Moreover, elevated levels of neuroplasticity related postsynaptic density protein 95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclosed several biological pathways, which were involved in cell survival and neuroplasticity and were activated by the treatment. Through these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interferes with its pathogenesis. As such, L-norvaline is a promising neuroprotective molecule that might be tailored for the treatment of a range of neurodegenerative disorders. The study was approved by the Bar-Ilan University Animal Care and Use Committee (approval No. 82-10-2017) on October 1, 2017.
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RESEARCH ARTICLES: BRAIN INJURY AND NEURAL REGENERATION Top

Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria p. 1573
Li Li, Hong-Ping Tan, Cheng-Yong Liu, Lin-Tao Yu, Da-Nian Wei, Zi-Chen Zhang, Kui Lu, Ke-Sen Zhao, Marc Maegele, Dao-Zhang Cai, Zheng-Tao Gu
DOI:10.4103/1673-5374.255972  
Polydatin is thought to protect mitochondria in different cell types in various diseases. Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury. To investigate the protective effect of polydatin after traumatic brain injury, a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults. Rat models were intraperitoneally injected with polydatin (30 mg/kg) or the SIRT1 activator SRT1720 (20 mg/kg, as a positive control to polydatin). At 6 hours post-traumatic brain injury insults, western blot assay was used to detect the expression of SIRT1, endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side. Flow cytometry was used to analyze neuronal mitochondrial superoxide, mitochondrial membrane potential and mitochondrial permeability transition pore opened. Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy. Our results showed that after treatment with polydatin, release of reactive oxygen species in neuronal mitochondria was markedly reduced; swelling of mitochondria was alleviated; mitochondrial membrane potential was maintained; mitochondrial permeability transition pore opened. Also endoplasmic reticulum stress related proteins were inhibited, including the activation of p-PERK, spliced XBP-1 and cleaved ATF6. SIRT1 expression and activity were increased; p38 phosphorylation and cleaved caspase-9/3 activation were inhibited. Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury. These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria. The mechanisms may be linked to increased SIRT1 expression and activity, which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway. This study was approved by the Animal Care and Use Committee of the Southern Medical University, China (approval number: L2016113) on January 1, 2016.
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RESEARCH ARTICLES: SPINAL CORD INJURY AND NEURAL REGENERATION Top

RNA sequencing screening of differentially expressed genes after spinal cord injury p. 1583
Yi Li, Ying Chen, Xiang Li, Jian Wu, Jing-Ying Pan, Ri-Xin Cai, Ri-Yun Yang, Xiao-Dong Wang
DOI:10.4103/1673-5374.255994  
In the search for a therapeutic schedule for spinal cord injury, it is necessary to understand key genes and their corresponding regulatory networks involved in the spinal cord injury process. However, ad hoc selection and analysis of one or two genes cannot fully reveal the complex molecular biological mechanisms of spinal cord injury. The emergence of second-generation sequencing technology (RNA sequencing) has provided a better method. In this study, RNA sequencing technology was used to analyze differentially expressed genes at different time points after spinal cord injury in rat models established by contusion of the eighth thoracic segment. The numbers of genes that changed significantly were 944, 1362 and 1421 at 1, 4 and 7 days after spinal cord injury respectively. After gene ontology analysis and temporal expression analysis of the differentially expressed genes, C5ar1, Socs3 and CCL6 genes were then selected and identified by real-time polymerase chain reaction and western blot assay. The mRNA expression trends of C5ar1, Socs3 and CCL6 genes were consistent with the RNA sequencing results. Further verification and analysis of C5ar1 indicate that the level of protein expression of C5ar1 was consistent with its nucleic acid level after spinal cord injury. C5ar1 was mainly expressed in neurons and astrocytes. Finally, the gene Itgb2, which may be related to C5ar1, was found by Chilibot database and literature search. Immunofluorescence histochemical results showed that the expression of Itgb2 was highly consistent with that of C5ar1. Itgb2 was expressed in astrocytes. RNA sequencing technology can screen differentially expressed genes at different time points after spinal cord injury. Through analysis and verification, genes strongly associated with spinal cord injury can be screened. This can provide experimental data for further determining the molecular mechanism of spinal cord injury, and also provide possible targets for the treatment of spinal cord injury. This study was approved ethically by the Laboratory Animal Ethics Committee of Jiangsu Province, China (approval No. 2018-0306-001) on March 6, 2018.
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RESEARCH ARTICLES: BRAIN INJURY AND NEURAL REGENERATION Top

Interleukin-4 affects microglial autophagic flux p. 1594
Run-Hong Tang, Rui-Qun Qi, Hua-Yan Liu
DOI:10.4103/1673-5374.255975  
Interleukin-4 plays an important protective role in Alzheimer’s disease by regulating microglial phenotype, phagocytosis of amyloid-β, and secretion of anti-inflammatory and neurotrophic cytokines. Recently, increasing evidence has suggested that autophagy regulates innate immunity by affecting M1/M2 polarization of microglia/macrophages. However, the role of interleukin-4 in microglial autophagy is unknown. In view of this, BV2 microglia were treated with 0, 10, 20 or 50 ng/mL interleukin-4 for 24, 48, or 72 hours. Subsequently, light chain 3-II and p62 protein expression levels were detected by western blot assay. BV2 microglia were incubated with interleukin-4 (20 ng/mL, experimental group), 3-methyladenine (500 μM, autophagy inhibitor, negative control group), rapamycin (100 nM, autophagy inductor, positive control group), 3-methyladenine + interleukin-4 (rescue group), or without treatment for 24 hours, and then exposed to amyloid-β (1 μM, model group) or vehicle control (control) for 24 hours. LC3-II and p62 protein expression levels were again detected by western blot assay. In addition, expression levels of multiple markers of M1 and M2 phenotype were assessed by real-time fluorescence quantitative polymerase chain reaction, while intracellular and supernatant amyloid-β protein levels were measured by enzyme-linked immunosorbent assay. Our results showed that interleukin-4 induced microglial autophagic flux, most significantly at 20 ng/mL for 48 hours. Interleukin-4 pretreated microglia inhibited blockade of amyloid-β-induced autophagic flux, and promoted amyloid-β uptake and degradation partly through autophagic flux, but inhibited switching of amyloid-β-induced M1 phenotype independent on autophagic flux. These results indicate that interleukin-4 pretreated microglia increases uptake and degradation of amyloid-β in a process partly mediated by autophagy, which may play a protective role against Alzheimer’s disease.
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RESEARCH ARTICLES: NEURODEGENERATIVE DISEASES AND NEURAL REGENERATION Top

miR-15b-5p targeting amyloid precursor protein is involved in the anti-amyloid eflect of curcumin in swAPP695-HEK293 cells p. 1603
Hong-Ying Liu, Xian Fu, You-Fu Li, Xian-Liang Li, Zhen-Yu Ma, Ying Zhang, Qing-Chun Gao
DOI:10.4103/1673-5374.255979  
Curcumin exerts a neuroprotective effect on Alzheimer’s disease; however, it is not known whether microRNAs are involved in this protective effect. This study was conducted using swAPP695-HEK293 cells as an Alzheimer’s disease cell model. swAPP695-HEK293 cells were treated with 0, 0.5, 1, 2, 5, and 10 μM curcumin for 24 hours. The changes in miR-15b-5p, miR-19a-3p, miR-195-5p, miR-101-3p, miR-216b-5p, miR-16-5p and miR-185-5p expression were assessed by real-time quantitative polymerase chain reaction. The mRNA and protein levels of amyloid precursor protein, amyloid-β40 and amyloid-β42 were evaluated by quantitative real-time polymerase chain reaction, western blot assays and enzyme-linked immunosorbent assays. swAPP695-HEK293 cells were transfected with miR-15b-5p mimic, or treated with 1 μM curcumin 24 hours before miR-15b-5p inhibitor transfection. The effects of curcumin on amyloid precursor protein, amyloid-β40 and amyloid-β42 levels were evaluated by western blot assays and enzyme-linked immunosorbent assay. Luciferase assays were used to analyze the interaction between miR-15b-5p and the 3′-untranslated region of amyloid precursor protein. The results show that amyloid precursor protein and amyloid-β expression were enhanced in swAPP695-HEK293 cells compared with HEK293 parental cells. Curcumin suppressed the expression of amyloid precursor protein and amyloid-β and up-regulated the expression of miR-15b-5p in swAPP695-HEK293 cells. In addition, we found a negative association of miR-15b-5p expression with amyloid precursor protein and amyloid-β levels in the curcumin-treated cells. Luciferase assays revealed that miR-15b-5p impaired the luciferase activity of the plasmid harboring the 3′-untranslated region of amyloid precursor protein. These findings indicate that curcumin down-regulates the expression of amyloid precursor protein and amyloid-β in swAPP695-HEK293 cells, which was partially mediated by miR-15b-5p via targeting of the 3′-untranslated region of amyloid precursor protein.
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RESEARCH ARTICLES: PERIPHERAL NERVE INJURY AND NEURAL REGENERATION Top

Identification of microRNAs and messenger RNAs involved in human umbilical cord mesenchymal stem cell treatment of ischemic cerebral infarction using integrated bioinformatics analysis p. 1610
Yin-Meng Qu, Xin Sun, Xiu-Li Yan, Hang Jin, Zhen-Ni Guo, Yi Yang
DOI:10.4103/1673-5374.255998  
In recent years, a large number of differentially expressed genes have been identified in human umbilical cord mesenchymal stem cell (hUMSC) transplants for the treatment of ischemic cerebral infarction. These genes are involved in various biochemical processes, but the role of microRNAs (miRNAs) in this process is still unclear. From the Gene Expression Omnibus (GEO) database, we downloaded two microarray datasets for GSE78731 (messenger RNA (mRNA) profile) and GSE97532 (miRNA profile). The differentially expressed genes screened were compared between the hUMSC group and the middle cerebral artery occlusion group. Gene ontology enrichment and pathway enrichment analyses were subsequently conducted using the online Database for Annotation, Visualization, and Integrated Discovery. Identified genes were applied to perform weighted gene co-suppression analyses, to establish a weighted co-expression network model. Furthermore, the protein-protein interaction network for differentially expressed genes from turquoise modules was built using Cytoscape (version 3.40) and the most highly correlated subnetwork was extracted from the protein-protein interaction network using the MCODE plugin. The predicted target genes for differentially expressed miRNAs were also identified using the online database starBase v3.0. A total of 3698 differentially expressed genes were identified. Gene ontology analysis demonstrated that differentially expressed genes that are related to hUMSC treatment of ischemic cerebral infarction are involved in endocytosis and inflammatory responses. We identified 12 differentially expressed miRNAs in middle cerebral artery occlusion rats after hUMSC treatment, and these differentially expressed miRNAs were mainly involved in signaling in inflammatory pathways, such as in the regulation of neutrophil migration. In conclusion, we have identified a number of differentially expressed genes and differentially expressed mRNAs, miRNA-mRNAs, and signaling pathways involved in the hUMSC treatment of ischemic cerebral infarction. Bioinformatics and interaction analyses can provide novel clues for further research into hUMSC treatment of ischemic cerebral infarction.
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Novel electrospun poly(ε-caprolactone)/type I collagen nanofiber conduits for repair of peripheral nerve injury p. 1617
Chun-Ming Yen, Chiung-Chyi Shen, Yi-Chin Yang, Bai-Shuan Liu, Hsu-Tung Lee, Meei-Ling Sheu, Meng-Hsiun Tsai, Wen-Yu Cheng
DOI:10.4103/1673-5374.255997  
Recent studies have shown the potential of artificially synthesized conduits in the repair of peripheral nerve injury. Natural biopolymers have received much attention because of their biocompatibility. To investigate the effects of novel electrospun absorbable poly(ε-caprolactone)/type I collagen nanofiber conduits (biopolymer nanofiber conduits) on the repair of peripheral nerve injury, we bridged 10-mm-long sciatic nerve defects with electrospun absorbable biopolymer nanofiber conduits, poly(ε-caprolactone) or silicone conduits in Sprague-Dawley rats. Rat neurologica1 function was weekly evaluated using sciatic function index within 8 weeks after repair. Eight weeks after repair, sciatic nerve myelin sheaths and axon morphology were observed by osmium tetroxide staining, hematoxylin-eosin staining, and transmission electron microscopy. S-100 (Schwann cell marker) and CD4 (inflammatory marker) immunoreactivities in sciatic nerve were detected by immunohistochemistry. In rats subjected to repair with electrospun absorbable biopolymer nanofiber conduits, no serious inflammatory reactions were observed in rat hind limbs, the morphology of myelin sheaths in the injured sciatic nerve was close to normal. CD4 immunoreactivity was obviously weaker in rats subjected to repair with electrospun absorbable biopolymer nanofiber conduits than in those subjected to repair with poly(ε-caprolactone) or silicone. Rats subjected to repair with electrospun absorbable biopolymer nanofiber conduits tended to have greater sciatic nerve function recovery than those receiving poly(ε-caprolactone) or silicone repair. These results suggest that electrospun absorbable poly(ε-caprolactone)/type I collagen nanofiber conduits have the potential of repairing sciatic nerve defects and exhibit good biocompatibility. All experimental procedures were approved by Institutional Animal Care and Use Committee of Taichung Veteran General Hospital, Taiwan, China (La-1031218) on October 2, 2014.
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RESEARCH ARTICLES: NEURODEGENERATIVE DISEASES AND NEURAL REGENERATION Top

Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer’s disease p. 1626
Edwin E Reza-Zaldivar, Mercedes A Hernández-Sapiéns, Yanet K Gutiérrez-Mercado, Sergio Sandoval-Ávila, Ulises Gomez-Pinedo, Ana L Márquez-Aguirre, Estefanía Vázquez-Méndez, Eduardo Padilla-Camberos, Alejandro A Canales-Aguirre
DOI:10.4103/1673-5374.255978  
Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment. The purpose of this study was to investigate the effects of mesenchymal stem cell-derived exosomes on neurogenesis and cognitive capacity in a mouse model of Alzheimer’s disease. Alzheimer’s disease mouse models were established by injection of beta amyloid 1−42 aggregates into dentate gyrus bilaterally. Morris water maze and novel object recognition tests were performed to evaluate mouse cognitive deficits at 14 and 28 days after administration. Afterwards, neurogenesis in the subventricular zone was determined by immunofluorescence using doublecortin and PSA-NCAM antibodies. Results showed that mesenchymal stem cells-derived exosomes stimulated neurogenesis in the subventricular zone and alleviated beta amyloid 1−42-induced cognitive impairment, and these effects are similar to those shown in the mesenchymal stem cells. These findings provide evidence to validate the possibility of developing cell-free therapeutic strategies for Alzheimer’s disease. All procedures and experiments were approved by Institutional Animal Care and Use Committee (CICUAL) (approval No. CICUAL 2016-011) on April 25, 2016.
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Lesions of mediodorsal thalamic nucleus reverse abnormal firing of the medial prefrontal cortex neurons in parkinsonian rats p. 1635
Ling-Ling Fan, Bo Deng, Jun-Bao Yan, Zhi-Hong Hu, Ai-Hong Ren, Dong-Wei Yang
DOI:10.4103/1673-5374.255982  
The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease. However, the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear. To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex, a model of Parkinson’s disease was established by injecting 8 µg 6-hydroxydopamine into the substantia nigra compacta of rats. After 1 or 3 weeks, 0.3 µg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain. At 3 or 5 weeks after the initial injury, neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically. The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining. Results demonstrated that after injury, the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats. Compared with normal medial prefrontal cortical neurons, at 3 and 5 weeks after substantia nigra compacta injury, the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge, with an increased discharge interval. The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge, but the discharge interval was only higher at 3 weeks. At 3 weeks after the combined lesions, the discharge frequency, discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex. These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex. The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefrontal cortex neurons after substantia nigra compacta injury. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University, China (approval No. XJTULAC2017-067) on August 26, 2017.
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Knowledge domain and emerging trends in Alzheimer’s disease: a scientometric review based on CiteSpace analysis p. 1643
Shuo Liu, Ya-Ping Sun, Xu-Ling Gao, Yi Sui
DOI:10.4103/1673-5374.255995  
Alzheimer’s disease is the most common cause of dementia. It is an increasingly serious global health problem and has a significant impact on individuals and society. However, the precise cause of Alzheimer’s disease is still unknown. In this study, 11,748 Web-of-Science-indexed manuscripts regarding Alzheimer’s disease, all published from 2015 to 2019, and their 693,938 references were analyzed. A document co-citation network map was drawn using CiteSpace software. Research frontiers and development trends were determined by retrieving subject headings with apparent changing word frequency trends, which can be used to forecast future research developments in Alzheimer’s disease.
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RESEARCH ARTICLES: PERIPHERAL NERVE INJURY AND NEURAL REGENERATION Top

Novel miRNA, miR-sc14, promotes Schwann cell proliferation and migration p. 1651
Xi-Meng Ji, Shan-Shan Wang, Xiao-Dong Cai, Xing-Hui Wang, Qian-Yan Liu, Pan Wang, Zhang-Chun Cheng, Tian-Mei Qian
DOI:10.4103/1673-5374.255996  
MicroRNAs refer to a class of endogenous, short non-coding RNAs that mediate numerous biological functions. MicroRNAs regulate various physiological and pathological activities of peripheral nerves, including peripheral nerve repair and regeneration. Previously, using a rat sciatic nerve injury model, we identified many functionally annotated novel microRNAs, including miR-sc14. Here, we used real-time reverse transcription-polymerase chain reaction to examine miR-sc14 expression in rat sciatic nerve stumps. Our results show that miR-sc14 is noticeably altered following sciatic nerve injury, being up-regulated at 1 day and diminished at 7 days. EdU and transwell chamber assay results showed that miR-sc14 mimic promoted proliferation and migration of Schwann cells, while miR-sc14 inhibitor suppressed their proliferation and migration. Additionally, bioinformatic analysis examined potential target genes of miR-sc14, and found that fibroblast growth factor receptor 2 might be a potential target gene. Specifically, our results show changes of miR-sc14 expression in the sciatic nerve of rats at different time points after nerve injury. Appropriately, up-regulation of miR-sc14 promoted proliferation and migration of Schwann cells. Consequently, miR-sc14 may be an intervention target to promote repair of peripheral nerve injury. The study was approved by the Jiangsu Provincial Laboratory Animal Management Committee, China on March 4, 2015 (approval No. 20150304-004).
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CORRIGENDUM Top

Corrigendum: A high methionine, low folate and vitamin B 6 /B 12 containing diet can be associated with memory loss by epigenetic silencing of netrin-1  

DOI:10.4103/1673-5374.255999  
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