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15 August 2020, Volume 15 Issue 8 Previous Issue    Next Issue

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Exercise promotes recovery after motoneuron injury via hormonal mechanisms Cory Chew, Dale R. Sengelaub 2020, 15 (8):  1373-1376.  doi: 10.4103/1673-5374.274323 Abstract ( 114 )   PDF (2009KB) ( 160 )   Save Injuries to spinal motoneurons manifest in a variety of forms, including damage to peripheral axons, neurodegenerative disease, or direct insult centrally. Such injuries produce a variety of negative structural and functional changes in both the directly affected and neighboring motoneurons. Exercise is a relatively simple behavioral intervention that has been demonstrated to protect against, and accelerate recovery from, these negative changes. In this article, we describe how exercise is neuroprotective for motoneurons, accelerating axon regeneration following axotomy and attenuating dendritic atrophy following the death of neighboring motoneurons. In both of these injury models, the positive effects of exercise have been found to be dependent on gonadal hormone action. Here we describe a model in which exercise, hormones, and brain-derived neurotrophic factor might all interact to produce neuroprotective effects on motoneuron structure following neural injury. Related Articles | Metrics

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Large animal ischemic stroke models: replicating human stroke pathophysiology Erin E. Kaiser, Franklin D. West 2020, 15 (8):  1377-1387.  doi: 10.4103/1673-5374.274324 Abstract ( 120 )   PDF (960KB) ( 260 )   Save The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions. Although promising therapeutics have been identified using these animal models, with most undergoing significant testing in rodent models, the vast majority of these interventions have failed in human clinical trials. This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models. Large animal models such as non-human primates, sheep, pigs, and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline. The objective of this review is to highlight key characteristics that potentially make these gyrencephalic, large animal ischemic stroke models more predictive by comparing pathophysiological responses, tissue-level changes, and model limitations. Related Articles | Metrics

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Autophagy and inflammation in ischemic stroke Yun Mo, Yin-Yi Sun , Kang-Yong Liu 2020, 15 (8):  1388-1396.  doi: 10.4103/1673-5374.274331 Abstract ( 182 )   PDF (1384KB) ( 188 )   Save Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role in the survival of nerve cells and the recovery of neural tissue after ischemia. Many studies have found an interaction between autophagy and inflammation in the pathogenesis of ischemic stroke. This study outlines recent advances regarding the role of autophagy in the post-stroke inflammatory response as follows. (1) Autophagy inhibits inflammatory responses caused by ischemic stimulation through mTOR, the AMPK pathway, and inhibition of inflammasome activation. (2) Activation of inflammation triggers the formation of autophagosomes, and the upregulation of autophagy levels is marked by a significant increase in the autophagy-forming markers LC3-II and Beclin-1. Lipopolysaccharide stimulates microglia and inhibits ULK1 activity by direct phosphorylation of p38 MAPK, reducing the flux and autophagy level, thereby inducing inflammatory activity. (3) By blocking the activation of autophagy, the activation of inflammasomes can alleviate cerebral ischemic injury. Autophagy can also regulate the phenotypic alternation of microglia through the nuclear factor-κB pathway, which is beneficial to the recovery of neural tissue after ischemia. Studies have shown that some drugs such as resveratrol can exert neuroprotective effects by regulating the autophagy-inflammatory pathway. These studies suggest that the autophagy-inflammatory pathway may provide a new direction for the treatment of ischemic stroke. Related Articles | Metrics

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Electrical stimulation and denervated muscles after spinal cord injury Subhalakshmi Chandrasekaran, John Davis, Ines Bersch, Gary Goldberg, Ashraf S. Gorgey 2020, 15 (8):  1397-1407.  doi: 10.4103/1673-5374.274326 Abstract ( 140 )   PDF (1903KB) ( 391 )   Save Spinal cord injury (SCI) population with injury below T10 or injury to the cauda equina region is characterized by denervated muscles, extensive muscle atrophy, infiltration of intramuscular fat and formation of fibrous tissue. These morphological changes may put individuals with SCI at higher risk for developing other diseases such as various cardiovascular diseases, diabetes, obesity and osteoporosis. Currently, there is no available rehabilitation intervention to rescue the muscles or restore muscle size in SCI individuals with lower motor neuron denervation. We, hereby, performed a review of the available evidence that supports the use of electrical stimulation in restoration of denervated muscle following SCI. Long pulse width stimulation (LPWS) technique is an upcoming method of stimulating denervated muscles. Our primary objective is to explore the best stimulation paradigms (stimulation parameters, stimulation technique and stimulation wave) to achieve restoration of the denervated muscle. Stimulation parameters, such as the pulse duration, need to be 100–1000 times longer than in innervated muscles to achieve desirable excitability and contraction. The use of electrical stimulation in animal and human models induces muscle hypertrophy. Findings in animal models indicate that electrical stimulation, with a combination of exercise and pharmacological interventions, have proven to be effective in improving various aspects like relative muscle weight, muscle cross sectional area, number of myelinated regenerated fibers, and restoring some level of muscle function. Human studies have shown similar outcomes, identifying the use of LPWS as an effective strategy in increasing muscle cross sectional area, the size of muscle fibers, and improving muscle function. Therefore, displaying promise is an effective future stimulation intervention. In summary, LPWS is a novel stimulation technique for denervated muscles in humans with SCI. Successful studies on LPWS of denervated muscles will help in translating this stimulation technique to the clinical level as a rehabilitation intervention after SCI. Related Articles | Metrics

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Beneficial effects of saffron (Crocus sativus L.) in ocular pathologies, particularly neurodegenerative retinal diseases Jose A. Fernández-Albarral, Rosa de Hoz, Ana I. Ramírez, Inés López-Cuenca , Elena Salobrar-García, María D. Pinazo-Durán, José M. Ramírez, Juan J. Salazar 2020, 15 (8):  1408-1416.  doi: 10.4103/1673-5374.274325 Abstract ( 166 )   PDF (673KB) ( 252 )   Save Saffron (Crocus sativus L.) has been traditionally used in food preparation and as a medicinal plant. It currently has numerous therapeutic properties attributed to it, such as protection against ischemia, as well as anticonvulsant, antidepressant, anxiolytic, hypolipidemic, anti-atherogenic, anti-hypertensive, antidiabetic, and anti-cancer properties. In addition, saffron has remarkable beneficial properties, such as anti-apoptotic, anti-inflammatory and antioxidant activities, due to its main metabolites, among which crocin and crocetin stand out. Furthermore, increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, both in experimental models and in clinical studies in patients. Currently, saffron supplementation is being tested for ocular neurodegenerative pathologies, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration and glaucoma, among others, and shows beneficial effects. The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases. This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases. Related Articles | Metrics

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Toxic tau: structural origins of tau aggregation in Alzheimer’s disease Abdullah Al Mamun , Md. Sahab Uddin, Bijo Mathew , Ghulam Md Ashraf 2020, 15 (8):  1417-1420.  doi: 10.4103/1673-5374.274329 Abstract ( 200 )   PDF (539KB) ( 270 )   Save Alzheimer’s disease is characterized by the extracellular accumulation of the amyloid β in the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles. Most of the Alzheimer’s drugs targeting amyloid β have been failed in clinical trials. Particularly, tau pathology connects greatly in the pathogenesis of Alzheimer’s disease. Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron. Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved. The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state. Therefore, aberrant phosphorylation, as well as truncation of tau protein, has come into focus as significant mechanisms that make tau protein in a pathological entity. Furthermore, the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely. In this review, we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease. Related Articles | Metrics

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Modification of tubular chitosan-based peripheral nerve implants: applications for simple or more complex approaches Nina Dietzmeyer, Maria Förthmann, Claudia Grothe, Kirsten Haastert-Talini 2020, 15 (8):  1421-1431.  doi: 10.4103/1673-5374.271668 Abstract ( 110 )   PDF (1253KB) ( 288 )   Save Surgical treatment of peripheral nerve injuries is still a major challenge in human clinic. Up to now, none of the well-developed microsurgical treatment options is able to guarantee a complete restoration of nerve function. This restriction is also effective for novel clinically approved artificial nerve guides. In this review, we compare surgical repair techniques primarily for digital nerve injuries reported with relatively high prevalence to be valuable attempts in clinical digital nerve repair and point out their advantages and shortcomings. We furthermore discuss the use of artificial nerve grafts with a focus on chitosan-based nerve guides, for which our own studies contributed to their approval for clinical use. In the second part of this review, very recent future perspectives for the enhancement of tubular (commonly hollow) nerve guides are discussed in terms of their clinical translatability and ability to form three-dimensional constructs that biomimick the natural nerve structure. This includes materials that have already shown their beneficial potential in in vivo studies like fibrous intraluminal guidance structures, hydrogels, growth factors, and approaches of cell transplantation. Additionally, we highlight upcoming future perspectives comprising co-application of stem cell secretome. From our overview, we conclude that already simple attempts are highly effective to increase the regeneration supporting properties of nerve guides in experimental studies. But for bringing nerve repair with bioartificial nerve grafts to the next level, e.g. repair of defects > 3 cm in human patients, more complex intraluminal guidance structures such as innovatively manufactured hydrogels and likely supplementation of stem cells or their secretome for therapeutic purposes may represent promising future perspectives. Related Articles | Metrics

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The potential of bone morphogenetic protein 2 as a neurotrophic factor for Parkinson’s disease Susan R. Goulding, Aideen M. Sullivan , Gerard W. O’Keeffe , Louise M. Collins 2020, 15 (8):  1432-1436.  doi: 10.4103/1673-5374.274327 Abstract ( 99 )   PDF (893KB) ( 196 )   Save Parkinson’s disease is the second most common neurodegenerative disorder; it affects 1% of the population over the age of 65. The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies. The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum, and the aggregation of α-synuclein; these result in a range of debilitating motor and non-motor symptoms. The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest. However, this strategy has had limited success to date. Clinical trials of two well-known neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have reported limited efficacy in Parkinson’s disease patients, despite these factors showing potent neurotrophic actions in animal studies. There is therefore a need to identify other neurotrophic factors that can protect against α-synuclein-induced degeneration of dopaminergic neurons. The bone morphogenetic protein (BMP) family is the largest subgroup of the transforming growth factor-β superfamily of proteins. BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system. Importantly, many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons. Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra, and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease. We also discuss studies that explored the effects of BMP2 treatment, in in vitro and in vivo models of Parkinson’s disease. These studies found potent effects of BMP2 on dopaminergic neurites, which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease. Thus, the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway, in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy. Related Articles | Metrics

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Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation Ya Zheng, Ye-Ran Mao, Ti-Fei Yuan , Dong-Sheng Xu , Li-Ming Cheng 2020, 15 (8):  1437-1450.  doi: 10.4103/1673-5374.274332 Abstract ( 139 )   PDF (1115KB) ( 399 )   Save Spinal cord injury is linked to the interruption of neural pathways, which results in irreversible neural dysfunction. Neural repair and neuroregeneration are critical goals and issues for rehabilitation in spinal cord injury, which require neural stem cell repair and multimodal neuromodulation techniques involving personalized rehabilitation strategies. Besides the involvement of endogenous stem cells in neurogenesis and neural repair, exogenous neural stem cell transplantation is an emerging effective method for repairing and replacing damaged tissues in central nervous system diseases. However, to ensure that endogenous or exogenous neural stem cells truly participate in neural repair following spinal cord injury, appropriate interventional measures (e.g., neuromodulation) should be adopted. Neuromodulation techniques, such as noninvasive magnetic stimulation and electrical stimulation, have been safely applied in many neuropsychiatric diseases. There is increasing evidence to suggest that neuromagnetic/electrical modulation promotes neuroregeneration and neural repair by affecting signaling in the nervous system; namely, by exciting, inhibiting, or regulating neuronal and neural network activities to improve motor function and motor learning following spinal cord injury. Several studies have indicated that fine motor skill rehabilitation training makes use of residual nerve fibers for collateral growth, encourages the formation of new synaptic connections to promote neural plasticity, and improves motor function recovery in patients with spinal cord injury. With the development of biomaterial technology and biomechanical engineering, several emerging treatments have been developed, such as robots, brain-computer interfaces, and nanomaterials. These treatments have the potential to help millions of patients suffering from motor dysfunction caused by spinal cord injury. However, large-scale clinical trials need to be conducted to validate their efficacy. This review evaluated the efficacy of neural stem cells and magnetic or electrical stimulation combined with rehabilitation training and intelligent therapies for spinal cord injury according to existing evidence, to build up a multimodal treatment strategy of spinal cord injury to enhance nerve repair and regeneration. Related Articles | Metrics

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The role of cofilin in age-related neuroinflammation Amsha S. Alsegiani, Zahoor A. Shah 2020, 15 (8):  1451-1459.  doi: 10.4103/1673-5374.274330 Abstract ( 106 )   PDF (339KB) ( 187 )   Save Aging brain becomes susceptible to neurodegenerative diseases due to the shifting of microglia and astrocyte phenotypes to an active “pro-inflammatory” state, causing chronic low-grade neuroinflammation. Despite the fact that the role of neuroinflammation during aging has been extensively studied in recent years, the underlying causes remain unclear. The identification of relevant proteins and understanding their potential roles in neuroinflammation can help explain their potential of becoming biomarkers in the aging brain and as drug targets for prevention and treatment. This will eventually reduce the chances of developing neurodegenerative diseases and promote healthier lives in the elderly. In this review, we have summarized the morphological and cellular changes in the aging brain, the effects of age-related neuroinflammation, and the potential role of cofilin-1 during neuroinflammation. We also discuss other factors contributing to brain aging and neuroinflammation. Related Articles | Metrics

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Role of the metabolism of branched-chain amino acids in the development of Alzheimer’s disease and other metabolic disorders Baruh Polis , Abraham O. Samson 2020, 15 (8):  1460-1470.  doi: 10.4103/1673-5374.274328 Abstract ( 186 )   PDF (2932KB) ( 242 )   Save Alzheimer’s disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia, imposing a growing economic burden upon society. The disease progression is associated with gradual deposition of amyloid plaques and the formation of neurofibrillary tangles within the brain parenchyma, yet severe dementia is the culminating phase of the enduring pathology. Converging evidence suggests that Alzheimer’s disease-related cognitive decline is the outcome of an extremely complex and persistent pathophysiological process. The disease is characterized by distinctive abnormalities apparent at systemic, histological, macromolecular, and biochemical levels. Moreover, besides the well-defined and self-evident characteristic profuse neurofibrillary tangles, dystrophic neurites, and amyloid-beta deposits, the Alzheimer’s disease-associated pathology includes neuroinflammation, substantial neuronal loss, apoptosis, extensive DNA damage, considerable mitochondrial malfunction, compromised energy metabolism, and chronic oxidative stress. Likewise, distinctive metabolic dysfunction has been named a leading cause and a hallmark of Alzheimer’s disease that is apparent decades prior to disease manifestation. State-of-theart metabolomics studies demonstrate that altered branched-chain amino acids (BCAAs) metabolism accompanies Alzheimer’s disease development. Lower plasma valine levels are correlated with accelerated cognitive decline, and, conversely, an increase in valine concentration is associated with reduced risk of Alzheimer’s disease. Additionally, a clear BCAAs-related metabolic signature has been identified in subjects with obesity, diabetes, and atherosclerosis. Also, arginine metabolism is dramatically altered in Alzheimer’s disease human brains and animal models. Accordingly, a potential role of the urea cycle in the Alzheimer’s disease development has been hypothesized, and preclinical studies utilizing intervention in the urea cycle and/or BCAAs metabolism have demonstrated clinical potential. Continual failures to offer a competent treatment strategy directed against amyloid-beta or Tau proteins-related lesions, which could face all challenges of the multifaceted Alzheimer’s disease pathology, led to the hypothesis that hyperphosphorylated Tau and deposited amyloid-beta proteins are just hallmarks or epiphenomena, but not the ultimate causes of Alzheimer’s disease. Therefore, approaches targeting amyloid-beta or Tau are not adequate to cure the disease. Accordingly, the modern scientific vision of Alzheimer’s disease etiology and pathogenesis must reach beyond the hallmarks, and look for alternative strategies and areas of research. Related Articles | Metrics

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LIM kinases in synaptic plasticity and their potential as therapeutic targets Éva Halász, Ellen Townes-Anderson, Weiwei Wang 2020, 15 (8):  1471-1472.  doi: 10.4103/1673-5374.274333 Abstract ( 61 )   PDF (982KB) ( 166 )   Save Related Articles | Metrics

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Rifampicin quinone pretreatment improves neuronal survival by modulating microglia inflammation induced by α-synuclein Leonardo Acuña , Natalia S. Corbalán, Rita Raisman-Vozari 2020, 15 (8):  1473-1474.  doi: 10.4103/1673-5374.274336 Abstract ( 71 )   PDF (527KB) ( 214 )   Save Related Articles | Metrics

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The roles of atypical protein kinase Cs (aPKCs) in the nervous system: targets for neuroregeneration? Dennis Dik-Long Chau, Kwok-Fai Lau 2020, 15 (8):  1475-1476.  doi: 10.4103/1673-5374.274334 Abstract ( 81 )   PDF (775KB) ( 196 )   Save Related Articles | Metrics

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Atypical antipsychotics, more than just an antipsychotic Hiram Tendilla-Beltrán, Gonzalo Flores 2020, 15 (8):  1477-1478.  doi: 10.4103/1673-5374.274337 Abstract ( 67 )   PDF (526KB) ( 193 )   Save Related Articles | Metrics

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Beneficial effects of AAV1-Rheb(S16H) administration in the adult hippocampus Sang Ryong Kim 2020, 15 (8):  1479-1480.  doi: 10.4103/1673-5374.274335 Abstract ( 95 )   PDF (536KB) ( 182 )   Save Related Articles | Metrics

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TET2, an “ambiguous” player in inflammation Ana María Espinosa-Oliva, Miguel Angel Burguillos 2020, 15 (8):  1481-1482.  doi: 10.4103/1673-5374.274338 Abstract ( 92 )   PDF (384KB) ( 168 )   Save Related Articles | Metrics

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Brain-derived neurotrophic factor mediates macrophage migration inhibitory factor to protect neurons against oxygen-glucose deprivation Su Hwan Bae, Mi Ran Yoo, Ye Yeong Kim, In Kyung Hong, Mi Hee Kim , Seung Hak Lee , Dae Yul Kim 2020, 15 (8):  1483-1489.  doi: 10.4103/1673-5374.274340 Abstract ( 103 )   PDF (1835KB) ( 172 )   Save Macrophage migration inhibitory factor (MIF) is a chemokine that plays an essential role in immune system function. Previous studies suggested that MIF protects neurons in ischemic conditions. However, few studies are reported on the role of MIF in neurological recovery after ischemic stroke. The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF. Human neuroblastoma cells were incubated in Dulbecco’s modified Eagle’s medium under oxygen-glucose deprivation (OGD) for 4 hours and then returned to normal aerobic environment for reperfusion (OGD/R). 30 ng/mL MIF recombinant (30 ng/mL) or ISO-1 (MIF antagonist; 50 μM) was administered to human neuroblastoma cells. Then cell cultures were assigned to one of four groups: control, OGD/R, OGD/R with MIF, OGD/R with ISO-1. Cell viability was analyzed using WST-1 assay. Expression levels of brain-derived neurotrophic factor (BDNF), microtubule-associated protein 2 (MAP2), Caspase-3, Bcl2, and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity. WST-1 assay results revealed that compared to the OGD/R group, cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group. Western blot assay and immunocytochemistry results revealed that expression levels of BDNF, Bcl2, and MAP2 were significantly higher, and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group. Expression levels of BDNF, Bcl2, and MAP2 were significantly lower, and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group. MIF administration promoted neuronal cell survival and induced high expression levels of BDNF, MAP2, and Bcl2 (anti-apoptosis) and low expression levels of Caspase-3 and Bax (pro-apoptosis) in an OGD/R model. These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury. Related Articles | Metrics

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Synaptic development of layer V pyramidal neurons in the prenatal human prefrontal neocortex: a Neurolucida-aided Golgi study Li-Xin He, Lily Wan, Wei Xiang, Jian-Ming Li, An-Hua Pan, Da-Hua Lu 2020, 15 (8):  1490-1495.  doi: 10.4103/1673-5374.274345 Abstract ( 99 )   PDF (3003KB) ( 171 )   Save The prefrontal neocortex is involved in many high cognitive functions in humans. Deficits in neuronal and neurocircuitry development in this part of the cerebrum have been associated with various neuropsychiatric disorders in adolescents and adults. There are currently little available data regarding prenatal dendrite and spine formation on projecting neurons in the human prefrontal neocortex. Previous studies have demonstrated that Golgi silver staining can identify neurons in the frontal lobe and visual cortex in human embryos. In the present study, five fetal brains, at 19, 20, 26, 35, and 38 gestational weeks, were obtained via the body donation program at Xiangya School of Medicine, Central South University, China. Golgi-stained pyramidal neurons in layer V of Brodmann area 46 in fetuses were quantitatively analyzed using the Neurolucida morphometry system. Results revealed that somal size, total dendritic length, and branching points of these neurons increased from 26 to 38 gestational weeks. There was also a large increase in dendritic spines from 35 to 38 gestational weeks. These findings indicate that, in the human prefrontal neocortex, dendritic growth in layer V pyramidal neurons occurs rapidly during the third trimester of gestation. The use of human fetal brain tissue was approved by the Animal Ethics Committee of Xiangya School of Medicine, Central South University, China (approval No. 2011-045) on April 5, 2011. Related Articles | Metrics

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Enduring alterations in hippocampal astrocytesynaptic proximity following adolescent alcohol exposure: reversal by gabapentin Kati L. Healey, Sandra Kibble, Sierra Hodges, Kathryn J. Reissner, Anze Testen, Tiffany A. Wills, Shawn K. Acheson, Benjamin M. Siemsen, John A. McFaddin, Michael D. Scofield, H. Scott Swartzwelder 2020, 15 (8):  1496-1501.  doi: 10.4103/1673-5374.274339 Abstract ( 128 )   PDF (3405KB) ( 216 )   Save Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years. Despite reports of a wide range of effects of adolescent intermittent ethanol (AIE) exposure on brain and behavior, little is known about the mechanisms that may underlie those effects, and even less about treatments that might reverse them. Recent studies from our laboratory have indicated that AIE produced enduring changes in astrocyte function and synaptic activity in the hippocampal formation, suggesting the possibility of an alteration in astrocyte-neuronal connectivity and function. We utilized astrocyte-specific, membrane restricted viral labeling paired with immunohistochemistry to perform confocal single cell astrocyte imaging, three-dimensional reconstruction, and quantification of astrocyte morphology in hippocampal area CA1 from adult rats after AIE. Additionally, we assessed the colocalization of astrocyte plasma membrane labeling with immunoreactivity for AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor 1, an AMPA receptor subunit and established neuronal marker of excitatory synapses, as a metric of astrocyte-synapse proximity. AIE significantly reduced the colocalization of the astrocyte plasma membrane with synaptic marker puncta in adulthood. This is striking in that it suggests not only an alteration of the physical association of astrocytes with synapses by AIE, but one that lasts into adulthood - well after the termination of alcohol exposure. Perhaps even more notable, the AIE-induced reduction of astrocyte-synapse interaction was reversed by sub-chronic treatment with the clinically used agent, gabapentin (Neurontin), in adulthood. This suggests that a medication in common clinical use may have the potential to reverse some of the enduring effects of adolescent alcohol exposure on brain function. All animal experiments conducted were approved by the Duke University Institutional Animal Care and Use Committee (Protocol Registry Number A159-18-07) on July 27, 2018. Related Articles | Metrics

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Biological characteristics of dynamic expression of nerve regeneration related growth factors in dorsal root ganglia after peripheral nerve injury Yin-Ying Shen, Xiao-Kun Gu, Rui-Rui Zhang , Tian-Mei Qian , Shi-Ying Li , Sheng Yi 2020, 15 (8):  1502-1509.  doi: 10.4103/1673-5374.274343 Abstract ( 126 )   PDF (2367KB) ( 373 )   Save The regenerative capacity of peripheral nerves is limited after nerve injury. A number of growth factors modulate many cellular behaviors, such as proliferation and migration, and may contribute to nerve repair and regeneration. Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing. Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3, 9 hours, 1, 4, or 7 days after nerve crush, compared with the 0 hour control. Thirty-six rat models of sciatic nerve crush injury were prepared as described previously. Then, they were divided into six groups to measure the expression changes of representative genes at 0, 3, 9 hours, 1, 4 or 7 days post crush. Our current study measured the expression levels of representative upstream growth factors, including nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor 2 and amphiregulin genes, and explored critical signaling pathways and biological process through bioinformatic analysis. Our data revealed that many of these dysregulated upstream growth factors, including nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor 2 and amphiregulin, participated in tissue remodeling and axon growth-related biological processes Therefore, the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury. Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves. All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals, China (approval No. 20170302- 017) on March 2, 2017. Related Articles | Metrics

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Acupuncture promotes functional recovery after cerebral hemorrhage by upregulating neurotrophic factor expression Dan Li , Qiu-Xin Chen , Wei Zou, Xiao-Wei Sun , Xue-Ping Yu , Xiao-Hong Dai , Wei Teng 2020, 15 (8):  1510-1517.  doi: 10.4103/1673-5374.257532 Abstract ( 97 )   PDF (6549KB) ( 255 )   Save Acupuncture is widely used in the treatment of cerebral hemorrhage, and it improves outcomes in experimental animal models and patients. However, the mechanisms underlying the effectiveness of acupuncture treatment for cerebral hemorrhage are still unclear. In this study, a model of intracerebral hemorrhage was produced by injecting 50 μL autologous blood into the caudate nucleus in Wistar rats. Acupuncture at Baihui (DU20) and Qubin (GB7) acupoints was performed at a depth of 1.0 inch, 12 hours after blood injection, once every 24 hours. The needle was rotated at 200 r/min for 5 minutes, For each 30-minute session, needling at 200 r/min was performed for three sessions, each lasting 5 minutes. For the positive control group, at 6 hours, and 1, 2, 3 and 7 days after induction of hemorrhage, the rats were intraperitoneally injected with 1 mL aniracetam (0.75 mg/mL), three times a day. The Bederson behavioral test was used to assess palsy in the contralateral limbs. Western blot assay was used to examine the expression levels of Nestin and basic fibroblast growth factor in the basal ganglia. Immunohistochemistry was performed to count the number of Nestin- and glial cell line-derived neurotrophic factor-positive cells in the basal ganglia. Acupuncture effectively reduced hemorrhage and brain edema, elevated the expression levels of Nestin and basic fibroblast growth factor in the basal ganglia, and increased the number of Nestin- and glial cell line-derived neurotrophic factor-positive cells in the basal ganglia. Together, these findings suggest that acupuncture promotes functional recovery after cerebral hemorrhage by increasing the expression of neurotrophic factors. The study was approved by the Committee for Experimental Animals of Heilongjiang Medical Laboratory Animal Center (approval No. 2017061001) on June 10, 2017. Related Articles | Metrics

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Emotion recognition and inhibitory control in manifest and pre-manifest Huntington’s disease: evidence from a new Stroop task Thomas Hünefeldt, , Sabrina Maffi , Simone Migliore , Ferdinando Squitieri , Marta Olivetti Belardinelli 2020, 15 (8):  1518-1525.  doi: 10.4103/1673-5374.274342 Abstract ( 112 )   PDF (464KB) ( 181 )   Save Huntington’s disease (HD) is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain. In particular, cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals’ mental state may emerge many years before the motor symptoms. This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose: 1) the impairment of emotion recognition in HD is moderated by the emotions’ valence, and 2) inhibitory control is impaired in HD. Forty manifest and 20 pre-manifest HD patients and their age- and gender-matched controls completed both the traditional “Stroop Color and Word Test” (SCWT) and the newly created “Stroop Emotion Recognition under Word Interference Task” (SERWIT), which consist in 120 photographs of sad, calm, or happy faces with either congruent or incongruent word interference. On the SERWIT, impaired emotion recognition in manifest HD was moderated by emotion type, with deficits being larger in recognizing sadness and calmness than in recognizing happiness, but it was not moderated by stimulus congruency. On the SCWT, six different interference scores yielded as many different patterns of group effects. Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions’ valence, but do not provide evidence for the hypothesis that inhibitory control is impaired in HD. Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD, and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD. Looking beyond this study, the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders. The research was approved by the Ethics Committee of the “Istituto Leonarda Vaccari”, Rome on January 24, 2018. Related Articles | Metrics

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Lycium barbarum polysaccharides protects retinal ganglion cells against oxidative stress injury Lian Liu , Xiao-Yuan Sha , Yi-Ning Wu , Meng-Ting Chen , Jing-Xiang Zhong, 2020, 15 (8):  1526-1531.  doi: 10.4103/1673-5374.274349 Abstract ( 174 )   PDF (1492KB) ( 232 )   Save The accumulation of excessive reactive oxygen species can exacerbate any injury of retinal tissue because free radicals can trigger lipid peroxidation, protein damage and DNA fragmentation. Increased oxidative stress is associated with the common pathological process of many eye diseases, such as glaucoma, diabetic retinopathy and ischemic optic neuropathy. Many studies have demonstrated that Lycium barbarum polysaccharides (LBP) protects against oxidative injury in numerous cells and tissues. For the model of hypoxia we used cultured retinal ganglion cells and induced hypoxia by incubating with 200 µM cobalt chloride (CoCl2) for 24 hours. To investigate the protective effect of LBP and its mechanism of action against oxidative stress injury, the retinal tissue was pretreated with 0.5 mg/mL LBP for 24 hours. The results of flow cytometric analysis showed LBP could effectively reduce the CoCl2-induced retinal ganglion cell apoptosis, inhibited the generation of reactive oxygen species and the reduction of mitochondrial membrane potential. These findings suggested that LBP could protect retinal ganglion cells from CoCl2-induced apoptosis by reducing mitochondrial membrane potential and reactive oxygen species. Related Articles | Metrics

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Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial Yang Yang, Mao Pang, Yu-Yong Chen , Liang-Ming Zhang , Hao Liu , Jun Tan , Bin Liu, Li-Min Rong 2020, 15 (8):  1532-1538.  doi: 10.4103/1673-5374.274347 Abstract ( 126 )   PDF (298KB) ( 185 )   Save Human umbilical cord mesenchymal stem cells (hUC-MSCs) support revascularization, inhibition of inflammation, regulation of apop tosis, and promotion of the release of beneficial factors. Thus, they are regarded as a promising candidate for the treatment of intractable spinal cord injury (SCI). Clinical studies on patients with early chronic SCI (from 2 months to 1 year post-injury), which is clinically common, are rare; therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University, West China Hospital of Sichuan University, and Shanghai East Hospital, Tongji University School of Medicine, China. The trial plans to recruit 66 early chronic SCI patients. Eligible patients will undergo randomization at a 2:1 ratio to two arms: the observation group and the control group. Subjects in the observation group will receive four intrathecal transplantations of stem cells, with a dosage of 1 × 106 /kg, at one calendar month intervals. Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations. Clinical safety will be assessed by the analysis of adverse events and laboratory tests. The American Spinal Injury Association (ASIA) total score will be the primary efficacy endpoint, and the secondary efficacy outcomes will be the following: ASIA impairment scale, International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale, muscle tension, electromyogram, cortical motor and cortical sensory evoked potentials, residual urine volume, magnetic resonance imaging–diffusion tensor imaging, T cell subtypes in serum, neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid. All evaluations will be performed at 1, 3, 6, and 12 months following the final intrathecal administration. During the entire study procedure, all adverse events will be reported as soon as they are noted. This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI. Moreover, it will establish whether cytotherapy can ameliorate local hostile microenvironments, promote tracking fiber regeneration, and strengthen spinal conduction ability, thus improving overall motor, sensory, and micturition/defecation function in patients with early chronic SCI. This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2018]-02) on March 30, 2018, and was registered with ClinicalTrials.gov (registration No. NCT03521323) on April 12, 2018. The revised trial protocol (protocol version 4.0) was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2019]-10) on February 25, 2019, and released on ClinicalTrials.gov on April 29, 2019. Related Articles | Metrics

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Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons Yan Zhang, Bao-You Fan, Yi-Lin Pang, Wen-Yuan Shen, Xu Wang, Chen-Xi Zhao, Wen-Xiang Li, Chang Liu , Xiao-Hong Kong , Guang-Zhi Ning, Shi-Qing Feng, Xue Yao 2020, 15 (8):  1539-1545.  doi: 10.4103/1673-5374.274344 Abstract ( 168 )   PDF (2385KB) ( 329 )   Save The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury. However, it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death. By comparing the survival rate and morphology of primary neurons and SH-SY5Y cells exposed to erastin, it was found that these cell types respond differentially to the duration and concentration of erastin treatment. Therefore, we studied the mechanisms of ferroptosis using primary cortical neurons from E16 mouse embryos. After treatment with 50 μM erastin for 48 hours, reactive oxygen species levels increased, and the expression of the cystine/glutamate antiporter system light chain and glutathione peroxidase 4 decreased. Pretreatment with deferoxamine for 12 hours inhibited these changes, reduced cell death, and ameliorated cellular morphology. Pretreatment with the apoptosis inhibitor Z-DEVD-FMK or the necroptosis inhibitor necrostain-1 for 12 hours did not protect against erastin-induced ferroptosis. Only deferoxamine protected the primary cortical neurons from ferroptosis induced by erastin, confirming the specificity of the in vitro ferroptosis model. This study was approved by the Animal Ethics Committee at the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences, China (approval No. DWLL-20180913) on September 13, 2018. Related Articles | Metrics

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Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus Courtney J. Mycroft-West , Anthony J. Devlin , Lynsay C. Cooper , Patricia Procter , Gavin J. Miller , David G. Fernig , Marco Guerrini , Scott E. Guimond, Marcelo A. Lima , Edwin A. Yates, Mark Andrew Skidmore 2020, 15 (8):  1546-1553.  doi: 10.4103/1673-5374.274341 Abstract ( 118 )   PDF (596KB) ( 144 )   Save The pharmaceutical and anticoagulant agent heparin, a member of the glycosaminoglycan family of carbohydrates, has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target, the primary neuronal β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1). The anticoagulant activity of heparin has, however, precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease therapeutic. Here, a glycosaminoglycan extract, composed predominantly of 4-sulfated chondroitin sulfate, has been isolated from Sardina pilchardus, which possess the ability to inhibit BACE1 (IC50 [half maximal inhibitory concentration] = 4.8 μg/mL), while displaying highly attenuated anticoagulant activities (activated partial thromboplastin time EC50 [median effective concentration] = 403.8 μg/mL, prothrombin time EC50 = 1.3 mg/mL). The marine-derived, chondroitin sulfate extract destabilizes BACE1, determined via differential scanning fluorimetry (ΔTm –5°C), to a similar extent as heparin, suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action, which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease. Related Articles | Metrics

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Abnormal brain activity in adolescents with Internet addiction who attempt suicide: an assessment using functional magnetic resonance imaging Yan Huang , Lu Xu, Li Kuang, Wo Wang , Jun Cao , Mu-Ni Xiao 2020, 15 (8):  1554-1559.  doi: 10.4103/1673-5374.274346 Abstract ( 115 )   PDF (720KB) ( 235 )   Save Internet addiction is associated with an increased risk of suicidal behavior and can lead to brain dysfunction among adolescents. However, whether brain dysfunction occurs in adolescents with Internet addiction who attempt suicide remains unknown. This observational cross-sectional study enrolled 41 young Internet addicts, aged from 15 to 20 years, from the Department of Psychiatry, the First Affiliated Hospital of Chongqing Medical University, China from January to May 2018. The participants included 21 individuals who attempted suicide and 20 individuals with Internet addiction without a suicidal attempt history. Brain images in the resting state were obtained by a 3.0 T magnetic resonance imaging scanner. The results showed that activity in the gyrus frontalis inferior of the right pars triangularis and the right pars opercularis was significantly increased in the suicidal attempt group compared with the non-suicidal attempt group. In the resting state, the prefrontal lobe of adolescents who had attempted suicide because of Internet addiction exhibited functional abnormalities, which may provide a new basis for studying suicide pathogenesis in Internet addicts. The study was authorized by the Ethics Committee of Chongqing Medical University, China (approval No. 2017 Scientific Research Ethics (2017-157)) on December 11, 2017. Related Articles | Metrics

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Expression of long non-coding RNAs in complete transection spinal cord injury: a transcriptomic analysis Lu Ding, Wen-Jin Fu, Hong-Yan Di, Xiao-Min Zhang , Yu-Tian Lei , Kang-Zhen Chen , Tao Wang , Hong-Fu Wu 2020, 15 (8):  1560-1567.  doi: 10.4103/1673-5374.274348 Abstract ( 119 )   PDF (1785KB) ( 192 )   Save Long non-coding RNAs (lncRNAs) are abundantly expressed in the central nervous system and exert a critical role in gene regulation via multiple biological processes. To uncover the functional significance and molecular mechanisms of lncRNAs in spinal cord injury (SCI), the expression signatures of lncRNAs were profiled using RNA sequencing (RNA-seq) technology in a Sprague-Dawley rat model of the 10th thoracic vertebra complete transection SCI. Results showed that 116 of 14,802 detected lncRNAs were differentially expressed, among which 16—including eight up-regulated (H19, Vof16, Hmox2-ps1, LOC100910973, Ybx1-ps3, Nnat, Gcgr, LOC680254) and eight down-regulated (Rmrp, Terc, Ngrn, Ppp2r2b, Cox6a2, Rpl37a-ps1, LOC360231, Rpph1)—demonstrated fold changes > 2 in response to transection SCI. A subset of these RNA-seq results was validated by quantitative real-time PCR. The levels of 821 mRNAs were also significantly altered post-SCI; 592 mRNAs were up-regulated and 229 mRNAs were down-regulated by more than 2-fold. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that differentially expressed mRNAs were related to GO biological processes and molecular functions such as injury and inflammation response, wound repair, and apoptosis, and were significantly enriched in 15 KEGG pathways, including cell phagocytosis, tumor necrosis factor alpha pathway, and leukocyte migration. Our results reveal the expression profiles of lncRNAs and mRNAs in the rat spinal cord of a complete transection model, and these differentially expressed lncRNAs and mRNAs represent potential novel targets for SCI treatment. We suggest that lncRNAs may play an important role in the early immuno-inflammatory response after spinal cord injury. This study was approved by the Administration Committee of Experimental Animals, Guangdong Province, China. Related Articles | Metrics

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Increased thalamocortical connectivity from the affected thalamus to the unaffected hemisphere in a stroke patient Sung Ho Jang, You Sung Seo, Sung Jun Lee 2020, 15 (8):  1568-1568.  Abstract ( 83 )   PDF (384KB) ( 179 )   Save Related Articles | Metrics