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15 April 2021, Volume 16 Issue 4 Previous Issue    Next Issue

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The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke: a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches Magdalini Tsintou, Kyriakos Dalamagkas, Tara L. Moore, Yogesh Rathi, Marek Kubicki, Douglas L. Rosene, Nikos Makris 2021, 16 (4):  605-613.  doi: 10.4103/1673-5374.295269 Abstract ( 113 )   PDF (1938KB) ( 189 )   Save Neural tissue engineering, nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system (CNS) repair. It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes, making development of CNS therapeutics challenging. Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society, it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels. Extracellular vesicles (EVs), also known as exosomes, when derived from mesenchymal stem cells, are one of the most promising approaches that have been attempted thus far, as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation. At the same time, advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur, as well as the release of biomolecules facilitating or inducing the reparative processes. This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels. The rationale behind this hypothesis is presented, analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain. This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur. Finally, the importance of including non-human primate models in the clinical translation pipeline, as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive, in vivo, quantifiable imaging-based biomarkers for CNS repair are discussed, aiming for more effective and safe clinical translation of such regenerative therapies to humans. Related Articles | Metrics

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Advances in human stem cell therapies: pre-clinical studies and the outlook for central nervous system regeneration Lindsey H. Forbes, Melissa R. Andrews 2021, 16 (4):  614-617.  doi: 10.4103/1673-5374.295287 Abstract ( 154 )   PDF (604KB) ( 201 )   Save Cell transplantation has come to the forefront of regenerative medicine alongside the discovery and application of stem cells in both research and clinical settings. There are several types of stem cells currently being used for pre-clinical regenerative therapies, each with unique characteristics, benefits and limitations. This brief review will focus on recent basic science advancements made with embryonic stem cells and induced pluripotent stem cells. Both embryonic stem cells and induced pluripotent stem cells provide platforms for new neurons to replace dead and/or dying cells following injury. Due to their capacity for reprogramming and differentiation into any neuronal type, research in preclinical rodent models has shown that embryonic stem cells and induced pluripotent stem cells can integrate, survive and form connections in the nervous system similar to de novo cells. Going forward however, there are some limitations to consider with the use of either stem cell type. Ethically, embryonic stem cells are not an ideal source of cells, genetically, induced pluripotent stem cells are not ideal in terms of personalized treatment for those with certain genetic diseases the latter of which may guide regenerative medicine away from personalized stem cell based therapies and into optimized stem cell banks. Nonetheless, the potential of these stem cells in central nervous system regenerative therapy is only beginning to be appreciated. For example, through genetic modification, stem cells serve as ideal platforms to reintroduce missing or downregulated molecules into the nervous system to further induce regenerative growth. In this review, we highlight the limitations of stem cell based therapies whilst discussing some of the means of overcoming these limitations.  Related Articles | Metrics

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Efficacy of epothilones in central nervous system trauma treatment: what has age got to do with it? Jayden Clark, Zhendan Zhu, Jyoti Chuckowree, Tracey Dickson, Catherine Blizzard 2021, 16 (4):  618-620.  doi: 10.4103/1673-5374.295312 Abstract ( 96 )   PDF (249KB) ( 120 )   Save Central nervous system injury, specifically traumatic brain and spinal cord injury, can have significant long lasting effects. There are no comprehensive treatments to combat the injury and sequalae of events that occurring following a central nervous system trauma. Herein we discuss the potential for the epothilone family of microtubule stabilizing agents to improve outcomes following experimentally induced trauma. These drugs, which are able to cross the blood-brain barrier, may hold great promise for the treatment of central nervous system trauma and the current literature presents the extensive range of beneficial effects these drugs may have following trauma in animal models. Importantly, the effect of the epothilones can vary and our most recent contributions to this field indicate that the efficacy of epothilones following traumatic brain injury is dependent upon the age of the animals. Therefore, we present a case for a greater emphasis to be placed upon age when using an intervention aimed at neural regeneration and highlight the importance of tailoring the therapeutic regime in the clinic to the age of the patient to promote improved patient outcomes. Related Articles | Metrics

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MicroRNAs in laser-induced choroidal neovascularization in mice and rats: their expression and potential therapeutic targets Bridget Martinez, Philip V. Peplow 2021, 16 (4):  621-627.  doi: 10.4103/1673-5374.295271 Abstract ( 127 )   PDF (611KB) ( 145 )   Save Choroidal neovascularization characterizes wet age-related macular degeneration. Choroidal neovascularization formation involves a primarily angiogenic process that is combined with both inflammation and proteolysis. A primary cause of choroidal neovascularization pathogenesis is alterations in pro- and anti-angiogenic factors derived from the retinal pigment epithelium, with vascular endothelium growth factor being mainly responsible for both clinical and experimental choroidal neovascularization. MicroRNAs (miRNAs) which are short, non-coding, endogenous RNA molecules have a major role in regulating various pathological processes, including inflammation and angiogenesis. A review of recent studies with the mouse laser-induced choroidal neovascularization model has shown alterations in miRNA expression in choroidal neovascularization tissues and could be potential therapeutic targets for wet age-related macular degeneration. Upregulation of miR-505 (days 1 and 3 post-laser), miR-155 (day 14) occurred in retina; miR-342-5p (days 3 and 7), miR-126-3p (day 14) in choroid; miR-23a, miR-24, miR-27a (day 7) in retina/choroid; miR-505 (days 1 and 3) in retinal pigment epithelium/choroid; downregulation of miR-155 (days 1 and 3), miR-29a, miR-29b, miR-29c (day 5), miR-93 (day 14), miR-126 (day 14) occurred in retinal pigment epithelium/choroid. Therapies using miRNA mimics or inhibitors were found to decrease choroidal neovascularization lesions. Choroidal neovascularization development was reduced by overexpression of miR-155, miR-188-5p, miR-(5,B,7), miR-126-3p, miR-342-5p, miR-93, miR-126, miR-195a-3p, miR-24, miR-21, miR-31, miR-150, and miR-184, or suppression of miR-505, miR-126-3p, miR-155, and miR-23/27. Further studies are warranted to determine miRNA expression in mouse laser-induced choroidal neovascularization models in order to validate and extend the reported findings. Important experimental variables need to be standardized; these include the strain and age of animals, gender, number and position of laser burns to the eye, laser parameters to induce choroidal neovascularization lesions including wavelength, power, spot size, and duration. Related Articles | Metrics

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The emerging role of probiotics in neurodegenerative diseases: new hope for Parkinson’s disease? Vanessa Castelli, Michele d’Angelo, Massimiliano Quintiliani, Elisabetta Benedetti, Maria Grazia Cifone, Annamaria Cimini 2021, 16 (4):  628-634.  doi: 10.4103/1673-5374.295270 Abstract ( 219 )   PDF (1174KB) ( 247 )   Save Neurodegenerative disease etiology is still unclear, but different contributing factors, such as lifestyle and genetic factors are involved. Altered components of the gut could play a key role in the gut-brain axis, which is a bidirectional system between the central nervous system and the enteric nervous system. Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic, autoimmune, cancer, and, notably, neurodegenerative disorders. Diet can alter the microbiota composition, affecting the gut-brain axis function. Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions, including the use of probiotics. Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry, modulating different pathways. This review will discuss the potential use of probiotics for Parkinson’s disease prevention or treatment or as adjuvant therapy, confirming that gut microbiota modulation influences different pro-survival pathways. Future investigations in Parkinson’s disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary. Related Articles | Metrics

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The phenotypic convergence between microglia and peripheral macrophages during development and neuroinflammation paves the way for new therapeutic perspectives Francesca Grassivaro, Gianvito Martino, Cinthia Farina 2021, 16 (4):  635-637.  doi: 10.4103/1673-5374.295272 Abstract ( 110 )   PDF (591KB) ( 160 )   Save Microglia, the tissue resident macrophages of the brain, are increasingly recognized as key players for central nervous system development and homeostasis. They are long-lived cells deriving from a transient wave of yolk-sac derived erythro-myeloid progenitors early in development. Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation. The first generation of genome-wide expression studies has provided a bundle of transcripts (such as Olfml3, Fcrls, Tmem119, P2ry12, Gpr34, and Siglech) useful to distinguish microglia from peripheral macrophages. However, more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-, and context-dependent manner. In this article, we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions. These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment. This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases. Related Articles | Metrics

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Modeling subcortical ischemic white matter injury in rodents: unmet need for a breakthrough in translational research Yuexian Cui, Xuelian Jin, Jun Young Choi, Byung Gon Kim 2021, 16 (4):  638-642.  doi: 10.4103/1673-5374.295313 Abstract ( 92 )   PDF (512KB) ( 174 )   Save Subcortical ischemic white matter injury (SIWMI), pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging, is a common cause of cognitive decline in elderly. Despite its high prevalence, it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model. The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components. The SIWMI animal models are categorized into 1) chemically induced SIWMI models, 2) vascular occlusive SIWMI models, and 3) SIWMI models with comorbid vascular risk factors. Chemically induced models display consistent lesions in predetermined areas of the white matter, but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities. Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified. When combined with comorbid vascular risk factors (specifically hypertension), however, they can produce progressive and definitive white matter lesions including diffuse rarefaction, demyelination, loss of oligodendrocytes, and glial activation, which are by far the closest to those found in human white matter hyperintensities lesions. However, considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models. In the meantime, in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury. Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.  Related Articles | Metrics

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Hippo signaling: bridging the gap between cancer and neurodegenerative disorders Neha Gogia, Anuradha Venkatakrishnan Chimata, Prajakta Deshpande, Aditi Singh, Amit Singh 2021, 16 (4):  643-652.  doi: 10.4103/1673-5374.295273 Abstract ( 146 )   PDF (3039KB) ( 280 )   Save During development, regulation of organ size requires a balance between cell proliferation, growth and cell death. Dysregulation of these fundamental processes can cause a variety of diseases. Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders. Many signaling pathways known-to-date have a role in growth regulation. Among them, evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development. Neurodegeneration, a complex process of progressive death of neuronal population, results in fatal disorders with no available cure to date.  During normal development, cell death is required for sculpting of an organ. However, aberrant cell death in neuronal cell population can result in neurodegenerative disorders. Hippo pathway has gathered major attention for its role in growth regulation and cancer, however, other functions like its role in neurodegeneration are also emerging rapidly. This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway. Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.  Related Articles | Metrics

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Neurons derived from human-induced pluripotent stem cells express mu and kappa opioid receptors Zhi-Hai Ju, Xuan Liang, Yao-Yao Ren, Luo-Wa Shu, Yan-Hong Yan, Xu Cui 2021, 16 (4):  653-658.  doi: 10.4103/1673-5374.295341 Abstract ( 141 )   PDF (3125KB) ( 204 )   Save Neuroprotection studies have shown that induced pluripotent stem (iPS) cells have the possibility to transform neuroprotection research. In the present study, iPS cells were generated from human renal epithelial cells and were then differentiated into neurons. Cells in the iPS-cell group were maintained in stem cell medium. In contrast, cells in the iPS-neuron group were first maintained in neural induction medium and expansion medium containing ROCK inhibitors, and then cultivated in neuronal differentiation medium and neuronal maturation medium to induce the neural stem cells to differentiate into neurons. The expression of relevant markers was compared at different stages of differentiation. Immunofluorescence staining revealed that cells in the iPS-neuron group expressed the neural stem cell markers SOX1 and nestin on day 11 of induction, and neuronal markers TUBB3 and NeuN on day 21 of induction. Polymerase chain reaction results demonstrated that, compared with the iPS-cell group, TUBB3 gene expression in the iPS-neuron group was increased 15.6-fold. Further research revealed that, compared with the iPS-cell group, the gene expression and immunoreactivity of mu opioid receptor in the iPS-neuron group were significantly increased (38.3-fold and 5.7-fold, respectively), but those of kappa opioid receptor had only a slight change (1.33-fold and 1.57-fold increases, respectively). Together, these data indicate that human iPS cells can be induced into mu opioid receptor- and  kappa opioid receptor-expressing neurons, and that they may be useful to simulate human opioid receptor function in vitro and explore the underlying mechanisms of human conditions. Related Articles | Metrics

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Deciphering the dual role and prognostic potential of PINK1 across cancer types Katherine Dai, Daniel P. Radin, Donna Leonardi 2021, 16 (4):  659-665.  doi: 10.4103/1673-5374.295314 Abstract ( 89 )   PDF (339KB) ( 150 )   Save Metabolic rewiring and deregulation of the cell cycle are hallmarks shared by many cancers. Concerted mutations in key tumor suppressor genes, such as PTEN, and oncogenes predispose cancer cells for marked utilization of resources to fuel accelerated cell proliferation and chemotherapeutic resistance. Mounting research has demonstrated that PTEN-induced putative kinase 1 (PINK1) acts as a pivotal regulator of mitochondrial homeostasis in several cancer types, a function that also extends to the regulation of tumor cell proliferative capacity. In addition, involvement of PINK1 in modulating inflammatory responses has been highlighted by recent studies, further expounding PINK1’s multifunctional nature. This review discusses the oncogenic roles of PINK1 in multiple tumor cell types, with an emphasis on maintenance of mitochondrial homeostasis, while also evaluating literature suggesting a dual oncolytic mechanism based on PINK1’s modulation of the Warburg effect. From a clinical standpoint, its expression may also dictate the response to genotoxic stressors commonly used to treat multiple malignancies. By detailing the evidence suggesting that PINK1 possesses distinct prognostic value in the clinical setting and reviewing the duality of PINK1 function in a context-dependent manner, we present avenues for future studies of this dynamic protein. Related Articles | Metrics

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Transcranial direct current stimulation for auditory verbal hallucinations: a systematic review of clinical trials Samaneh Rashidi, Myles Jones, Eric Murillo-Rodriguez, Sergio Machado, Youguo Hao, Ali Yadollahpour 2021, 16 (4):  666-671.  doi: 10.4103/1673-5374.295315 Abstract ( 119 )   PDF (358KB) ( 192 )   Save Transcranial direct current stimulation (tDCS) has been reportedly beneficial for different neurodegenerative disorders. tDCS has been reported as a potential adjunctive or alternative treatment for auditory verbal hallucination (AVH). This study aims to review the effects of tDCS on AVH in patients with schizophrenia through combining the evidence from randomized clinical trials (RCTs). The databases of PsycINFO (2000–2019), PubMed (2000–2019), EMBASE (2000–2019), CINAHL (2000–2019), Web of Science (2000–2019), and Scopus (2000–2019) were systematically searched. The clinical trials with RCT design were selected for final analysis. A total of nine RCTs were eligible and included in the review. Nine RCTs were included in the final analysis. Among them, six RCTs reported a significant reduction of AVH after repeated sessions of tDCS, whereas three RCTs did not show any advantage of active tDCS over sham tDCS. The current studies showed an overall decrease of approximately 28% of AVH after active tDCS and 10% after sham tDCS. The tDCS protocols targeting the sensorimotor frontal-parietal network showed greater treatment effects compared with the protocols targeting other regions. In this regard, cathodal tDCS over the left temporoparietal area showed inhibitory effects on AVHs. The most effective tDCS protocol on AVHs was twice-daily sessions (2 mA, 20-minute duration) over 5 consecutive days (10 sessions) with the anode over the left dorsolateral prefrontal cortex and the cathode over the left temporal area. Some patient-specific and disease-specific factors such as young age, nonsmoking status, and higher frequencies of AVHs seemed to be the predictors of treatment response. Taken together, the results of tDCS as an alternative treatment option for AVH show controversy among current literatures, since not all studies were positive. However, the studies targeting the same site of the brain showed that the tDCS could be a promising treatment option to reduce AVH. Further RCTs, with larger sample sizes, should be conducted to reach a conclusion on the efficacy of tDCS for AVH and to develop an effective therapeutic protocol for clinical setting.  Related Articles | Metrics

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Prevention and treatment of cerebral palsy with cord blood stem cells and cord-derived mesenchymal stem cells Haruo Shintaku 2021, 16 (4):  672-673.  doi: 10.4103/1673-5374.293139 Abstract ( 97 )   PDF (624KB) ( 112 )   Save Perinatal asphyxia is a well-known medical condition that can lead to CP. Several etiologies are involved in this process, but the primary cause is hypoxic-ischemic encephalopathy (HIE) that is characterized by reduced blood flow and oxygen supply to the baby’s brain. CP is one of the possible consequences of this neurologic injury. Once developed, CP is difficult to treat, and the role of rehabilitation in functional recovery is still limited. The Neonatal Resuscitation Program is one of the various approaches that have been tried to date. The program has been providing training courses since 2006 for midwives and nurses in addition to physicians, and we saw a marked reduction in mortality associated with birth asphyxia just after a year of the program. However, further efforts are required to achieve 0% mortality. Related Articles | Metrics

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Mitochondrial integrity in neuronal injury and repair Qi Han, Xiao-Ming Xu 2021, 16 (4):  674-675.  doi: 10.4103/1673-5374.295317 Abstract ( 162 )   PDF (727KB) ( 145 )   Save The mitochondrion is the powerhouse of a cell. As the principal subcellular organelles that mediate adenosine triphosphate (ATP) production and calcium buffering, mitochondria actively distribute to areas of high energy demand and calcium flux. The highly polarized nerve cells in the central nervous system (CNS), which have unparalleled size and complexity and long-projection axons, are cells with high-energy requirements. Mitochondria are regionally organized within these neurons, with higher accumulations in the soma, the hillock, the nodes of Ranvier, and the axon terminals. In the synaptic region, mitochondria regulate calcium and ATP levels, thereby maintaining synaptic transmission and structure. Defects in mitochondrial dynamics can cause deficits in neuronal transport, transmission, and metabolism (Misgeld and Schwarz, 2017). Related Articles | Metrics

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Sox9 in the developing central nervous system: a jack of all trades? Julia K. Vogel, Michael Wegner 2021, 16 (4):  676-677.  doi: 10.4103/1673-5374.295327 Abstract ( 95 )   PDF (858KB) ( 117 )   Save Neurons and glial cells are the major neuroectodermal cell types of the vertebrate central nervous system (CNS). Their generation from common progenitor cells takes place mostly during embryonic and early postnatal development. After closure of the neural tube, neural epithelial progenitor cells (NEPs) establish the ventricular zone (VZ). By asymmetrical cell division, NEPs first give rise to neuronal precursor cells (NPs) that then differentiate into various types of neurons. Later, NEPs predominantly produce glial precursor cells that become either astroglia or oligodendroglia. Related Articles | Metrics

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Strategies to prevent and detect intraoperative spinal cord ischemia during complex aortic surgery: from drainages and biomarkers Alexander Gombert, Florian Simon 2021, 16 (4):  678-679.  doi: 10.4103/1673-5374.295328 Abstract ( 78 )   PDF (403KB) ( 159 )   Save Spinal cord ischemia (SCI), a frequent complication following open and endovascular thoracoabdominal aortic aneurysm (TAAA) repair, is a feared complication with relevant impact on a patient’s quality of life. In the early days of open TAAA repair, more than one third of the patients suffered from SCI. Nowadays, due to improved preventive measures and the option of staged  endovascular TAAA repair, 10 % of all patients are affected by spinal cord problems after TAAA repair (Rocha et al., 2020). A recently published meta-analysis could not confirm a significant lower rate of SCI after endovascular TAAA repair if compared with open repair. The particular risk factors such as an extended length of covered aortic segments above 20 cm, the placement of endografts between T9–12, the occlusion of the left subclavian or hypogastric arteries, perioperative hypotension and anemia as well as a long total procedure time remain as relevant factors affecting the risk of post-procedural SCI (Tenorio et al., 2019). Recently, preemptive interventional occlusion of intercostal arteries in the area of stent deployment has been described as a possibility to amplify the collateral network of the spinal cord before the covering of relevant arteries (Simon et al., 2020).  Related Articles | Metrics

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Stem cell-derived extracellular vesicles as potential mechanism for repair of microvascular damage within and outside of the central nervous system in amyotrophic lateral sclerosis: perspective schema Svitlana Garbuzova-Davis, Cesario V. Borlongan 2021, 16 (4):  680-681.  doi: 10.4103/1673-5374.294337 Abstract ( 91 )   PDF (1021KB) ( 135 )   Save ALS is a fatal neurodegenerative disease leading to paralysis and eventual death within 3 to 5 years of diagnosis due to respiratory dysfunction. Numerous pathogenic intrinsic and extrinsic effectors are involved in the diffuse motor neuron degeneration. Also, impairment of neurovascular unit components in the brain and spinal cord in ALS patients and in animal models of disease was noted and points to vascular pathology being a key factor in the recognition of ALS as a neurovascular disease (Garbuzova-Davis et al., 2011). Our original (Garbuzova-Davis and Sanberg, 2014) and other studies (Winkler et al., 2014; Kakaroubas et al., 2019) provide convincing evidence on structural and functional alterations of the blood-CNS barrier (B-CNS-B) in ALS, potentially representing an additional pathogenic disease mechanism. Degeneration of endothelial cells (ECs) and astrocyte end-feet processes, reduced pericyte capillary coverage, dysfunction of tight junction proteins, and impairment of endothelial transport system have been shown to compromise B-CNS-B integrity. Vascular leakage and microhemorrhages were also noted in the spinal cord. The weakened barrier function may allow detrimental factors from the systemic circulation to penetrate the CNS and escalate motor neuron degeneration. Additionally, vascular pathologies in ALS were determined not only within, but also outside of the CNS. Recently, we showed damaged microvasculature in the lungs of G93ASOD1 mutant mice at the late stage of disease (Garbuzova-Davis et al., 2020). Numerous microhemorrhages, substantial capillary leakage and even capillary rupture resulting in lung petechiae, potentially via ECs damage, may represent essential effectors towards respiratory dysfunction in ALS. These findings are concurrent with noted capillary alterations within the CNS in both ALS patients and animal models of ALS. Since the damaged capillary endothelium in ALS does not properly maintain vascular homeostasis within and outside of the CNS, repairing the altered endothelium by cell administration may be a new therapeutic approach for this disease.  Related Articles | Metrics

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The important functional role of TDP-43 plays in amyotrophic lateral sclerosis-frontotemporal dementia Liam Chen 2021, 16 (4):  682-683.  doi: 10.4103/1673-5374.293142 Abstract ( 97 )   PDF (618KB) ( 176 )   Save Tar DNA-binding protein 43 (TDP-43, encoded by the gene TARDBP) neuronal and glial inclusions have unified amyotrophic lateral sclerosis (ALS, ~97% of all cases), a fatal adult onset motor neuron disease characterized by the selective loss of upper and lower motor neurons, and frontotemporal dementia (FTD, and sporadic FTD (~45% of all cases), a common form of dementia characterized by progressive deterioration in behavior, personality and/or language, into one disease spectrum. Although the majority of ALS-FTD cases are sporadic, identification of mutations in the TARDBP gene that cause familial ALS, strongly supports the idea that TDP-43 participates in the pathogenesis of ALS-FTD, not merely a secondary phenomenon. That several other genes associated with familial ALS and FTD, including C9ORF72, converge on TDP-43 proteinopathy as a key neuropathological hallmark further strengthens this view. In addition, TDP-43 has been implicated in other major forms of neurodegenerative disorders such as Alzheimer’s disease (AD) (Josephs et al., 2014), chronic traumatic encephalopathy (Chen, 2018) and multiple system atrophy (Koga et al., 2018). Although strong evidence supports an essentially linear progression of disease triggered by β-amyloid (Aβ) in familial AD, the evidence in sporadic AD cases supports a more multifactorial etiology. While extracellular neuritic plaques and intracellular tau neurofibrillary tangles are well-recognized canonical hallmarks for AD, TDP-43-positive inclusions have recently been identified in 30–70% of brains with pathologically diagnosed AD (Josephs et al., 2014). The morphological characteristics of the TDP-43 deposition are similar across different regions of the brain, predominantly neuronal cytoplasmic inclusions; less commonly dystrophic neurites and only rarely intranuclear inclusions. However, the TDP-43 burden in AD appears to follow a stereotypic topographic progression different from that in ALS-FTD. Importantly, greater cognitive impairment and medial temporal atrophy are associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 pathology-positive subjects are 10 times more likely to be cognitively impaired at death compared to TDP-43-pathology negative cases (Josephs et al., 2014). Related Articles | Metrics

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Regulation of Parkin-dependent mitophagy by Bcl-2-associated athanogene (BAG) family members Minesh Kapadia, Mitchell L. De Snoo, Lorraine V. Kalia, Suneil K. Kalia 2021, 16 (4):  684-685.  doi: 10.4103/1673-5374.295330 Abstract ( 90 )   PDF (489KB) ( 148 )   Save Mitochondria are essential organelles that play a central role in cellular metabolism and physiology. Their broad range of functions include supplying energy, regulating signaling pathways, and maintaining control of cell proliferation and apoptosis. As defective mitochondria can perturb cellular homeostasis, quality control mechanisms have evolved to preserve mitochondrial fidelity in response to stress and aging (Palikaras et al., 2018). Persistent defects, however, trigger elimination of the entire organelle by an evolutionarily conserved set of cellular processes that specifically remove dysfunctional or surplus mitochondria. This selective degradation of the mitochondria through autophagy, termed mitophagy, is important in fine-tuning mitochondrial number, integrity and ultimately function. Mitophagy impairments can cause progressive accumulation of defective mitochondria, particularly in terminally differentiated post-mitotic cells, like neurons, which remain alive and functional for decades. The ensuing rise in oxidative stress and aggregation of proteins is likely to contribute to tissue damage linked to a broad spectrum of pathological conditions, such as neurodegenerative diseases, myopathies, inflammation, metabolic disorders and cancer (Palikaras et al., 2018). Despite major milestones in the mitophagy field within the last decade, important questions regarding the in vivo role of specific components, their interplay in different mitophagy pathways and their spatiotemporal regulation in distinct physiological and pathological contexts remain unanswered (Pickles et al., 2018). This short perspective will focus on recent advances towards elucidating the molecular mechanisms that govern mitophagy and downstream cell fate decisions, with specific attention to the potential contribution of the co-chaperone Bcl-2-associated athanogene (BAG) protein family focusing on BAG5 in Parkinson’s disease (PD), ischemia and aging-associated inflammation. Related Articles | Metrics

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Mitochondrial bioenergetics and neurodegeneration: a paso doble Alice Rossi, Paola Pizzo 2021, 16 (4):  686-687.  doi: 10.4103/1673-5374.295331 Abstract ( 99 )   PDF (822KB) ( 158 )   Save The brain is one of the highest energy demanding organs, consuming ~20% of the total ATP produced by the whole body. Importantly, neurons mainly rely on ATP synthesized by mitochondrial bioenergetics and neuronal activity is strictly dependent on specific mitochondrial localization at synapses, sites consuming a high amount of energy requested for both pre- and post-synaptic processes. Here, mitochondria produce ATP and buffer Ca2+ rises, two essential processes for neurotransmission and generation of membrane potential along the axon (Magistretti and Allaman, 2015).  Related Articles | Metrics

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Impact of the metabolic syndrome on the evolution of neurodegenerative diseases Ana Paula de A. Boleti, Jeeser Alves Almeida, Ludovico Migliolo 2021, 16 (4):  688-689.  doi: 10.4103/1673-5374.295329 Abstract ( 87 )   PDF (565KB) ( 171 )   Save Metabolic syndrome (MetS) might be defined as the simultaneous accumulation of several functional changes that frequently occur in adults over 60 years of age (Gomez et al., 2018). The diagnosis of MetS requires the presence of three or more factors such as high body mass, type-2 diabetes mellitus (T2DM), dyslipidemia, and arterial hypertension, which increase the risk of cardiovascular diseases as well as neurological complications, as stroke and dementia (Dyken and Lacoste, 2018). Usually, these functional changes coincide and result in insensitivity for example hormones as leptin, adiponectin, and insulin (Dyken and Lacoste, 2018).  Related Articles | Metrics

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Analysis of corneal nerve plexus in corneal confocal microscopy images Yu-Chi Liu, Molly Tzu-Yu Lin, Jodhbir S. Mehta 2021, 16 (4):  690-691.  doi: 10.4103/1673-5374.289435 Abstract ( 142 )   PDF (782KB) ( 132 )   Save Small Aδ and C nerve fibers of the sensory and autonomic nervous systems constitute 70–90% of peripheral nerve fibers including corneal nerves (Muller et al., 2003). Corneal nerves originate from the ophthalmic branch of the trigeminal nerve and enter the cornea at the limbus radially from all directions toward the central cornea at the level of anterior and middle stroma. The subepithelial nerve plexus lies at the interface between the Bowman layer and anterior stroma. They then divide into smaller branches and turn 90° toward Bowman’s layer (Muller et al., 2003), travelling between Bowman’s layer and the basal epithelial layer and forming the sub-basal nerve plexus (Muller et al., 2003). Innervation of the cornea is comprised almost entirely of unmyelinated type C nerve fibers, with the fiber width ranging between 0.2–2.0 μm. Corneal nerves not only provide important sensory function but also maintain the functional integrity of the ocular surface by releasing trophic substances that promote corneal epithelial homeostasis and by activating brainstem circuits that stimulate reflex tear production and blinking (Marfurt et al., 2010). Disruption of corneal nerves result in reduced or absent corneal sensations as well as negative impacts on the ocular surface integrity and tear film dynamics, leading to dry eye symptoms, corneal epithelial breakdown, and neurotrophic keratopathy (Al-Aqaba et al., 2019).  Related Articles | Metrics

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Patterning inconsistencies restrict the true potential of dopaminergic neurons derived from human induced pluripotent stem cells  Sameehan Mahajani, Mathias Bähr, Sebastian Kügler 2021, 16 (4):  692-693.  doi: 10.4103/1673-5374.295316 Abstract ( 95 )   PDF (224KB) ( 149 )   Save Human induced pluripotent stem cells (hiPSCs) are multipotent stem cells genetically reprogrammed using transcription factors, such as Sox2, c-Myc, Oct3/4 and Klf4 (Takahashi and Yamanaka, 2006) from fibroblasts, derived from either patient or control individuals. These factors are highly expressed in embryonic stem cells, and their overexpression can induce pluripotency in human somatic cells such as fibroblasts. Upon the generation of hiPSCs after reprogramming, these cells can be further differentiated into multiple neuronal cell types by using a strictly designed protocol. This process is known as patterning. Correct use of these hiPSCs derived neurons holds immense potential for researchers to uncover the underpinnings of disease pathophysiology and therefore is considered as a powerful tool. For example, in the context of Parkinson’s disease (PD), numerous publications have highlighted the aggregation of an abnormally folded protein, α-Synuclein that forms intracellular inclusions in the cell body and neurite processes known as Lewy bodies. However, the mechanisms that cause neurodegeneration specifically in dopaminergic neurons as compared to other neuronal subtypes are still unknown. Unfortunately, it is rather difficult to culture genuine dopaminergic neurons from rodent embryos in sufficient amounts. Therefore, generating human dopaminergic or glutamatergic neurons from hiPSCs to determine the selective detrimental effect of α-Synuclein could offer an immensely valuable outlook. The use of hiPSCs derived dopaminergic neurons could enable us to decipher the pathophysiological mechanisms of this selective neurodegeneration in an in-vitro culture system. However, there are several inconsistences in the field of hiPSCs derived dopaminergic neurons, which need to be addressed in order to generate reliable, reproducible and efficient protocols for their patterning. References | Related Articles | Metrics

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Nerve growth factor in muscle afferent neurons of peripheral artery disease and autonomic function Lu Qin, Jianhua Li 2021, 16 (4):  694-699.  doi: 10.4103/1673-5374.293132 Abstract ( 80 )   PDF (904KB) ( 182 )   Save In peripheral artery disease patients, the blood supply directed to the lower limbs is reduced. This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs. The painful perception is induced and exaggerate during walking, and is relieved by rest. This symptom is termed by intermittent claudication. The limb ischemia also amplifies autonomic responses during exercise. In the process of pain and autonomic responses originating exercising muscle, a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses. This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle. For the sensory nerve receptors, we emphasize the role played by transient receptor potential vanilloid type 1, purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.  Related Articles | Metrics

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Modeling protein-protein interactions in axon initial segment to understand their potential impact on action potential initiation Piyush Bhardwaj, Don Kulasiri, Sandhya Samarasinghe 2021, 16 (4):  700-706.  doi: 10.4103/1673-5374.295332 Abstract ( 107 )   PDF (1720KB) ( 136 )   Save The axon initial segment (AIS) region is crucial for action potential initiation due to the presence of high-density AIS protein voltage-gated sodium channels (Nav). Nav channels comprise several serine residues responsible for the recruitment of Nav channels into the structure of AIS through interactions with ankyrin-G (AnkG). In this study, a series of computational experiments are performed to understand the role of AIS proteins casein kinase 2 and AnkG on Nav channel recruitment into the AIS. The computational simulation results using Virtual cell software indicate that Nav channels with all serine sites available for phosphorylation bind to AnkG with strong affinity. At the low initial concentration of AnkG and casein kinase 2, the concentration of Nav channels reduces significantly, suggesting the importance of casein kinase 2 and AnkG in the recruitment of Nav channels.  Related Articles | Metrics

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Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial Li-Qiong Yuan, Qing Zeng, Dan Wang, Xiu-Yun Wen, Yu Shi, Fen Zhu, Shang-Jie Chen, Guo-Zhi Huang 2021, 16 (4):  707-713.  doi: 10.4103/1673-5374.295345 Abstract ( 182 )   PDF (1388KB) ( 268 )   Save Individuals with amnestic mild cognitive impairment (aMCI) have a high risk of developing Alzheimer’s disease. Although repetitive transcranial magnetic stimulation (rTMS) is considered a potentially effective treatment for cognitive impairment in patients with aMCI, the neuroimaging mechanisms are poorly understood. Therefore, we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University, China. Twenty-four patients with aMCI were randomly assigned to receive true rTMS (treatment group, n = 12, 6 men and 6 women; age 65.08 ± 4.89 years) or sham stimulation (sham group, n = 12, 5 men and 7 women; age 64.67 ± 4.77 years). rTMS parameters included a stimulation frequency of 10 Hz, stimulation duration of 2 seconds, stimulation interval of 8 seconds, 20 repetitions at 80% of the motor threshold, and 400 pulses per session. rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks. Our results showed that compared with baseline, Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation (ALFF) was significantly increased at the end of treatment and 1 month after treatment. Compared with the sham group, the ALFF values in the right inferior frontal gyrus, triangular part of the inferior frontal gyrus, right precuneus, left angular gyrus, and right supramarginal gyrus were significantly increased, and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group. These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas. This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University, China (approval No. BYL20190901) on September 3, 2019 and registered in the Chinese Clinical Trials Registry (registration No. ChiCTR1900028180) on December 14, 2019. Related Articles | Metrics

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Caveolin-1 downregulation promotes the dopaminergic neuron-like differentiation of human adipose-derived mesenchymal stem cells Chao Han, Ya-Jun Wang, Ya-Chen Wang, Xin Guan, Liang Wang, Li-Ming Shen, Wei Zou, Jing Liu 2021, 16 (4):  714-720.  doi: 10.4103/1673-5374.295342 Abstract ( 92 )   PDF (2965KB) ( 159 )   Save Previous studies have shown that caveolin-1 is involved in regulating the differentiation of mesenchymal stem cells. However, its role in the differentiation of human adipose mesenchymal stem cells into dopaminergic neurons remains unclear. The aim of this study was to investigate whether caveolin-1 regulates the differentiation of human adipose mesenchymal stem cells into dopaminergic-like neurons. We also examined whether the expression of caveolin-1 could be modulated by RNA interference technology to promote the differentiation of human adipose mesenchymal stem cells into dopaminergic-like neurons. The differentiation of human adipose mesenchymal stem cells into dopaminergic neurons was evaluated morphologically and by examining expression of the markers tyrosine hydroxylase, Lmx1a and Nurr1. The analyses revealed that during the differentiation of human adipose mesenchymal stem cells into dopaminergic neurons, the expression of caveolin-1 is decreased. Notably, the downregulation of caveolin-1 promoted the differentiation of human adipose mesenchymal stem cells into dopaminergic-like neurons, and it increased the expression of tyrosine hydroxylase, Lmx1a and Nurr1. Together, our findings suggest that caveolin-1 plays a negative regulatory role in the differentiation of dopaminergic-like neurons from stem cells, and it may therefore be a potential molecular target for strategies for regulating the differentiation of these cells. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Dalian Medical University of China (approval No. PJ-KS-KY-2020-54) on March 7, 2017. Related Articles | Metrics

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Batroxobin inhibits astrocyte activation following nigrostriatal pathway injury  Zhuo Zhang, Xue Bao, Dan Li 2021, 16 (4):  721-726.  doi: 10.4103/1673-5374.295343 Abstract ( 133 )   PDF (2015KB) ( 175 )   Save Batroxobin is a thrombin-like serine protease from the venom of the Bothrops atrox and Bothrops moojeni snake species. Sirtuin 1 (Sirt1) has been shown to play an important role in neuroprotection after traumatic brain injury. However, its underlying mechanism of action remains poorly understood. The purpose of this study was to investigate whether the mechanism by which batroxobin participates in the activation of astrocytes is associated with Sirt1. Mouse models of nigrostriatal pathway injury were established. Immediately after modeling, mice were intraperitoneally administered 39 U/kg batroxobin. Batroxobin significantly reduced the expression of cleaved caspase-3 in both the substantia nigra and striatum, inhibited neuronal apoptosis, and promoted the recovery of rat locomotor function. These changes coincided with a remarkable reduction in astrocyte activation. Batroxobin also reduced Sirt1 expression and extracellular signal-regulated kinase activation in brain tissue. Intraperitoneal administration of the Sirt1-specific inhibitor EX527 (5 mg/kg) 30 minutes prior to injury could inhibit the abovementioned effects. In mouse astrocyte cultures, 1 ng/mL batroxobin attenuated interleukin-1β-induced activation of astrocytes and extracellular signal-regulated kinase. EX527 could also inhibit the effects of batroxobin. These findings suggest that batroxobin inhibits astrocyte activation after nigrostriatal pathway injury through the Sirt1 pathway. This study was approved by the Animal Ethics Committee of China Medical University, China (approval No. CMU2020037) on July 19, 2015.  Related Articles | Metrics

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Abnormal Glu/mGluR2/3/PI3K pathway in the hippocampal neurovascular unit leads to diabetes-related depression Jian Liu, Yuan-Shan Han, Lin Liu, Lin Tang, Hui Yang, Pan Meng, Hong-Qing Zhao, Yu-Hong Wang 2021, 16 (4):  727-733.  doi: 10.4103/1673-5374.296418 Abstract ( 176 )   PDF (3196KB) ( 233 )   Save Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression, and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetes-related depression. However, the underlying mechanism remains unclear. We hypothesized that diabetes-related depression might be associated with the glutamate (Glu)/metabotropic glutamate receptor2/3 (mGluR2/3)/phosphoinositide 3-kinase (PI3K) pathway, activated by glucocorticoid receptors in the hippocampal neurovascular unit. To test this hypothesis, rat hippocampal neurovascular unit models, containing hippocampal neurons, astrocytes, and brain microvascular endothelial cells, were treated with 150 mM glucose and 200 µM corticosterone, to induce diabetes-related depression. Our results showed that under conditions of diabetes complicated by depression, hippocampal neurovascular units were damaged, leading to decreased barrier function; elevated Glu levels; upregulated glucocorticoid receptor, vesicular glutamate transporter 3 (VGLUT-3), and metabotropic glutamate receptor 2/3 (mGluR2/3) expression; downregulated excitatory amino acid transporter 1 (EAAT-1) expression; and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase (ERK)/glial cell-derived neurotrophic factor (GDNF)/PI3K signaling pathway. Moreover, the viability of neurons was dramatically reduced in the model of diabetes-related depression, and neuronal apoptosis, and caspase-3 and caspase-9 expression levels, were increased. Our results suggest that the Glu/mGluR2/3/PI3K pathway, induced by glucocorticoid receptor activation in the hippocampal neurovascular unit, may be associated with diabetes-related depression. This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine, China (approval No. HN-ZYFY-2019-11-12) on November 12, 2019. Related Articles | Metrics

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Altered electroencephalographic networks in developmental dyslexia after remedial training: a prospective case-control study Juliana A. Dushanova, Stefan A. Tsokov 2021, 16 (4):  734-743.  doi: 10.4103/1673-5374.295334 Abstract ( 134 )   PDF (1335KB) ( 212 )   Save Electroencephalographic studies using graph theoretic analysis have found aberrations in functional connectivity in children with developmental dyslexia. However, how the training with visual tasks can change the functional connectivity of the semantic network in developmental dyslexia is still unclear. We looked for differences in local and global topological properties of functional networks between 21 healthy controls and 22 dyslexic children (8–9 years old) before and after training with visual tasks in this prospective case-control study. The minimum spanning tree method was used to construct the subjects’ brain networks in multiple electroencephalographic frequency ranges during a visual word/pseudoword discrimination task. We found group differences in the theta, alpha, beta and gamma bands for four graph measures suggesting a more integrated network topology in dyslexics before the training compared to controls. After training, the network topology of dyslexic children had become more segregated and similar to that of the controls. In the θ, α and β1-frequency bands, compared to the controls, the pre-training dyslexics exhibited a reduced degree and betweenness centrality of the left anterior temporal and parietal regions. The simultaneous appearance in the left hemisphere of hubs in temporal and parietal (α, β1), temporal and superior frontal cortex (θ, α), parietal and occipitotemporal cortices (β1), identified in the networks of normally developing children was not present in the brain networks of dyslexics. After training, the hub distribution for dyslexics in the theta and beta1 bands had become similar to that of the controls. In summary, our findings point to a less efficient network configuration in dyslexics compared to a more optimal global organization in the controls. This is the first study to investigate the topological organization of functional brain networks of Bulgarian dyslexic children. Approval for the study was obtained from the Ethics Committee of the Institute of Neurobiology and the Institute for Population and Human Studies, Bulgarian Academy of Sciences (approval No. 02-41/12.07.2019) on March 28, 2017, and the State Logopedic Center and the Ministry of Education and Science (approval No. 09-69/14.03.2017) on July 12, 2019. Related Articles | Metrics

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Synaptic remodeling in mouse motor cortex after spinal cord injury Ke-Xue Zhang, Jia-Jia Zhao, Wei Chai, Ji-Ying Chen 2021, 16 (4):  744-749.  doi: 10.4103/1673-5374.295346 Abstract ( 123 )   PDF (1416KB) ( 248 )   Save Spinal cord injury dramatically blocks information exchange between the central nervous system and the peripheral nervous system. The resulting fate of synapses in the motor cortex has not been well studied. To explore synaptic reorganization in the motor cortex after spinal cord injury, we established mouse models of T12 spinal cord hemi-section and then monitored the postsynaptic dendritic spines and presynaptic axonal boutons of pyramidal neurons in the hindlimb area of the motor cortex in vivo. Our results showed that spinal cord hemi-section led to the remodeling of dendritic spines bilaterally in the motor cortex and the main remodeling regions changed over time. It made previously stable spines unstable and eliminated spines more unlikely to be re-emerged. There was a significant increase in new spines in the contralateral motor cortex. However, the low survival rate of the new spines demonstrated that new spines were still fragile. Observation of presynaptic axonal boutons found no significant change. These results suggest the existence of synapse remodeling in motor cortex after spinal cord hemi-section and that spinal cord hemi-section affected postsynaptic dendritic spines rather than presynaptic axonal boutons. This study was approved by the Ethics Committee of Chinese PLA General Hospital, China (approval No. 201504168S) on April 16, 2015. Related Articles | Metrics

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Lineage tracing of direct astrocyte-to-neuron conversion in the mouse cortex Zongqin Xiang, Liang Xu, Minhui Liu, Qingsong Wang, Wen Li, Wenliang Lei, Gong Chen 2021, 16 (4):  750-756.  doi: 10.4103/1673-5374.295925 Abstract ( 166 )   PDF (2798KB) ( 746 )   Save Regenerating functional new neurons in the adult mammalian central nervous system has been proven to be very challenging due to the inability of neurons to divide and repopulate themselves after neuronal loss. Glial cells, on the other hand, can divide and repopulate themselves under injury or diseased conditions. We have previously reported that ectopic expression of NeuroD1 in dividing glial cells can directly convert them into neurons. Here, using astrocytic lineage-tracing reporter mice (Aldh1l1-CreERT2 mice crossing with Ai14 mice), we demonstrate that lineage-traced astrocytes can be successfully converted into NeuN-positive neurons after expressing NeuroD1 through adeno-associated viruses. Retroviral expression of NeuroD1 further confirms that dividing glial cells can be converted into neurons. Importantly, we demonstrate that for in vivo cell conversion study, using a safe level of adeno-associated virus dosage (1010–1012 gc/mL, 1 µL) in the rodent brain is critical to avoid artifacts caused by toxic dosage, such as that used in a recent bioRxiv study  (2 × 1013 gc/mL, 1 µL, mouse cortex). For therapeutic purpose under injury or diseased conditions, or for non-human primate studies, adeno-associated virus dosage needs to be optimized through a series of dose-finding experiments. Moreover, for future in vivo glia-to-neuron conversion studies, we recommend that the adeno-associated virus results are further verified with retroviruses that mainly express transgenes in dividing glial cells in order to draw solid conclusions. The study was approved by the Laboratory Animal Ethics Committee of Jinan University, China (approval No. IACUC-20180330-06) on March 30, 2018. Related Articles | Metrics

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Exogenous platelet-derived growth factor improves neurovascular unit recovery after spinal cord injury Lu-Xia Ye, Ning-Chen An, Peng Huang, Duo-Hui Li, Zhi-Long Zheng, Hao Ji, Hao Li, Da-Qing Chen, Yan-Qing Wu, Jian Xiao, Ke Xu, Xiao-Kun Li, Hong-Yu Zhang 2021, 16 (4):  757-763.  doi: 10.4103/1673-5374.295347 Abstract ( 156 )   PDF (4490KB) ( 166 )   Save The blood-spinal cord barrier plays a vital role in recovery after spinal cord injury. The neurovascular unit concept emphasizes the relationship between nerves and vessels in the brain, while the effect of the blood-spinal cord barrier on the neurovascular unit is rarely reported in spinal cord injury studies. Mouse models of spinal cord injury were established by heavy object impact and then immediately injected with platelet-derived growth factor (80 μg/kg) at the injury site. Our results showed that after platelet-derived growth factor administration, spinal cord injury, neuronal apoptosis, and blood-spinal cord barrier permeability were reduced, excessive astrocyte proliferation and the autophagy-related apoptosis signaling pathway were inhibited, collagen synthesis was increased, and mouse locomotor function was improved. In vitro, human umbilical vein endothelial cells were established by exposure to 200 μM H2O2. At 2 hours prior to injury, in vitro cell models were treated with 5 ng/mL platelet-derived growth factor. Our results showed that expression of blood-spinal cord barrier-related proteins, including Occludin, Claudin 5, and β-catenin, was significantly decreased and autophagy was significantly reduced. Additionally, the protective effects of platelet-derived growth factor could be reversed by intraperitoneal injection of 80 mg/kg chloroquine, an autophagy inhibitor, for 3 successive days prior to spinal cord injury. Our findings suggest that platelet-derived growth factor can promote endothelial cell repair by regulating autophagy, improve the function of the blood-spinal cord barrier, and promote the recovery of locomotor function post-spinal cord injury. Approval for animal experiments was obtained from the Animal Ethics Committee, Wenzhou Medical University, China (approval No. wydw2018-0043) in July 2018. Related Articles | Metrics

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LncRNA Airsci increases the inflammatory response after spinal cord injury in rats through the nuclear factor kappa B signaling pathway Tao Zhang, Kang Li, Zi-Lu Zhang, Kai Gao, Chao-Liang Lv 2021, 16 (4):  764-769.  doi: 10.4103/1673-5374.295335 Abstract ( 66 )   PDF (2118KB) ( 202 )   Save Spinal cord injury (SCI) is a serious traumatic event to the central nervous system. Studies show that long non-coding RNAs (lncRNAs) play an important role in regulating the inflammatory response in the acute stage of SCI. Here, we investigated a new lncRNA related to spinal cord injury and acute inflammation. We analyzed the expression profile of lncRNAs after SCI, and explored the role of lncRNA Airsci (acute inflammatory response in SCI) on recovery following acute SCI. The rats were divided into the control group, SCI group, and SCI + lncRNA Airsci-siRNA group. The expression of inflammatory factors, including nuclear factor kappa B [NF-κB (p65)], NF-κB inhibitor IκBα and phosphorylated IκBα (p-IκBα), and the p-IκBα/IκBα ratio were examined 1–28 days after SCI in rats by western blot assay. The differential lncRNA expression profile after SCI was assessed by RNA sequencing. The differentially expressed lncRNAs were analyzed by bioinformatics technology. The differentially expressed lncRNA Airsci, which is involved in NF-κB signaling and associated with the acute inflammatory response, was verified by quantitative real-time PCR. Interleukin (IL-1β), IL-6 and tumor necrosis factor (TNF-α) at 3 days after SCI were measured by western blot assay and quantitative real-time PCR. The histopathology of the spinal cord was evaluated by hematoxylin-eosin and Nissl staining. Motor function was assessed with the Basso, Beattie and Bresnahan Locomotor Rating Scale. Numerous differentially expressed lncRNAs were detected after SCI, including 151 that were upregulated and 186 that were downregulated in the SCI 3 d group compared with the control group. LncRNA Airsci was the most significantly expressed among the five lncRNAs involved in the NF-κB signaling pathway. LncRNA Airsci-siRNA reduced the inflammatory response by inhibiting the NF-κB signaling pathway, alleviated spinal cord tissue injury, and promoted the recovery of motor function in SCI rats. These findings show that numerous lncRNAs are differentially expressed following SCI, and that inhibiting lncRNA Airsci reduces the inflammatory response through the NF-κB signaling pathway, thereby promoting functional recovery. All experimental procedures and protocols were approved by the approved by the Animal Ethics Committee of Jining Medical University (approval No. JNMC-2020-DW-RM-003) on January 18, 2020. Related Articles | Metrics

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Comparison of cerebral activation between motor execution and motor imagery of self-feeding activity Moemi Matsuo, Naoki Iso, Kengo Fujiwara, Takefumi Moriuchi, Daiki Matsuda, Wataru Mitsunaga, Akira Nakashima, Toshio Higashi 2021, 16 (4):  770-774.  doi: 10.4103/1673-5374.295333 Abstract ( 97 )   PDF (735KB) ( 167 )   Save Motor imagery is defined as an act wherein an individual contemplates a mental action of motor execution without apparent action. Mental practice executed by repetitive motor imagery can improve motor performance without simultaneous sensory input or overt output. We aimed to investigate cerebral hemodynamics during motor imagery and motor execution of a self-feeding activity using chopsticks. This study included 21 healthy right-handed volunteers. The self-feeding activity task comprised either motor imagery or motor execution of eating sliced cucumber pickles with chopsticks to examine eight regions of interest: pre-supplementary motor area, supplementary motor area, bilateral prefrontal cortex, premotor area, and sensorimotor cortex. The mean oxyhemoglobin levels were detected using near-infrared spectroscopy to reflect cerebral activation. The mean oxyhemoglobin levels during motor execution were significantly higher in the left sensorimotor cortex than in the supplementary motor area and the left premotor area. Moreover, significantly higher oxyhemoglobin levels were detected in the supplementary motor area and the left premotor area during motor imagery, compared to motor execution. Supplementary motor area and premotor area had important roles in the motor imagery of self-feeding activity. Moreover, the activation levels of the supplementary motor area and the premotor area during motor execution and motor imagery are likely affected by intentional cognitive processes. Levels of cerebral activation differed in some areas during motor execution and motor imagery of a self-feeding activity. This study was approved by the Ethical Review Committee of Nagasaki University (approval No. 18110801) on December 10, 2018. Related Articles | Metrics

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Regulated upon activation, normal T cell expressed and secreted (RANTES) levels in the peripheral blood of patients with Alzheimer’s disease Gabriela Vacínová, Daniela Vejražkova, Robert Rusina, Iva Holmerová, Hana Vaňková, Eva Jarolímová, Josef Včelák, Běla Bendlová, Markéta Vaňková 2021, 16 (4):  775-779.  doi: 10.4103/1673-5374.295340 Abstract ( 132 )   PDF (309KB) ( 161 )   Save Alzheimer’s disease (AD) is the most common type of dementia, but it is very difficult to diagnose with certainty, so many AD studies have attempted to find early and relevant diagnostic markers. Regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand) is a chemokine involved in the migration of T cells and other lymphoid cells. Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases, such as Parkinson’s disease and multiple sclerosis, but also in metabolic diseases in which inflammation plays a role. The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD. Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD (median 8.5 months after diagnosis; 39 men and 46 women; average age 75.7 years), and in 78 control subjects (24 men and 54 women; average age 66 years). We found much higher plasma levels of RANTES in AD patients compared to controls. A negative correlation of RANTES levels with age, disease duration, Fazekas scale score, and the medial temporal lobe atrophy (MTA) score (Scheltens’s scale) was found in AD patients, i.e., the higher levels corresponded to earlier stages of the disease. Plasma RANTES levels were not correlated with cognitive scores. In AD patients, RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which is consistent with the well-known fact that AD is associated with inflammatory processes. RANTES levels were also positively correlated with insulin levels in AD patients, with insulin resistance (HOMA-R) and pancreatic beta cell function (HOMA-F). This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES, but these factors could not explain the increases in RANTES levels observed in AD patients. Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD. The study was approved by the Ethics Committee of Institute of Endocrinology, Prague, Czech Republic on July 22, 2011. Related Articles | Metrics

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Co-nanoencapsulated meloxicam and curcumin improves cognitive impairment induced by amyloid-beta through modulation of cyclooxygenase-2 in mice#br# Maria Eduarda Ziani Gutierrez, Anne Suély Pinto Savall, Edina da Luz Abreu, Kelly Ayumi Nakama, Renata Bem Dos Santos, Marina Costa Monteiro Guedes, Daiana Silva Ávila, Cristiane Luchese, Sandra Elisa Haas, Caroline Brandão Quines, Simone Pinton 2021, 16 (4):  780-786.  doi: 10.4103/1673-5374.295339 Abstract ( 111 )   PDF (1043KB) ( 208 )   Save Alzheimer’s disease is a progressive brain disorder and complex mechanisms are involved in the physiopathology of Alzheimer’s disease. However, there is data suggesting that inflammation plays a role in its development and progression. Indeed, some non-steroidal anti-inflammatory drugs, such as meloxicam, which act by inhibiting cyclooxygenase-2 have been used as neuroprotective agents in different neurodegenerative disease models. The purpose of this study was to investigate the effects of co-nanoencapsulated curcumin and meloxicam in lipid core nanocapsules (LCN) on cognitive impairment induced by amyloid-beta peptide injection in mice. LCN were prepared by the nanoprecipitation method. Male Swiss mice received a single intracerebroventricular injection of amyloid-beta peptide aggregates (fragment 25–35, 3 nmol/3 μL) or vehicle and were subsequently treated with curcumin-loaded LCN (10 mg/kg) or meloxicam-loaded LCN (5 mg/kg) or meloxicam + curcumin-co-loaded LCN (5 and 10 mg/kg, respectively). Treatments were given on alternate days for 12 days (i.e., six doses, once every 48 hours, by intragastric gavage). Our data showed that amyloid-beta peptide infusion caused long-term memory deficits in the inhibitory avoidance and object recognition tests in mice. In the inhibitory avoidance test, both meloxicam and curcumin formulations (oil or co-loaded LCN) improved amyloid-beta-induced memory impairment in mice. However, only meloxicam and curcumin-co-loaded LCN attenuated non-aversive memory impairment in the object recognition test. Moreover, the beneficial effects of meloxicam and curcumin-co-loaded LCN could be explained by the anti-inflammatory properties of these drugs through cortical cyclooxygenase-2 downregulation. Our study suggests that the neuroprotective potential of meloxicam and curcumin co-nanoencapsulation is associated with cortical cyclooxygenase-2 modulation. This study was approved by the Committee on Care and Use of Experimental Animal Resources, the Federal University of Pampa, Brazil (approval No. 02-2015) on April 16, 2015.  Related Articles | Metrics

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Melatonin ameliorates microvessel abnormalities in the cerebral cortex and hippocampus in a rat model of Alzheimer’s disease Pan Wang, Hai-Juan Sui, Xiao-Jia Li, Li-Na Bai, Jing Bi, Hong Lai 2021, 16 (4):  787-794.  doi: 10.4103/1673-5374.295349 Abstract ( 227 )   PDF (6660KB) ( 265 )   Save Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury, but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities. Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloid-beta 1–42, administered once every other day. Melatonin (30 mg/kg) was intraperitoneally administered for 13 successive days, with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42. Melatonin ameliorated learning and memory impairments in the Morris water maze test, improved the morphology of microvessels in the cerebral cortex and hippocampus, increased microvessel density, alleviated pathological injuries of cerebral neurons, and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2. These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors, thereby improving the cognitive function of patients with Alzheimer’s disease. This study was approved by the Animal Care and Use Committee of Jinzhou Medical University, China (approval No. 2019015) on December 6, 2018. Related Articles | Metrics

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Association between plasma immunoproteasome and 90-day prognosis after first-ever ischemic stroke Xing-Yong Chen, Ming Fu, Shao-Fen Wan, Xu Zhang, Yin-Zhou Wang 2021, 16 (4):  795-800.  doi: 10.4103/1673-5374.295344 Abstract ( 108 )   PDF (462KB) ( 182 )   Save Many blood biomarkers are reportedly helpful for predicting post-stroke cognitive impairment (PSCI), but no biomarkers are widely used in clinical practice. The purpose of this study was to investigate the association between the plasma immunoproteasome and patients’ 90-day prognosis after first-ever acute ischemic stroke. In our prospective, single-center study, 259 patients with first-ever acute ischemic stroke were enrolled from the Department of Neurology, Fujian Provincial Hospital, China, from March to September 2014. Of these, 27 patients (10.4%) had unfavorable outcomes as assessed by the Modified Rankin Scale (scores of 3–6). The National Institutes of Health Stroke Scale score on admission, plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels, and immunopro-teasome subunit (low molecular mass peptide [LMP]2, LMP5, and LMP7) levels were significantly higher in the unfavorable outcome group than in the favorable outcome group. To predict unfavorable outcomes, the optimal cutoff points were National Institutes of Health Stroke Scale score > 12, NT-pro-BNP level > 1883.5 pg/mL, and LMP2 level > 841.4 pg/mL. Of the 193 patients that were able to complete the Mini-Mental State Examination at 90 days post-stroke, 66 patients (34.2%) had PSCI. Plasma levels of NT-pro-BNP and LMP2 were higher in patients with PSCI than in those without PSCI. To predict PSCI, the optimal cutoff values were age > 70.5 years and LMP2 level > 630.5 pg/mL. These findings indicate that plasma LMP2 may serve as a new prognostic biomarker of poor outcome and PSCI at 90 days after stroke. This study was approved by the Ethics Committee of Fujian Provincial Hospital, Provincial Clinical Medical College of Fujian Medical University (approval No. K2014-01-003) on January 15, 2014. Related Articles | Metrics