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15 August 2021, Volume 16 Issue 8 Previous Issue   

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Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage Liu-Lin Xiong, Jie Chen, Ruo-Lan Du, Jia Liu, Yan-Jun Chen, Mohammed Al Hawwas, Xin-Fu Zhou, Ting-Hua Wang, Si-Jin Yang, Xue Bai 2021, 16 (8):  1453-1459.  doi: 10.4103/1673-5374.303033 Abstract ( 100 )   PDF (1944KB) ( 207 )   Save Brain-derived neurotrophic factor (BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The mRNA expression levels of BDNF and its processing enzymes and receptors (Furin, matrix metallopeptidase 9, tissue-type plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury; however, the expression levels of these mRNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia (approval No. U12-18) on July 30, 2018.  Related Articles | Metrics

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Environmental enrichment combined with fasudil treatment inhibits neuronal death in the hippocampal CA1 region and ameliorates memory deficits Gao-Jing Xu, Qun Zhang, Si-Yue Li, Yi-Tong Zhu, Ke-Wei Yu, Chuan-Jie Wang, Hong-Yu Xie, Yi Wu 2021, 16 (8):  1460-1466.  doi: 10.4103/1673-5374.303034 Abstract ( 155 )   PDF (5183KB) ( 135 )   Save Currently, no specific treatment exists to promote recovery from cognitive impairment after a stroke. Dysfunction of the actin cytoskeleton correlates well with poststroke cognitive declines, and its reorganization requires proper regulation of Rho-associated kinase (ROCK) proteins. Fasudil downregulates ROCK activation and protects neurons against cytoskeleton collapse in the acute phase after stroke. An enriched environment can reduce poststroke cognitive impairment. However, the efficacy of environmental enrichment combined with fasudil treatment remains poorly understood. A photothrombotic stroke model was established in 6-week-old male C57BL/6 mice. Twenty-four hours after modeling, these animals were intraperitoneally administered fasudil (10 mg/kg) once daily for 14 successive days and/or provided with environmental enrichment for 21 successive days. After exposure to environmental enrichment combined with fasudil treatment, the number of neurons in the hippocampal CA1 region increased significantly, the expression and proportion of p-cofilin in the hippocampus decreased, and the distribution of F-actin in the hippocampal CA1 region increased significantly. Furthermore, the performance of mouse stroke models in the tail suspension test and step-through passive avoidance test improved significantly. These findings suggest that environmental enrichment combined with fasudil treatment can ameliorate memory dysfunction through inhibition of the hippocampal ROCK/cofilin pathway, alteration of the dynamic distribution of F-actin, and inhibition of neuronal death in the hippocampal CA1 region. The efficacy of environmental enrichment combined with fasudil treatment was superior to that of fasudil treatment alone. This study was approved by the Animal Ethics Committee of Fudan University of China (approval No. 2019-Huashan Hospital JS-139) on February 20, 2019.  Related Articles | Metrics

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Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases Isaac G. Onyango, James P. Bennett, Jr, Gorazd B. Stokin 2021, 16 (8):  1467-1482.  doi: 10.4103/1673-5374.303007 Abstract ( 92 )   PDF (793KB) ( 191 )   Save Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases. Related Articles | Metrics

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The secretome of endothelial progenitor cells: a potential therapeutic strategy for ischemic stroke Mansour Alwjwaj, Rais Reskiawan A. Kadir, Ulvi Bayraktutan 2021, 16 (8):  1483-1489.  doi: 10.4103/1673-5374.303012 Abstract ( 101 )   PDF (1028KB) ( 102 )   Save Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as the only pharmacological therapy for stroke patients. However, due to short therapeutic window (4.5 hours of stroke onset) and increased risk of hemorrhage beyond this point, each year globally less than 1% of stroke patients receive this therapy which necessitate the discovery of safe and efficacious therapeutics that can be used beyond the acute phase of stroke. Accumulating evidence indicates that endothelial progenitor cells (EPCs), equipped with an inherent capacity to migrate, proliferate and differentiate, may be one such therapeutics. However, the limited availability of EPCs in peripheral blood and early senescence of few isolated cells in culture conditions adversely affect their application as effective therapeutics. Given that much of the EPC-mediated reparative effects on neurovasculature is realized by a wide range of biologically active substances released by these cells, it is possible that EPC-secretome may serve as an important therapeutic after an ischemic stroke. In light of this assumption, this review paper firstly discusses the main constituents of EPC-secretome that may exert the beneficial effects of EPCs on neurovasculature, and then reviews the currently scant literature that focuses on its therapeutic capacity. Related Articles | Metrics

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The neuroimaging of neurodegenerative and vascular disease in the secondary prevention of cognitive decline Morgan J. Schaeffer, Leona Chan, Philip A. Barber 2021, 16 (8):  1490-1499.  doi: 10.4103/1673-5374.303011 Abstract ( 115 )   PDF (964KB) ( 266 )   Save Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer’s disease (amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.  Related Articles | Metrics

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Induced pluripotent stem cell technology for spinal cord injury: a promising alternative therapy Yu Li, Ping-Ping Shen, Bin Wang 2021, 16 (8):  1500-1509.  doi: 10.4103/1673-5374.303013 Abstract ( 145 )   PDF (1236KB) ( 163 )   Save Spinal cord injury has long been a prominent challenge in the trauma repair process. Spinal cord injury is a research hotspot by virtue of its difficulty to treat and its escalating morbidity. Furthermore, spinal cord injury has a long period of disease progression and leads to complications that exert a lot of mental and economic pressure on patients. There are currently a large number of therapeutic strategies for treating spinal cord injury, which range from pharmacological and surgical methods to cell therapy and rehabilitation training. All of these strategies have positive effects in the course of spinal cord injury treatment. This review mainly discusses the problems regarding stem cell therapy for spinal cord injury, including the characteristics and action modes of all relevant cell types. Induced pluripotent stem cells, which represent a special kind of stem cell population, have gained impetus in cell therapy development because of a range of advantages. Induced pluripotent stem cells can be developed into the precursor cells of each neural cell type at the site of spinal cord injury, and have great potential for application in spinal cord injury therapy. Related Articles | Metrics

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The interaction of stem cells and vascularity in peripheral nerve regeneration Sara Saffari, Tiam M. Saffari, Dietmar J. O. Ulrich, Steven E. R. Hovius, Alexander Y. Shin 2021, 16 (8):  1510-1517.  doi: 10.4103/1673-5374.303009 Abstract ( 101 )   PDF (892KB) ( 130 )   Save The degree of nerve regeneration after peripheral nerve injury can be altered by the microenvironment at the site of injury. Stem cells and vascularity are postulated to be a part of a complex pathway that enhances peripheral nerve regeneration; however, their interaction remains unexplored. This review aims to summarize current knowledge on this interaction, including various mechanisms through which trophic factors are promoted by stem cells and angiogenesis. Angiogenesis after nerve injury is stimulated by hypoxia, mediated by vascular endothelial growth factor, resulting in the growth of pre-existing vessels into new areas. Modulation of distinct signaling pathways in stem cells can promote angiogenesis by the secretion of various angiogenic factors. Simultaneously, the importance of stem cells in peripheral nerve regeneration relies on their ability to promote myelin formation and their capacity to be influenced by the microenvironment to differentiate into Schwann-like cells. Stem cells can be acquired through various sources that correlate to their differentiation potential, including embryonic stem cells, neural stem cells, and mesenchymal stem cells. Each source of stem cells serves its particular differentiation potential and properties associated with the promotion of revascularization and nerve regeneration. Exosomes are a subtype of extracellular vesicles released from cell types and play an important role in cell-to-cell communication. Exosomes hold promise for future transplantation applications, as these vesicles contain fewer membrane-bound proteins, resulting in lower immunogenicity. This review presents pre-clinical and clinical studies that focus on selecting the ideal type of stem cell and optimizing stem cell delivery methods for potential translation to clinical practice. Future studies integrating stem cell-based therapies with the promotion of angiogenesis may elucidate the synergistic pathways and ultimately enhance nerve regeneration.  Related Articles | Metrics

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Cortical plasticity and nerve regeneration after peripheral nerve injury Ci Li, Song-Yang Liu, Wei Pi, Pei-Xun Zhang 2021, 16 (8):  1518-1523.  doi: 10.4103/1673-5374.303008 Abstract ( 203 )   PDF (848KB) ( 166 )   Save With the development of neuroscience, substantial advances have been achieved in peripheral nerve regeneration over the past decades. However, peripheral nerve injury remains a critical public health problem because of the subsequent impairment or absence of sensorimotor function. Uncomfortable complications of peripheral nerve injury, such as chronic pain, can also cause problems for families and society. A number of studies have demonstrated that the proper functioning of the nervous system depends not only on a complete connection from the central nervous system to the surrounding targets at an anatomical level, but also on the continuous bilateral communication between the two. After peripheral nerve injury, the interruption of afferent and efferent signals can cause complex pathophysiological changes, including neurochemical alterations, modifications in the adaptability of excitatory and inhibitory neurons, and the reorganization of somatosensory and motor regions. This review discusses the close relationship between the cerebral cortex and peripheral nerves. We also focus on common therapies for peripheral nerve injury and summarize their potential mechanisms in relation to cortical plasticity. It has been suggested that cortical plasticity may be important for improving functional recovery after peripheral nerve damage. Further understanding of the potential common mechanisms between cortical reorganization and nerve injury will help to elucidate the pathophysiological processes of nerve injury, and may allow for the reduction of adverse consequences during peripheral nerve injury recovery. We also review the role that regulating reorganization mechanisms plays in functional recovery, and conclude with a suggestion to target cortical plasticity along with therapeutic interventions to promote peripheral nerve injury recovery. Related Articles | Metrics

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The neuroprotective role of Wnt signaling in the retina Stefan Kassumeh, Gregor R. Weber, Matthias Nobl, Siegfried G. Priglinger, Andreas Ohlmann 2021, 16 (8):  1524-1528.  doi: 10.4103/1673-5374.303010 Abstract ( 130 )   PDF (844KB) ( 151 )   Save The canonical Wnt/β-catenin signaling pathway has been shown to play a major role during embryonic development and maturation of the central nervous system including the retina. It has a significant impact on retinal vessel formation and maturation, as well as on the establishment of synaptic structures and neuronal function in the central nervous system. Mutations in components of the Wnt/β-catenin signaling cascade may lead to severe retinal diseases, while dysregulation of Wnt signaling can contribute to disease progression. Apart from the angiogenic role of Wnt/β-catenin signaling, research in the last decades leads to the theory of a protective effect of Wnt/β-catenin signaling on damaged neurons. In this review, we focus on the neuroprotective properties of the Wnt/β-catenin pathway as well as its downstream signaling in the retina. Related Articles | Metrics

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Histone acetylation and deacetylation in ischemic stroke Anatoly B. Uzdensky, Svetlana Demyanenko 2021, 16 (8):  1529-1530.  doi: 10.4103/1673-5374.303024 Abstract ( 118 )   PDF (365KB) ( 114 )   Save Stroke is the second leading cause of death in the world. A significant part of survived people become invalids, dependent on others and in need of outside care. This is a heavy burden for their families and society. The life of patients surviving ischemic stroke (~80% of all strokes) may be subdivided by three main phases: (a) The acute phase that lasts about first 24 hours, when the neurons may be saved and the neuroprotective therapy may be efficient; (b) The early recovery phase that lasts for several days and weeks, when the repair and regeneration processes develop, and partial recovery of brain functions occurs; and (c) The chronic phase (weeks, months and years), in which the organism state is stabilized and the patient gets the partial or full recovery. Different structural and functional modifications are possible throughout the whole post-stroke period, and the specific pharmacotherapy may be applied at each stage (Hankey, 2017). Related Articles | Metrics

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Microglia accumulation and activation after subarachnoid hemorrhage Junfan Chen, George Kwok Chu Wong 2021, 16 (8):  1531-1532.  doi: 10.4103/1673-5374.303028 Abstract ( 128 )   PDF (565KB) ( 133 )   Save Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease accounting for a significant portion of young patients with stroke with high morbidity and mortality (van Gijn et al., 2007). Secondary brain injury resulting from neuroinflammation is considered to be a key pathological process (Zheng and Wong, 2017). Microglia, the resident immune cells of the brain, are implicated in numerous neurological diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, and brain tumors (Colonna and Butovsky, 2017). Recent evidence suggests that microglia-mediated neuroinflammation plays a critical role in injury expansion and brain damage after SAH. In fact, two recent clinical studies have shown evidence of microglia accumulation and activation in the human brain parenchyma and cerebrospinal fluid (CSF) respectively after aneurysmal SAH. Schneider et al. (2015) examined 21 patients that had died within the course of SAH which had not suffered central nervous system (CNS) infection nor from cerebral vasospasm and found that microglia accumulation in human brain autopsy specimens after SAH between days 5 and 15 correlated with mortality rate of patients, and at a microscopic level, microglia accumulation was associated with neuronal apoptosis in a distribution concordant to axonal injury. Coinciding with this cellular inflammatory response, they found signs for axonal injury, displayed by an intraparenchymal accumulation of extracellular amyloid precursor protein; they also identified a significantly higher activity of DNA fragmentation in neurons during the course of experiment (Schneider et al., 2015). In cell counts, an increase of neuronal apoptosis could be detected from day 4 onwards to a peak on day 14 after SAH with a corresponding decline in the absolute number of vital neurons (Schneider et al., 2015). Roa et al. (2020) recruited 13 aneurysmal SAH patients for their study and found that the number of CSF microglia cells (CD45dimCD11b+) progressively increased over time after aneurysmal SAH, in particularly in patients with cerebral vasospasm. In contrast, CSF analysis demonstrated elevated counts of natural killer (NK) cells (CD3–CD161+) and Tc17 cells (CD8+CD161+) during the very acute phase on days 0–1, followed by a rapid reduction of cell numbers (Roa et al., 2020). The time course of microglial activation and accumulation suggested a window of opportunity for pharmacological intervention.  Related Articles | Metrics

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Potential role of noise to improve intracortical microstimulation in tactile neuroprostheses Pedro Mabil, Nayeli Huidobro, Amira Flores, Elias Manjarrez 2021, 16 (8):  1533-1534.  doi: 10.4103/1673-5374.303018 Abstract ( 110 )   PDF (572KB) ( 160 )   Save The intracortical microstimulation (ICMS) from 40 to 100 µA is useful to elicit tactile sensations, which could be employed in neuroprostheses to control the robotic arms’ movement. However, this electrical current applied for prolonged periods of time could damage the neuronal tissue. Therefore, there is a necessity to create new strategies for the practical use of ICMS in a safe intensity range for potential clinical applications in tetraplegic patients. Here we describe crucial studies supporting the use of electrical and optical noise to guarantee a safe ICMS delivered through brain-machine interface technologies.  Related Articles | Metrics

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Tips and tricks for cannabinoid receptor 1 detection, interaction and interpretation Pedro F. Esteban, Eduardo Molina-Holgado 2021, 16 (8):  1535-1536.  doi: 10.4103/1673-5374.300984 Abstract ( 83 )   PDF (380KB) ( 123 )   Save Proteomic approaches are currently used to explore and identify interacting partners of proteins involved in diverse biological processes or with therapeutic potential. The cannabinoid receptor 1, CB1, is the main mediator of cannabinoids effects in the central nervous system. The role of the endocannabinoid system in development and physiology and as a target of pharmacological and cellular therapies is the subject of intense research. Therefore, the scarcity of proteomic studies on the interactome of CB1 is, somehow, surprising (Mattheus et al., 2016). We addressed the proteomic study of the CB1 receptor interactome in rat primary cortical neuron cultures after immunoprecipitation (IP) of the receptor, but were puzzled by the confusing and disparate data regarding the identification of the CB1 receptor by western blot (WB). Therefore, we established handling conditions for IP and WB detection of CB1 that resulted in the consistent and specific detection and immunopreciptitation of CB1 with different antibodies. Based on WB results after deglycosylation and IP of the CB1 receptor performed with different antibodies, we propose a new interpretation of the molecular identity of CB1 multiple apparent molecular weights reported in the literature (Esteban et al., 2020). We believe our findings may contribute to clarify the identification of the receptor by WB and IP and make proteomic studies more solid and robust. The reinterpretation of WB and IP results discussed in our report may open new lines of research which will contribute to the understanding of the molecular nature of the CB1 receptor. Related Articles | Metrics

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Role of dehydroepiandrosterone sulfate as a scavenging antioxidant: the evidence from Caenorhabditis elegans’ nervous system under hypoxia Leonardo Hernandez, Gabriela Camargo 2021, 16 (8):  1537-1538.  doi: 10.4103/1673-5374.303022 Abstract ( 112 )   PDF (774KB) ( 142 )   Save In nature, changes in O2 levels occur frequently. An inadequate supply of oxygen often happens in living systems, which induces an imbalance between oxygen entering cells and their oxygen demand to produce energy. The condition is known as hypoxia. Although hypoxia takes place in multiple physiological processes, it can be a primary cause of cellular injury and death (Nystul and Roth, 2004). Consequently, cells and tissues are habitually at risk, and they have developed many strategies to cope with low oxygen levels leading to pathological conditions (Fawcett et al., 2015). These adaptative responses to hypoxia though not entirely understood, seem to be evolutively conserved. Notwithstanding these responses, hypoxia can still have harmful effects.  Related Articles | Metrics

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CD40L/CD40 bidirectional signaling is a major regulator of neuronal morphology in the developing nervous system Paulina Carriba, Alun M. Davies 2021, 16 (8):  1539-1541.  doi: 10.4103/1673-5374.303025 Abstract ( 139 )   PDF (988KB) ( 118 )   Save Appropriate nervous system function depends on a precise but plastic neural architecture. Neuronal morphology determines how neurons interact with each other and with other cells. Every kind of neuron has its own morphological characteristics, which are determined by both intrinsic and extrinsic factors. In addition to intrinsic genetic programmes and patterns of neural activity, a variety of extrinsic factors regulate the growth and branching of neural processes and synaptogenesis. Work over the past decade has revealed that several members of the tumor necrosis factor superfamily (TNFSF) are potent positive and negative physiological regulators of neural process growth and branching in the developing nervous system without affecting neuronal survival. Extensively characterized in the immune system, where they play key roles in orchestrating and regulating immune responses, TNFSF members bind one or more members of the TNF receptor superfamily (TNFRSF), initiating canonical forward signaling. In addition, several TNFRSF members can act as ligands for the membrane-integrated TNFSF, triggering reverse signaling that has distinctive cellular responses to forward signaling (Eissner et al., 2004). In the developing nervous system, TNFSF/TNFRSF bidirectional signaling plays a major role in modulating neuronal architecture and has been studied most extensively for CD40 ligand (CD40L, TNFSF5) and CD40 (TNFRSF5).  Related Articles | Metrics

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Klotho and neurons: mutual crosstalk between autophagy, endoplasmic reticulum, and inflammatory response Jennifer Mytych 2021, 16 (8):  1542-1543.  doi: 10.4103/1673-5374.303014 Abstract ( 132 )   PDF (648KB) ( 134 )   Save Klotho is one of a number of well-known longevity-associated genes. Its depletion in aging or disease may promote several neuropathologies associated with the central nervous system, including hypomyelination and phosphorylation of neurofilaments, synaptic loss and modulation of their plasticity, behavioral impairments, neuroinflammation, and finally neurodegeneration. Therefore, the complexity of neuronal physiology and function raises some fundamental questions about the molecular mechanisms involved in Klotho action. To date, the evidence is summarized that the common link between Klotho and neuropathological changes are perturbations in oxidative homeostasis leading to the irreversible accumulation of molecular damage in DNA, protein, and lipids fractions, and finally to cell death or senescence. However, recent studies shed more detailed light on a possible protective mechanism of Klotho in neuronal cells through modulation of endoplasmic reticulum (ER) stress pathways, autophagic process, and inflammatory reaction in response to misfolded protein accumulation. Related Articles | Metrics

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Low-dose testosterone replacement therapy and electrically evoked resistance training enhance muscle quality after spinal cord injury Raymond E. Lai, Ashraf S. Gorgey 2021, 16 (8):  1544-1545.  doi: 10.4103/1673-5374.303026 Abstract ( 119 )   PDF (374KB) ( 132 )   Save The current perspective is aimed to highlight the significance of adding low-dose testosterone replacement therapy (TRT) to electrically evoked resistance training (RT). Evoked RT is primarily designed to load the paralyzed lower extremity muscles to elicit muscle hypertrophy in persons with spinal cord injury (SCI) (Ryan et al., 2013; Gorgey et al., 2019). The rationale was based on previous work that indicated that high-dose TRT is likely to enhance muscle quality, increase muscle cross-sectional area, and attenuate trabecular bone loss in a rodent model of SCI (Yarrow et al., 2014). However, high-dose TRT may lead to negative medical consequences including the increased risk for blood clots and enlargement of the prostate gland in humans with SCI (Yarrow et al., 2014). As such a complementary approach of adding low-dose TRT to loading exercise may reciprocate the negative effects of SCI on body composition and cardio-metabolic profiles. Related Articles | Metrics

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Stem cell-derived three-dimensional (organoid) models of Alzheimer’s disease: a precision medicine approach Sujung Jun Kim, Jiaxin Li, Vasiliki Mahairaki 2021, 16 (8):  1546-1547.  doi: 10.4103/1673-5374.303019 Abstract ( 141 )   PDF (870KB) ( 147 )   Save The major challenges of the “brain disorders” field – dementia, schizophrenia, other neuropsychiatric disorders – are that these are defined by clinical phenotypes whose underlying biology is poorly understood. There is great variability in definition, prognosis, trajectory, and treatment response indicating that the next step is defining subgroups by combining clinical and biologic information at the level of the individual. These challenges are especially relevant and urgent in the case of dementia and related disorders.  Related Articles | Metrics

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Mens sana in corpore sano: lifestyle changes modify astrocytes to contain Alzheimer’s disease Marcus Augusto-Oliveira, Alexei Verkhratsky 2021, 16 (8):  1548-1549.  doi: 10.4103/1673-5374.303023 Abstract ( 79 )   PDF (495KB) ( 143 )   Save Alzheimer`s disease (AD) is the widespread and the most feared neurodegenerative disorder leading to dementia in the elderly. AD, by eliminating intelligence, diminishes a man to helpless body, places an unbearable strain on patients, families, and fuels socio-economic healthcare crises around the world. The main histopathological hallmarks of AD are the accumulation of extracellular amyloid depositions known as senile plaques and intracellular neurofibrillary tangles, together with severe dysfunctional synaptic connectivity and neuronal death leading to brain atrophy.  Related Articles | Metrics

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Therapeutic potential of alpha 5 subunit containing GABAA receptors in Alzheimer’s disease Andrea Kwakowsky, Henry J. Waldvogel, Richard L.M. Faull 2021, 16 (8):  1550-1551.  doi: 10.4103/1673-5374.300987 Abstract ( 111 )   PDF (714KB) ( 142 )   Save Alzheimer’s disease (AD) is a common neurodegenerative disorder and the leading cause of dementia. It has been estimated that over 50 million people worldwide were affected by dementia in 2019, and the prevalence of dementia is expected to double approximately once every 20 years (Govindpani et al., 2017). Most people who die with AD require high levels of care for long periods of time. The underlying causes of AD are not well understood, and there are no current treatments preventing the onset or delaying the progression of the disease. Several decades of intensive research have yielded a range of drugs that alter the metabolism of amyloid-β (Aβ) and tau protein levels, the main components of the aggregates found in the brains of people with AD. Numerous therapeutic approaches that target the production, toxicity, and removal of Aβ and tau protein are being developed, but these have yet to fulfill expectations in clinical trials. A large number of major failed trials are alarming to the AD community of researchers and affected families. Therefore, there is an urgent need to discover ways to improve and restore memory function and find better and more effective ways to care for people with AD.  Related Articles | Metrics

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TLR2 and TLR4-mediated inflammation in Alzheimer’s disease: self-defense or sabotage? Mark L. Dallas, Darius Widera 2021, 16 (8):  1552-1553.  doi: 10.4103/1673-5374.303016 Abstract ( 99 )   PDF (609KB) ( 154 )   Save Alzheimer’s disease (AD) is an irreversible disease that leads to neurodegeneration. The underpinning mechanisms of neuronal cell death are a matter of ongoing debate regarding the impact of accumulation of the amyloid beta (Aβ) peptide and post-translation modifications of the tau protein. However, a growing area of research and one that may provide a more rigorous account of the early changes seen in Alzheimer’s brains is inflammation. Brain inflammation is a coordinated immune response to subtle changes in the brain’s microenvironment indicative of injury and disease. Neuroinflammation can be either short lived or chronic and lead to changes in brain structure and its neurochemistry. In AD, the ability of the brain to self-regulate inflammatory signals is compromised and leads to a chronic and deleterious inflammatory response. Understanding the molecular entities that are involved in neuroinflammation in AD will open the door to much needed novel therapeutic strategies. However, this is a cautionary tale with respect to the timing and exact nature of the proposed therapeutic strategy. In this perspective article, we will briefly introduce the current view of the dual nature of Toll-like receptor (TLR) 2 and TLR4-driven inflammation in AD and highlight why we believe that modulating the inflammatory status within a defined time window might provide a better therapeutic concept than globally supressing it for a prolonged time.  Related Articles | Metrics

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Application of PROTAC strategy to TTR-Aβ protein-protein interaction for the development of Alzheimer’s disease drugs Nicoló Tonali, Susanna Nencetti, Elisabetta Orlandini, Lidia Ciccone 2021, 16 (8):  1554-1555.  doi: 10.4103/1673-5374.303017 Abstract ( 66 )   PDF (808KB) ( 324 )   Save Alzheimer’s disease (AD) is a complex and multifaced neurodegenerative disorder for which the precise pathological molecular mechanisms are still not completely known.  Related Articles | Metrics

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Direct oral anticoagulants: a new therapy against Alzheimer’s disease? Klaus Grossmann 2021, 16 (8):  1556-1557.  doi: 10.4103/1673-5374.303029 Abstract ( 101 )   PDF (366KB) ( 98 )   Save More than 40 million people worldwide are thought to be affected by Alzheimer´s disease (AD). Of these, estimated less than 10% develop symptoms usually well before the age of 65, due to familial (hereditary) AD predisposition (Sierksma et al., 2020). AD is a multifactorial disorder, which includes a multitude of progressive degenerations in the brain parenchyma, but also in the vascular and hemostatic system. Currently, no drug is available or recognizable in the research pipeline for the effective treatment of this terrible disease. Therefore, the search for novel more effective drugs is an urgent task of pharmaceutical research. Already in the 1970s, clinical studies with small groups of senile dementia patients showed a positive effect of anticoagulant treatment on disease development (Grossmann, 2020). Particularly, results of basic research in the last 6 years on a contribution of cerebrovascular dysfunction to AD have brought back to light this idea. This perspective paper summarizes the role of toxic proteins of amyloid-beta (Aβ), thrombin and fibrin as key drivers in triggering vascular dysfunction and derived neurodegenerative changes, which leads to AD, and discuss how they can be treated with direct oral anticoagulants (DOACs). Related Articles | Metrics

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Non-invasive electrical stimulation as a potential treatment for retinal degenerative diseases Karen Chang, Sam Enayati, Kin-Sang Cho, Tor P. Utheim, Dong Feng Chen 2021, 16 (8):  1558-1559.  doi: 10.4103/1673-5374.303015 Abstract ( 90 )   PDF (215KB) ( 112 )   Save More than 38.5 million people are estimated to be affected by blindness worldwide in 2020 (Flaxman et al., 2017). Among the diseases that cause visual impairment, refractive errors are typically corrected with glasses and cataract with surgery. The leading causes of irreversible blindness nowadays are usually degenerative diseases related to the retina and its extending optic nerves, such as glaucoma, age-related macular degeneration, and retinitis pigmentosa (Quigley et al., 2006; Flaxman et al., 2017). The regenerative ability of the adult central nervous system in mammals is limited. As part of the central nervous system, impairments of the retina and optic nerve caused by trauma or diseases often lead to neurodegeneration and result in permanent blindness, which currently remains no cures. As the global population grows and ages, the number of people with vision loss will also increase. However, treatments for retinal degenerative diseases remain as unmet medical needs. Related Articles | Metrics

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Targeting transglutaminase 2 as a potential disease modifying therapeutic strategy for synucleinopathies Jie Zhang, Hilary Grosso Jasutkar†, M. Maral Mouradian 2021, 16 (8):  1560-1561.  doi: 10.4103/1673-5374.303027 Abstract ( 88 )   PDF (334KB) ( 134 )   Save Synucleinopathies are a group of progressive neurodegenerative disorders characterized by the accumulation of α-synuclein (α-Syn) aggregates in Lewy bodies (LBs) and Lewy neurites (LNs) in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and in glial cytoplasmic inclusions in multiple system atrophy (MSA). α-Syn is a 140 amino acid intrinsically disordered protein, which tends to self-aggregate and form fibrils in these neuropathological hallmark inclusions. Several lines of evidence suggest that misfolding and aggregation of α-Syn is a critical step leading to neuronal dysfunction and death. Additionally, propagation of α-Syn aggregates across neurons to synaptically connected brain regions correlates with the progressive nature of synucleinopathies and the emergence of additional clinical manifestations as the disease advances over time. Currently, there is no cure for these disorders. Available treatments for PD improve the motor symptoms but do not halt the underlying neurodegeneration. Thus, from the therapeutic perspective, identifying factors that initiate or promote misfolding of α-Syn is critical to developing strategies that reduce or prevent the formation of pathologic aggregates and thereby slow disease progression. In addition to well established genetic factors such as disease linked point mutations and SNCA gene locus multiplication leading to elevated levels of α-Syn, a number of exogenous and endogenous factors have been identified that can contribute to the formation of these aggregates including oxidative stress, exposure to neurotoxins, hyper-phosphorylation of α-Syn, and protein cross-linking. Several lines of evidence have attributed the latter to the activity of transglutaminase 2 (TG2).  Related Articles | Metrics

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Amyloid hypothesis through the lens of Aβ supersaturation Zhefeng Guo 2021, 16 (8):  1562-1563.  doi: 10.4103/1673-5374.303021 Abstract ( 101 )   PDF (566KB) ( 135 )   Save Deposition of aggregated amyloid-β (Aβ) protein in the form of amyloid plaques is a pathological hallmark of Alzheimer’s disease. According to the amyloid hypothesis, Aβ aggregation initiates a pathogenic cascade, eventually leading to dementia. Being the prevailing theory for Alzheimer’s disease, amyloid hypothesis has been used to guide basic research and therapeutic interventions. Supersaturation is a phenomenon that occurs when the concentration of a solute in the solution exceeds its thermodynamic solubility. In the brain, Aβ proteins are usually supersaturated. Aβ aggregation follows the principle of supersaturation (So et al., 2016). In this perspective, I discuss the biochemical implications of Aβ supersaturation in the framework of amyloid hypothesis and how this knowledge can be used to improve therapeutic development for Alzheimer’s disease. Related Articles | Metrics

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Therapeutic potential of insulin-like growth factor 2 in Huntington’s disease: controlling proteostasis to alleviate the load of misfolded protein Paulina Troncoso-Escudero, Claudio Hetz, Rene L. Vidal 2021, 16 (8):  1564-1565.  doi: 10.4103/1673-5374.303020 Abstract ( 80 )   PDF (807KB) ( 130 )   Save Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder characterized by the development of adult-onset motor dysfunction, psychiatric disturbances and intellectual decline. HD is associated with an expansion of CAG repeat sequence in the huntingtin gene (Htt). Exon 1 of Htt normally contains between 6 to 35 CAG repeats, whereas in patients affected with HD it contains more than 40 trinucleotides. The mutant Htt protein (mHtt) exhibits gain-of-toxic properties that cause neuronal dysfunction and death (Saudou and Humbert, 2016). Protein misfolding and aggregation is a common molecular feature of HD, suggesting that impairment in the buffer capacity of the proteostasis network contributes to the pathogenesis of the disease. Multiple studies in cell culture and animal models, in addition to the analysis of postmortem human tissue, have indicated that one of the main nodes of the proteostasis network affected in HD involves the function of the endoplasmic reticulum (Vidal et al., 2011). XBP1 is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with endoplasmic reticulum stress (Hetz et al., 2020). We previously reported that the genetic disruption of the transcription factor XBP1 delays disease progression and reduces protein aggregation in models of HD (Vidal et al., 2012), in addition to amyotrophic lateral sclerosis (ALS; Hetz et al., 2009), Parkinson´s disease (Valdes et al., 2014) and Alzheimer´s disease (Duran-Aniotz et al., 2017). Related Articles | Metrics

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Bimanual motor skill learning and robotic assistance for chronic hemiparetic stroke: a randomized controlled trial Maral Yeganeh Doost, Benoît Herman, Adrien Denis, Julien Sapin, Daniel Galinski, Audrey Riga, Patrice Laloux, Benoît Bihin, Yves Vandermeeren 2021, 16 (8):  1566-1573.  doi: 10.4103/1673-5374.301030 Abstract ( 111 )   PDF (1030KB) ( 186 )   Save Using robotic devices might improve recovery post-stroke, but the optimal way to apply robotic assistance has yet to be determined. The current study aimed to investigate whether training under the robotic active-assisted mode improves bimanual motor skill learning (biMSkL) more than training under the active mode in stroke patients. Twenty-six healthy individuals (HI) and 23 chronic hemiparetic stroke patients with a detectable lesion on MRI or CT scan, who demonstrated motor deficits in the upper limb, were randomly allocated to two parallel groups. The protocol included a two-day training on a new bimanual cooperative task, LIFT-THE-TRAY, under either the active or active-assisted modes (where assistance decreased in a pre-determined stepwise fashion) with the bimanual version of the REAplan® robotic device. The hypothesis was that the active-assisted mode would result in greater biMSkL than the active mode. The biMSkL was quantified by a speed-accuracy trade-off (SAT) before (T1) and immediately after (T2) training on days 1 and 2 (T3 and T4). The change in SAT after 2 days of training (T4/T1) indicated that both HI and stroke patients learned and retained the bimanual cooperative task. After 2 days of training, the active-assisted mode did not improve biMSkL more than the active mode (T4/T1) in HI nor stroke patients. Whereas HI generalized the learned bimanual skill to different execution speeds in both the active and active-assisted subgroups, the stroke patients generalized the learned skill only in the active subgroup. Taken together, the active-assisted mode, applied in a pre-determined stepwise decreasing fashion, did not improve biMSkL more than the active mode in HI and stroke subjects. Stroke subjects might benefit more from robotic assistance when applied “as-needed.” This study was approved by the local ethical committee (Comité d’éthique médicale, CHU UCL Namur, Mont-Godinne, Yvoir, Belgium; Internal number: 54/2010, EudraCT number: NUB B039201317382) on July 14, 2016 and was registered with ClinicalTrials.gov (Identifier: NCT03974750) on June 5, 2019.  Related Articles | Metrics

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Inhibition of nitric oxide synthase aggravates brain injury in diabetic rats with traumatic brain injury Wan-Chao Yang, Hong-Ling Cao, Yue-Zhen Wang, Ting-Ting Li, Hong-Yu Hu, Qiang Wan, Wen-Zhi Li 2021, 16 (8):  1574-1581.  doi: 10.4103/1673-5374.303035 Abstract ( 132 )   PDF (2262KB) ( 145 )   Save Studies have shown that hyperglycemia aggravates brain damage by affecting vascular endothelial function. However, the precise mechanism remains unclear. Male Sprague-Dawley rat models of diabetes were established by a high-fat diet combined with an intraperitoneal injection of streptozotocin. Rat models of traumatic brain injury were established using the fluid percussion method. Compared with traumatic brain injury rats without diabetic, diabetic rats with traumatic brain injury exhibited more severe brain injury, manifested as increased brain water content and blood-brain barrier permeability, the upregulation of heme oxygenase-1, myeloperoxidase, and Bax, the downregulation of occludin, zona-occludens 1, and Bcl-2 in the penumbra, and reduced modified neurological severity scores. The intraperitoneal injection of a nitric oxide synthase inhibitor N(5)-(1-iminoethyl)-L-ornithine (10 mg/kg) 15 minutes before brain injury aggravated the injury. These findings suggested that nitric oxide synthase plays an important role in the maintenance of cerebral microcirculation, including anti-inflammatory, anti-oxidative stress, and anti-apoptotic activities in diabetic rats with traumatic brain injury. The experimental protocols were approved by the Institutional Animal Care Committee of Harbin Medical University, China (approval No. ky2017-126) on March 6, 2017. Related Articles | Metrics

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P2X7 receptor activation aggravates NADPH oxidase 2-induced oxidative stress after intracerebral hemorrhage Hong Deng, Ye Zhang, Gai-Gai Li, Hai-Han Yu, Shuang Bai, Guang-Yu Guo, Wen-Liang Guo, Yang Ma, Jia-Hui Wang, Na Liu, Chao Pan, Zhou-Ping Tang 2021, 16 (8):  1582-1591.  doi: 10.4103/1673-5374.303036 Abstract ( 130 )   PDF (5775KB) ( 293 )   Save Oxidative stress is a crucial pathological process that contributes to secondary injury following intracerebral hemorrhage. P2X7 receptor (P2X7R), which is activated by the abnormal accumulation of extracellular ATP, plays an important role in the regulation of oxidative stress in the central nervous system, although the effects of activated P2X7R-associated oxidative stress after intracerebral hemorrhage remain unclear. Mouse models of intracerebral hemorrhage were established through the stereotactic injection of 0.075 U VII collagenase into the right basal ganglia. The results revealed that P2X7R expression peaked 24 hours after intracerebral hemorrhage, and P2X7R expressed primarily in neurons. The inhibition of P2X7R, using A438079 (100 mg/kg, intraperitoneal), reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and malondialdehyde generation, increased superoxide dismutase and glutathione/oxidized glutathione levels, and alleviated neurological damage, brain edema, and apoptosis after intracellular hemorrhage. The P2X7R inhibitor A438079 (100 mg/kg, intraperitoneal injection) inhibited the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB) after intracerebral hemorrhage. Blocking ERK1/2 activation, using the ERK1/2 inhibitor U0126 (2 µg, intraventricular injection), reduced the level of NOX2-mediated oxidative stress induced by P2X7R activation after intracellular hemorrhage. Similarly, the inhibition of NF-κB, using the NF-κB inhibitor JSH-23 (3.5 µg, intraventricular), reduced the level of NOX2-mediated oxidative stress induced by P2X7R activation. Finally, GSK2795039 (100 mg/kg, intraperitoneal), a NOX2 antagonist, attenuated P2X7R-mediated oxidative stress, neurological damage, and brain edema after intracerebral hemorrhage. The results indicated that P2X7R activation aggravated NOX2-induced oxidative stress through the activation of the ERK1/2 and NF-κB pathways following intracerebral hemorrhage in mice. The present study was approved by the Ethics Committee of Huazhong University of Science and Technology, China (approval No. TJ-A20160805) on August 26, 2016. Related Articles | Metrics

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DDAH2 (-449 G/C) G allele is positively associated with leukoaraiosis in northeastern China: a double-blind, intergroup comparison, case-control study Ying Fan, Qiang Gao, Jia-Xin Guan, Lei Liu, Ming Hong, Li Jun, Li Wang, Hai-Feng Ding, Li-Hong Jiang, Bo-Yu Hou, Mei Li, Zhi-Qiang Song, De-Qin Sun, Chao-Qi Yan, Lan Ma 2021, 16 (8):  1592-1597.  doi: 10.4103/1673-5374.303037 Abstract ( 116 )   PDF (580KB) ( 196 )   Save Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase (DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this double-blind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, SmaI restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2 (-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models (GG and CG), while 89.13% of healthy control subjects had dominant genetic models (CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls (P = 0.0002). The frequency of G alleles in the leukoaraiosis patients (71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower (χ2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes (Kruskal–Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2 (-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2 (-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of the 2nd Affiliated Hospital of Harbin Medical University of China (approval No. KY2016-177) on July 28, 2016. Related Articles | Metrics

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ISP and PAP4 peptides promote motor functional recovery after peripheral nerve injury Shi-Qin Lv, Wutian Wu 2021, 16 (8):  1598-1605.  doi: 10.4103/1673-5374.294565 Abstract ( 168 )   PDF (4769KB) ( 256 )   Save Both intracellular sigma peptide (ISP) and phosphatase and tensin homolog agonist protein (PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small peptides in peripheral nerve injury remains unclear. A rat model of brachial plexus injury was established by crush of the C6 ventral root. The rats were then treated with subcutaneous injection of PAP4 (497 µg/d, twice per day) or ISP (11 µg/d, once per day) near the injury site for 21 successive days. After ISP and PAP treatment, the survival of motoneurons was increased, the number of regenerated axons and neuromuscular junctions was increased, muscle atrophy was reduced, the electrical response of the motor units was enhanced and the motor function of the injured upper limbs was greatly improved in rats with brachial plexus injury. These findings suggest that ISP and PAP4 promote the recovery of motor function after peripheral nerve injury in rats. The animal care and experimental procedures were approved by the Laboratory Animal Ethics Committee of Jinan University of China (approval No. 20111008001) in 2011. Related Articles | Metrics

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Biocompatibility and biosafety of butterfly wings for the clinical use of tissue-engineered nerve grafts Shu Wang, Miao Gu, Cheng-Cheng Luan, Yu Wang, Xiaosong Gu, Jiang-Hong He 2021, 16 (8):  1606-1612.  doi: 10.4103/1673-5374.303041 Abstract ( 113 )   PDF (5585KB) ( 304 )   Save In a previous study, we used natural butterfly wings as a cell growth matrix for tissue engineering materials and found that the surface of different butterfly wings had different ultramicrostructures, which can affect the qualitative growth of cells and regulate cell growth, metabolism, and gene expression. However, the biocompatibility and biosafety of butterfly wings must be studied. In this study, we found that Sprague-Dawley rat dorsal root ganglion neurons could grow along the structural stripes of butterfly wings, and Schwann cells could normally attach to and proliferate on different species of butterfly wings. The biocompatibility and biosafety of butterfly wings were further examined through subcutaneous implantation in Sprague-Dawley rats, intraperitoneal injection in Institute of Cancer Research mice, intradermal injection in rabbits, and external application to guinea pigs. Our results showed that butterfly wings did not induce toxicity, and all examined animals exhibited normal behaviors and no symptoms, such as erythema or edema. These findings suggested that butterfly wings possess excellent biocompatibility and biosafety and can be used as a type of tissue engineering material. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China (approval No. 20190303-18) on March 3, 2019. Related Articles | Metrics

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Gene expression profiles of human adipose-derived mesenchymal stem cells dynamically seeded on clinically available processed nerve allografts and collagen nerve guides Femke Mathot, Nadia Rbia, Roman Thaler, Allan B. Dietz, Andre J. van Wijnen, Allen T. Bishop, Alexander Y. Shin 2021, 16 (8):  1613-1621.  doi: 10.4103/1673-5374.303031 Abstract ( 139 )   PDF (1276KB) ( 151 )   Save It was hypothesized that mesenchymal stem cells (MSCs) could provide necessary trophic factors when seeded onto the surfaces of commonly used nerve graft substitutes. We aimed to determine the gene expression of MSCs when influenced by Avance® Nerve Grafts or NeuraGen® Nerve Guides. Human adipose-derived MSCs were cultured and dynamically seeded onto 30 Avance® Nerve Grafts and 30 NeuraGen® Nerve Guides for 12 hours. At six time points after seeding, quantitative polymerase chain reaction analyses were performed for five samples per group. Neurotrophic [nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), pleiotrophin (PTN), growth associated protein 43 (GAP43) and brain-derived neurotrophic factor (BDNF)], myelination [peripheral myelin protein 22 (PMP22) and myelin protein zero (MPZ)], angiogenic [platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) and vascular endothelial cell growth factor alpha (VEGFA)], extracellular matrix (ECM) [collagen type alpha I (COL1A1), collagen type alpha III (COL3A1), Fibulin 1 (FBLN1) and laminin subunit beta 2 (LAMB2)] and cell surface marker cluster of differentiation 96 (CD96) gene expression was quantified. Unseeded Avance® Nerve Grafts and NeuraGen® Nerve Guides were used to evaluate the baseline gene expression, and unseeded MSCs provided the baseline gene expression of MSCs. The interaction of MSCs with the Avance® Nerve Grafts led to a short-term upregulation of neurotrophic (NGF, GDNF and BDNF), myelination (PMP22 and MPZ) and angiogenic genes (CD31 and VEGFA) and a long-term upregulation of BDNF, VEGFA and COL1A1. The interaction between MSCs and the NeuraGen® Nerve Guide led to short term upregulation of neurotrophic (NGF, GDNF and BDNF) myelination (PMP22 and MPZ), angiogenic (CD31 and VEGFA), ECM (COL1A1) and cell surface (CD96) genes and long-term upregulation of neurotrophic (GDNF and BDNF), angiogenic (CD31 and VEGFA), ECM genes (COL1A1, COL3A1, and FBLN1) and cell surface (CD96) genes. Analysis demonstrated MSCs seeded onto NeuraGen® Nerve Guides expressed significantly higher levels of neurotrophic (PTN), angiogenic (VEGFA) and ECM (COL3A1, FBLN1) genes in the long term period compared to MSCs seeded onto Avance® Nerve Grafts. Overall, the interaction between human MSCs and both nerve graft substitutes resulted in a significant upregulation of the expression of numerous genes important for nerve regeneration over time. The in vitro interaction of MSCs with the NeuraGen® Nerve Guide was more pronounced, particularly in the long term period (> 14 days after seeding). These results suggest that MSC-seeding has potential to be applied in a clinical setting, which needs to be confirmed in future in vitro and in vivo research. Related Articles | Metrics

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Changes in proteins related to early nerve repair in a rat model of sciatic nerve injury Yu-Song Yuan, Fei Yu, Ya-Jun Zhang, Su-Ping Niu, Hai-Lin Xu, Yu-Hui Kou 2021, 16 (8):  1622-1627.  doi: 10.4103/1673-5374.301025 Abstract ( 197 )   PDF (1128KB) ( 213 )   Save Peripheral nerves have a limited capacity for self-repair and those that are severely damaged or have significant defects are challenging to repair. Investigating the pathophysiology of peripheral nerve repair is important for the clinical treatment of peripheral nerve repair and regeneration. In this study, rat models of right sciatic nerve injury were established by a clamping method. Protein chip assay was performed to quantify the levels of neurotrophic, inflammation-related, chemotaxis-related and cell generation-related factors in the sciatic nerve within 7 days after injury. The results revealed that the expression levels of neurotrophic factors (ciliary neurotrophic factor) and inflammation-related factors (intercellular cell adhesion molecule-1, interferon γ, interleukin-1α, interleukin-2, interleukin-4, interleukin-6, monocyte chemoattractant protein-1, prolactin R, receptor of advanced glycation end products and tumor necrosis factor-α), chemotaxis-related factors (cytokine-induced neutrophil chemoattractant-1, L-selectin and platelet-derived growth factor-AA) and cell generation-related factors (granulocyte-macrophage colony-stimulating factor) followed different trajectories. These findings will help clarify the pathophysiology of sciatic nerve injury repair and develop clinical treatments of peripheral nerve injury. This study was approved by the Ethics Committee of Peking University People’s Hospital of China (approval No. 2015-50) on December 9, 2015.  Related Articles | Metrics

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Research trends, hot spots and prospects for necroptosis in the field of neuroscience Wei-Tao Yan, Shuang Lu, Yan-Di Yang, Wen-Ya Ning, Yan Cai, Xi-Min Hu, Qi Zhang, Kun Xiong 2021, 16 (8):  1628-1637.  doi: 10.4103/1673-5374.303032 Abstract ( 214 )   PDF (4469KB) ( 228 )   Save There are two types of cell death-apoptosis and necrosis. Apoptosis is cell death regulated by cell signaling pathways, while necrosis has until recently been considered a passive mechanism of cell death caused by environmental pressures. However, recent studies show that necrosis can also be regulated by specific cell signaling pathways. This mode of death, termed necroptosis, has been found to be related to the occurrence and development of many diseases. We used bibliometrics to analyze the global output of literature on necroptosis in the field of neuroscience published in the period 2007–2019 to identify research hotspots and prospects. We included 145 necroptosis-related publications and 2239 references published in the Web of Science during 2007–2019. Visualization analysis revealed that the number of publications related to necroptosis has increased year by year, reaching a peak in 2019. China is the country with the largest number of publications. Key word and literature analyses demonstrated that mitochondrial function change, stroke, ischemia/reperfusion and neuroinflammation are likely the research hotspots and future directions of necroptosis research in the nervous system. The relationship between immune response-related factors, damage-associated molecular patterns, pathogen-associated molecular patterns and necroptosis may become a potential research hotspot in the future. Taken together, our findings suggest that although the inherent limitations of bibliometrics may affect the accuracy of the literature-based prediction of research hotspots, the results obtained from the included publications can provide a reference for the study of necroptosis in the field of neuroscience. Related Articles | Metrics

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Olfactory ensheathing cell transplantation alters the expression of chondroitin sulfate proteoglycans and promotes axonal regeneration after spinal cord injury Guo-Yu Wang, Zhi-Jian Cheng, Pu-Wei Yuan, Hao-Peng Li, Xi-Jing He 2021, 16 (8):  1638-1644.  doi: 10.4103/1673-5374.301023 Abstract ( 160 )   PDF (3230KB) ( 176 )   Save Cell transplantation is a potential treatment for spinal cord injury. Olfactory ensheathing cells (OECs) play an active role in the repair of spinal cord injury as a result of the dual characteristics of astrocytes and Schwann cells. However, the specific mechanisms of repair remain poorly understood. In the present study, a rat model of spinal cord injury was established by transection of T10. OECs were injected into the site, 1 mm from the spinal cord stump. To a certain extent, OEC transplantation restored locomotor function in the hindlimbs of rats with spinal cord injury, but had no effect on the formation or volume of glial scars. In addition, OEC transplantation reduced the immunopositivity of chondroitin sulfate proteoglycans (neural/glial antigen 2 and neurocan) and glial fibrillary acidic protein at the injury site, and increased the immunopositivity of growth-associated protein 43 and neurofilament. These findings suggest that OEC transplantation can regulate the expression of chondroitin sulfate proteoglycans in the spinal cord, inhibit scar formation caused by the excessive proliferation of glial cells, and increase the numbers of regenerated nerve fibers, thus promoting axonal regeneration after spinal cord injury. The study was approved by the Animal Ethics Committee of the Medical College of Xi’an Jiaotong University, China (approval No. 2018-2048) on September 9, 2018. Related Articles | Metrics

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Therapeutic effects of dental pulp stem cells on vascular dementia in rat models Xue-Mei Zhang, Yang Sun, Ying-Lian Zhou, Zhuo-Min Jiao, Dan Yang, Yuan-Jiao Ouyang, Mei-Yu Yu, Jin-Yue Li, Wei Li, Duo Wang, Hui Yue, Jin Fu 2021, 16 (8):  1645-1651.  doi: 10.4103/1673-5374.303042 Abstract ( 97 )   PDF (6905KB) ( 26 )   Save Dental pulp stem cells are a type of adult stem cells with strong proliferative ability and multi-differentiation potential. There are no studies on treatment of vascular dementia with dental pulp stem cells. In the present study, rat models of vascular dementia were established by two-vessel occlusion, and 30 days later, rats were injected with 2 × 107 dental pulp stem cells via the tail vein. At 70 days after vascular dementia induction, dental pulp stem cells had migrated to the brain tissue of rat vascular dementia models and differentiated into neuron-like cells. At the same time, doublecortin, neurofilament 200, and NeuN mRNA and protein expression levels in the brain tissue were increased, and glial fibrillary acidic protein mRNA and protein expression levels were decreased. Behavioral testing also revealed that dental pulp stem cell transplantation improved the cognitive function of rat vascular dementia models. These findings suggest that dental pulp stem cell transplantation is effective in treating vascular dementia possibly through a paracrine mechanism. The study was approved by the Animal Ethics Committee of Harbin Medical University (approval No. KY2017-132) in 2017. Related Articles | Metrics

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Safety and efficacy of a nerve matrix membrane as a collagen nerve wrapping: a randomized, single-blind, multicenter clinical trial Yong-Bin Gao, Zhi-Gang Liu, Guo-Dong Lin, Yang Guo, Lei Chen, Bo-Tao Huang, Yao-Bin Yin, Chen Yang, Li-Ying Sun, Yan-Bo Rong, Shanlin Chen 2021, 16 (8):  1652-1659.  doi: 10.4103/1673-5374.303040 Abstract ( 172 )   PDF (1868KB) ( 163 )   Save A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane (n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping (n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes–Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes–Weinstein monofilament examination. The ratio (percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00% and 94.44%, respectively, with no significant difference between the two groups. There were no significant differences in the results of routine blood tests, liver and renal function tests, coagulation function tests, or immunoglobulin tests at 14 and 180 days postoperatively between the two groups. These findings suggest that the novel nerve matrix membrane is similar in efficacy to the commercially-available bovine-derived collagen membrane in the repair of peripheral nerve injury, and it may therefore serve as an alternative in the clinical setting. The clinical trial was approved by the Institutional Ethics Committee of Beijing Jishuitan Hospital, China (approval No. 20160902) on October 8, 2016, the Institutional Ethics Committee of the First Bethune Hospital of Jilin University, China (approval No. 160518-088) on December 14, 2016, and the Institutional Ethics Committee of Yantai Yuhuangding Hospital, China (approval No. 2016-10-01) on December 9, 2016. The clinical trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000033324) on May 28, 2020. Related Articles | Metrics

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Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide dual receptor agonist DA-CH5 is superior to exendin-4 in protecting neurons in the 6-hydroxydopamine rat Parkinson model Ling-Yu Zhang, Qian-Qian Jin, Christian Hölscher, Lin Li 2021, 16 (8):  1660-1670.  doi: 10.4103/1673-5374.303045 Abstract ( 215 )   PDF (3281KB) ( 173 )   Save Patients with Parkinson’s disease (PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular co-agonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine (6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1 (IRS-1)/alpha serine/threonine-protein kinase (Akt)/cAMP response element-binding protein (CREB) pathway. We also found that DA-CH5 (10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was up-regulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDA-unilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China. Related Articles | Metrics

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Peri-infarct reorganization of an injured corticospinal tract in a patient with cerebral infarction Min Kyeong Cho, Sung Ho Jang 2021, 16 (8):  1671-1672.  doi: 10.4103/1673-5374.303046 Abstract ( 113 )   PDF (796KB) ( 137 )   Save Corticospinal tract (CST), a major neural tract in the human brain for motor function, is involved mainly in the movement of the distal extremities (Jang and Lee, 2019). Recovery of an injured CST is essential for good recovery of impaired motor function in stroke patients (Jang and Lee, 2019). Peri-infarct reorganization of an injured CST is an important mechanism underlying recovery of motor function in stroke patients (Jang, 2007). In this study, we reported on a patient with cerebral infarction who showed recovery of an injured CST by peri-infarct reorganization using diffusion tensor tractography (DTT) and transcranial magnetic stimulation (TMS). Related Articles | Metrics