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    15 December 2022, Volume 17 Issue 12 Previous Issue    Next Issue
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    Random noise stimulation in the treatment of patients with neurological disorders
    Mateo A. Herrera-Murillo, Mario Treviño, Elias Manjarrez
    2022, 17 (12):  2557-2562.  doi: 10.4103/1673-5374.339474
    Abstract ( 204 )   PDF (1925KB) ( 102 )   Save
    Random noise stimulation technique involves applying any form of energy (for instance, light, mechanical, electrical, sound) with unpredictable intensities through time to the brain or sensory receptors to enhance sensory, motor, or cognitive functions. Random noise stimulation initially employed mechanical noise in auditory and cutaneous stimuli, but electrical energies applied to the brain or the skin are becoming more frequent, with a series of clinical applications. Indeed, recent evidence shows that transcranial random noise stimulation can increase corticospinal excitability, improve cognitive/motor performance, and produce beneficial aftereffects at the behavioral and psychological levels. Here, we present a narrative review about the potential uses of random noise stimulation to treat neurological disorders, including attention deficit hyperactivity disorder, schizophrenia, amblyopia, myopia, tinnitus, multiple sclerosis, post-stroke, vestibular-postural disorders, and sensitivity loss. Many of the reviewed studies reveal that the optimal way to deliver random noise stimulation-based therapies is with the concomitant use of neurological and neuropsychological assessments to validate the beneficial aftereffects. In addition, we highlight the requirement of more randomized controlled trials and more physiological studies of random noise stimulation to discover another optimal way to perform the random noise stimulation interventions.
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    The “mitochondrial stress responses”: the “Dr. Jekyll and Mr. Hyde” of neuronal disorders
    Simone Patergnani, Giampaolo Morciano, Marianna Carinci, Sara Leo, Paolo Pinton, Alessandro Rimessi
    2022, 17 (12):  2563-2575.  doi: 10.4103/1673-5374.339473
    Abstract ( 300 )   PDF (1980KB) ( 206 )   Save
    Neuronal disorders are associated with a profound loss of mitochondrial functions caused by various stress conditions, such as oxidative and metabolic stress, protein folding or import defects, and mitochondrial DNA alteration. Cells engage in different coordinated responses to safeguard mitochondrial homeostasis. In this review, we will explore the contribution of mitochondrial stress responses that are activated by the organelle to perceive these dangerous conditions, keep them under control and rescue the physiological condition of nervous cells. In the sections to come, particular attention will be dedicated to analyzing how compensatory mitochondrial hyperfusion, mitophagy, mitochondrial unfolding protein response, and apoptosis impact human neuronal diseases. Finally, we will discuss the relevance of the new concept: the “mito-inflammation”, a mitochondria-mediated inflammatory response that is recently found to cover a relevant role in the pathogenesis of diverse inflammatory-related diseases, including neuronal disorders.
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    Proteomic-based evidence for adult neurogenesis in birds and mammals as indicated from cerebrospinal fluid
    Eleni Voukali, Michal Vinkler
    2022, 17 (12):  2576-2581.  doi: 10.4103/1673-5374.329002
    Abstract ( 121 )   PDF (63088KB) ( 18 )   Save
    Adult neurogenesis is the life-long process of neural stem cell proliferation, differentiation into neurons, migration, and incorporation into the existing neuronal circuits. After decades of research, it is now widely accepted that mammals and birds retain the capacity to regenerate neurons even after their subadult ontogeny. Cerebrospinal fluid participates in the regulation of the neurogenic niches of the vertebrate brain through signaling pathways not fully elucidated. Proteomic studies of cerebrospinal fluid have the potential to allow the in-depth characterization of its molecular composition. Comparative studies help to delineate those pathways that are universally critical for the regulation of neurogenesis in adulthood. In this review, we performed literature-based data mining in studies using liquid chromatography-tandem mass spectroscopy that analyzed cerebrospinal fluid samples from healthy adult humans (Homo sapiens); mice (Mus musculus); sheep (Ovis aries); chickens (Gallus gallus); and two parrot species, the budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). We identified up to 911 proteins represented in cerebrospinal fluid, involved in various pathways regulating adult neurogenesis. However, only 196 proteins were common across humans, mice, and birds. Pathway components involved in nervous system development, cell migration, and axonal guidance were commonly evident in all species investigated so far. Extensive bioinformatic analysis revealed that the universally over-represented pathways involved L1 cell adhesion molecule protein interactions, cell-adhesion molecules, signals regulating extracellular matrix remodeling, regulation of insulin growth factor signaling, axonal guidance, programmed cell death, immune signaling, and post-translational modifications. Most of the reported proteins are part of extracellular vesicles enriched in cerebrospinal fluid. However, the information presently available is still highly fragmentary, and far more questions persist than are answered. Technological advances will allow cerebrospinal fluid comparative proteomic research to delve into the fundamental processes of adult neurogenesis and eventually translate this research into any regenerative interventions.
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    Astrocyte polarization in glaucoma: a new opportunity
    Yi-Xin Liu , Hao Sun , Wen-Yi Guo
    2022, 17 (12):  2582-2588.  doi: 10.4103/1673-5374.339470
    Abstract ( 338 )   PDF (801KB) ( 329 )   Save
    Astrocyte polarization is a new concept which is similar to microglia polarization and in which astrocytes are classified as A1 (neurotoxic) and A2 (neuroprotective). Several studies on astrocyte polarization have focused mainly on neurodegenerative diseases, trauma, and infections. However, the role of astrocyte polarization in glaucoma, a neurodegenerative disease, has not been fully explored. In this review, we first describe the characteristics of astrocyte astrogliosis in glaucoma, including morphological, molecular, proliferative and functional changes. We then summarize understanding of astrocyte polarization in other diseases, and show that A1 astrocytes are involved in the death of retinal ganglion cells in glaucoma, and that their neurotoxins kill only damaged retinal ganglion cells. Based on this, we propose new interesting conjecture on astrocyte polarization in glaucoma: (1) That the neurotoxin from A1 astrocytes is a product of the complement system (membrane-attacking complex), since this system is known to mediate synaptic elimination and the C3 expression is clearly increased in A1 astrocytes; (2) that reactive scar-forming astrocytes in the optic nerve head may be classified as A2 astrocytes since their ablation leads to a worse prognosis in glaucoma. Finally, current therapeutic research progress on astrocyte polarization in other diseases is also addressed. Regulation of astrocyte polarization can be achieved by extracellular microglia-related and intracellular pathways. Reduced A1 or increased A2 astrocytes can rescue the nerve. For example, glucagon-like peptide-1 receptor agonist rescues retinal ganglion cells by reducing A1 astrocytes via the extracellular microglia-related pathway in an ocular hypertension model, suggesting that regulation of astrocyte polarization as a therapeutic target in glaucoma is feasible.
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    Better together? Treating traumatic brain injury with minocycline plus N-acetylcysteine
    Siobhán Lawless, Peter J. Bergold
    2022, 17 (12):  2589-2592.  doi: 10.4103/1673-5374.336136
    Abstract ( 135 )   PDF (415KB) ( 59 )   Save
    Traumatic brain injury has a complex pathophysiology that produces both rapid and delayed brain damage. Rapid damage initiates immediately after injury. Treatment of traumatic brain injury is typically delayed many hours, thus only delayed damage can be targeted with drugs. Delayed traumatic brain injury includes neuroinflammation, oxidative damage, apoptosis, and glutamate toxicity. Both the speed and complexity of traumatic brain injury pathophysiology present large obstacles to drug development. Repurposing of Food and Drug Administration-approved drugs may be a highly efficient approach to get therapeutics to the clinic. This review examines the preclinical outcomes of minocycline and N-acetylcysteine as individual drugs and compares them to the minocycline plus N-acetylcysteine combination. Both minocycline and N-acetylcysteine are Food and Drug Administration-approved drugs with pleiotropic therapeutic effects. As individual drugs, minocycline and N-acetylcysteine are well tolerated, with known pharmacokinetics, and enter the brain through an intact blood-brain barrier. At concentrations greater than needed for anti-microbial action, minocycline is a potent anti-inflammatory minocycline, also acts as an antioxidant and inhibits multiple enzymes that promote brain injury including metalloproteases, caspases, and polyADP-ribose-polymerase-1. N-acetylcysteine alone is also an antioxidant. It increases brain glutathione, prevents lipid oxidation, and protects mitochondria. N-acetylcysteine also acts as an anti-inflammatory as well as increases extracellular glutamate by activating the Xc cystine-glutamate anti-transporter. These multiple actions of minocycline and N-acetylcysteine have made them attractive candidates to treat traumatic brain injury. When first dosed within the one hour after injury, either minocycline or N-acetylcysteine improves a diverse set of therapeutic outcome measures in multiple traumatic brain injury animal models. A small number of clinical trials for traumatic brain injury have established the safety of minocycline or N-acetylcysteine and suggested that either drug has some efficacy. Preclinical studies have shown that minocycline plus N-acetylcysteine have positive synergy resulting in therapeutic effects and a more prolonged therapeutic time window not seen with the individual drugs. This review compares the actions of minocycline and N-acetylcysteine, individually and in combination. Evidence supports that the combination has greater utility to treat traumatic brain injury than the individual drugs.
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    The roles of microRNAs in spinal cord ischemia-reperfusion injury
    Feng-Shou Chen, Xiang-Yi Tong, Bo Fang, Dan Wang, Xiao-Qian Li, Zai-Li Zhang
    2022, 17 (12):  2593-2599.  doi: 10.4103/1673-5374.339471
    Abstract ( 153 )   PDF (2486KB) ( 111 )   Save
    Spinal cord ischemia/reperfusion injury is a devastating medical disorder with poor prognosis that is associated with several pathophysiological conditions. However, multiple stimuli can trigger SCII, so the underlying mechanism of this pathology has not yet been fully established. MicroRNAs (miRNAs) are a class of non-coding RNAs that mediate a variety of nervous system diseases and regulate numerous physiological functions, including apoptosis, autophagy, inflammation, and blood-spinal cord barrier damage. miRNA expression profiles are known to be altered after spinal cord ischemia/reperfusion injury. Therefore, gaining a better understanding of the significant roles that miRNAs play in spinal cord ischemia/reperfusion injury could help develop potential preventive and therapeutic strategies for spinal cord ischemia/reperfusion injury. This review summarizes the current state of our knowledge about the relationship between miRNAs and spinal cord ischemia/reperfusion injury, as well as potential miRNAs that could be targeted to treat spinal cord ischemia/reperfusion injury.
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    An electroencephalography-based human-machine interface combined with contralateral C7 transfer in the treatment of brachial plexus injury
    Meng Zhang, Ci Li, Song-Yang Liu, Feng-Shi Zhang, Pei-Xun Zhang
    2022, 17 (12):  2600-2605.  doi: 10.4103/1673-5374.335838
    Abstract ( 178 )   PDF (2119KB) ( 99 )   Save
    Transferring the contralateral C7 nerve root to the median or radial nerve has become an important means of repairing brachial plexus nerve injury. However, outcomes have been disappointing. Electroencephalography (EEG)-based human-machine interfaces have achieved promising results in promoting neurological recovery by controlling a distal exoskeleton to perform functional limb exercises early after nerve injury, which maintains target muscle activity and promotes the neurological rehabilitation effect. This review summarizes the progress of research in EEG-based human-machine interface combined with contralateral C7 transfer repair of brachial plexus nerve injury. Nerve transfer may result in loss of nerve function in the donor area, so only nerves with minimal impact on the donor area, such as the C7 nerve, should be selected as the donor. Single tendon transfer does not fully restore optimal joint function, so multiple functions often need to be reestablished simultaneously. Compared with traditional manual rehabilitation, EEG-based human-machine interfaces have the potential to maximize patient initiative and promote nerve regeneration and cortical remodeling, which facilitates neurological recovery. In the early stages of brachial plexus injury treatment, the use of an EEG-based human-machine interface combined with contralateral C7 transfer can facilitate postoperative neurological recovery by making full use of the brain’s computational capabilities and actively controlling functional exercise with the aid of external machinery. It can also prevent disuse atrophy of muscles and target organs and maintain neuromuscular junction effectiveness. Promoting cortical remodeling is also particularly important for neurological recovery after contralateral C7 transfer. Future studies are needed to investigate the mechanism by which early movement delays neuromuscular junction damage and promotes cortical remodeling. Understanding this mechanism should help guide the development of neurological rehabilitation strategies for patients with brachial plexus injury.
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    From cradle to grave: neurogenesis, neuroregeneration and neurodegeneration in Alzheimer’s and Parkinson’s diseases
    Debia Wakhloo, Jane Oberhauser, Angela Madira, Sameehan Mahajani
    2022, 17 (12):  2606-2614.  doi: 10.4103/1673-5374.336138
    Abstract ( 310 )   PDF (799KB) ( 454 )   Save
    Two of the most common neurodegenerative disorders – Alzheimer’s and Parkinson’s diseases – are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation. The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease pathology. The major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, following the formation of Lewy bodies, which consists primarily of alpha-synuclein aggregates. However, the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood. Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders. Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients. While some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases, they also highlight the limitations and obstacles to the development of neuroregenerative therapies. In this review, we summarize in vitro and in vivo findings related to neurogenesis, neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.
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    A new age in understanding adult hippocampal neurogenesis in Alzheimer’s disease
    Maya A. Hanspal, Sébastien Gillotin
    2022, 17 (12):  2615-2618.  doi: 10.4103/1673-5374.339472
    Abstract ( 245 )   PDF (956KB) ( 86 )   Save
    Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus, a process named adult hippocampal neurogenesis, contribute to maintaining healthy cognitive functions throughout life. The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues. The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has, however, not been established. This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans. While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease, consensual results have yet to be reached to fully explore this hypothesis. In this review, we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases, especially in Alzheimer’s disease. We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease. In particular, we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems, as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues, could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.
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    Unfolded p53 in non-neuronal cells supports bacterial etiology of Alzheimer’s disease
    Peter W. French
    2022, 17 (12):  2619-2622.  doi: 10.4103/1673-5374.339476
    Abstract ( 284 )   PDF (491KB) ( 88 )   Save
    Alzheimer’s disease has proven to be largely intractable to treatment, despite years of research, and numerous trials of therapies that target the hallmarks of the disease – amyloid plaques and neurofibrillary tangles. The etiology of Alzheimer’s disease remains elusive. There is a growing body of evidence for an infectious trigger of Alzheimer’s disease, and, in particular, the focus has been on the oral pathogen Porphyromonas gingivalis (P. gingivalis). Reports of the expression of a misfolded form of p53 in non-neuronal cells (fibroblasts, peripheral blood mononuclear cells, and B cells) and serum, which appears several years before clinical symptoms manifest, may provide further support for the role of bacteria in general, and P. gingivalis in particular, in the initiation of the disease. This review presents a model of the pathway from initial oral infection with P. gingivalis to amyloid plaque formation and neuronal degeneration, via the steps of chronic periodontitis; secretion of the inflammagens lipopolysaccharide and gingipains into the bloodstream; induction of an inflammatory response in both peripheral cells and tissues; disruption of the blood-brain barrier, and entry into the central nervous system of the inflammagens and the P. gingivalis bacteria themselves. In this model, the misfolded p53 (or “unfolded p53”; up53) is induced in non-neuronal cells and upregulated in serum as a result of oxidative stress due to lipopolysaccharide from P. gingivalis. up53 is therefore a potential biomarker for early diagnosis of the presence of a causative agent of Alzheimer’s disease. Fastidious dental hygiene and aggressive antibiotic treatment may prevent the patient progressing to clinical Alzheimer’s disease if serum up53 is detected at this pre-symptomatic stage.
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    Advantages of Rho-associated kinases and their inhibitor fasudil for the treatment of neurodegenerative diseases
    Qing Wang, Li-Juan Song, Zhi-Bin Ding, Zhi Chai, Jie-Zhong Yu, Bao-Guo Xiao, Cun-Gen Ma
    2022, 17 (12):  2623-2631.  doi: 10.4103/1673-5374.335827
    Abstract ( 399 )   PDF (1273KB) ( 150 )   Save
    Ras homolog (Rho)-associated kinases (ROCKs) belong to the serine-threonine kinase family, which plays a pivotal role in regulating the damage, survival, axon guidance, and regeneration of neurons. ROCKs are also involved in the biological effects of immune cells and glial cells, as well as the development of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Previous studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the abovementioned neurodegenerative diseases by inhibiting neuroinflammation, regulating immune imbalance, repairing the blood-brain barrier, and promoting nerve repair and myelin regeneration. Fasudil, the first ROCKs inhibitor to be used clinically, has a good therapeutic effect on neurodegenerative diseases. Fasudil increases the activity of neural stem cells and mesenchymal stem cells, thus optimizing cell therapy. This review will systematically describe, for the first time, the effects of abnormal activation of ROCKs on T cells, B cells, microglia, astrocytes, oligodendrocytes, and pericytes in neurodegenerative diseases of the central nervous system, summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases, and clarify the possible cellular and molecular mechanisms of ROCKs inhibition. This review also proposes that fasudil is a novel potential treatment, especially in combination with cell-based therapy. Findings from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases.
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    Artificial intelligence for assessment of Stargardt macular atrophy
    Ziyuan Wang, Zhihong Jewel Hu
    2022, 17 (12):  2632-2636.  doi: 10.4103/1673-5374.339477
    Abstract ( 151 )   PDF (41259KB) ( 21 )   Save
    Stargardt disease (also known as juvenile macular degeneration or Stargardt macular degeneration) is an inherited disorder of the retina, which can occur in the eyes of children and young adults. It is the most prevalent form of juvenile-onset macular dystrophy, causing progressive (and often severe) vision loss. Images with Stargardt disease are characterized by the appearance of flecks in early and intermediate stages, and the appearance of atrophy, due to cells wasting away and dying, in the advanced stage. The primary measure of late-stage Stargardt disease is the appearance of atrophy. Fundus autofluorescence is a widely available two-dimensional imaging technique, which can aid in the diagnosis of the disease. Spectral-domain optical coherence tomography, in contrast, provides three-dimensional visualization of the retinal microstructure, thereby allowing the status of the individual retinal layers. Stargardt disease may cause various levels of disruption to the photoreceptor segments as well as other outer retinal layers. In recent years, there has been an exponential growth in the number of applications utilizing artificial intelligence for help with processing such diseases, heavily fueled by the amazing successes in image recognition using deep learning. This review regarding artificial intelligence deep learning approaches for the Stargardt atrophy screening and segmentation on fundus autofluorescence images is first provided, followed by a review of the automated retinal layer segmentation with atrophic-appearing lesions and fleck features using artificial intelligence deep learning construct. The paper concludes with a perspective about using artificial intelligence to potentially find early risk factors or biomarkers that can aid in the prediction of Stargardt disease progression.
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    Endogenous versus exogenous cell replacement for Parkinson’s disease: where are we at and where are we going?
    Theodora Mourtzi, Ilias Kazanis
    2022, 17 (12):  2637-2642.  doi: 10.4103/1673-5374.336137
    Abstract ( 283 )   PDF (2914KB) ( 43 )   Save
    Parkinson’s disease is the second most common neurodegenerative disease and has currently no effective treatment, one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars compacta. In addition, Parkinson’s disease diagnosis is typically done when a significant percentage of the dopaminergic neurons is already lost. In neurodegenerative disorders, some therapeutic strategies could be effective only at inhibiting further degeneration; on the other hand, cell replacement therapies aim at replacing lost neurons, an approach that would be ideal for the treatment of Parkinson’s disease. Many cell replacement therapies have been tested since the 1970s in the field of Parkinson’s disease; however, there are still significant limitations prohibiting a successful clinical application. From the first fetal midbrain intrastriatal graft to the most recent conversion of astrocytes into dopaminergic neurons, we have gained equally, significant insights and questions still looking for an answer. This review aims to summarize the main milestones in cell replacement approaches against Parkinson’s disease. By focusing on achievements and failures, as well as on the additional research steps needed, we aim to provide perspective on how future cell replacement therapies treats Parkinson’s disease.
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    Growth hormone-releasing hormone receptor signaling in experimental ocular inflammation and neuroprotection
    Ling-Ping Cen, Tsz Kin Ng, Wai Kit Chu, Chi Pui Pang
    2022, 17 (12):  2643-2648.  doi: 10.4103/1673-5374.336135
    Abstract ( 169 )   PDF (826KB) ( 84 )   Save
    Both inflammation and anti-inflammation are involved in the protection of retinal cells. Antagonists of the hypothalamic growth hormone-releasing hormone receptor (GHRHR) have been shown to possess potent anti-inflammatory properties in experimental disease models of various organs, some with systemic complications. Such effects are also found in ocular inflammatory and neurologic injury studies. In experimental models of mice and rats, both growth hormone-releasing hormone receptor agonists and antagonists may alleviate death of ocular neural cells under certain experimental conditions. This review explores the properties of growth hormone-releasing hormone receptor agonists and antagonists that lead to its protection against inflammatory responses induced by extrinsic agents or neurologic injures in ocular animal models.
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    Spinal cord injury-induced cognitive impairment: a narrative review
    Oscar V. Alcántar-Garibay, Diego Incontri-Abraham, Antonio Ibarra
    2022, 17 (12):  2649-2654.  doi: 10.4103/1673-5374.339475
    Abstract ( 363 )   PDF (1490KB) ( 126 )   Save
    Spinal cord injury is a serious damage to the spinal cord that can lead to life-long disability. Based on its etiology, spinal cord injury can be classified as traumatic or non-traumatic spinal cord injury. Furthermore, the pathology of spinal cord injury can be divided into two phases, a primary injury phase, and a secondary injury phase. The primary spinal cord injury phase involves the initial mechanical injury in which the physical force of impact is directly imparted to the spinal cord, disrupting blood vessels, axons, and neural cell membranes. After the primary injury, a cascade of secondary events begins, expanding the zone of neural tissue damage, and exacerbating neurological deficits. Secondary injury is a progressive condition characterized by pro-inflammatory cytokines, reactive oxygen species, oxidative damage, excitatory amino acids such as glutamate, loss of ionic homeostasis, mitochondrial dysfunction, and cell death. This secondary phase lasts for several weeks or months and can be further subdivided into acute, subacute, and chronic. One of the most frequent and devastating complications developed among the spinal cord injury population is cognitive impairment. The risk of cognitive decline after spinal cord injury has been reported to be 13 times higher than in healthy individuals. The exact etiology of this neurological complication remains unclear, however, many factors have been proposed as potential contributors to the development of this disorder, such as concomitant traumatic brain injury, hypoxia, anoxia, autonomic dysfunction, sleep disorders such as obstructive sleep apnea, body temperature dysregulation, alcohol abuse, and certain drugs. This review focuses on a deep understanding of the pathophysiology of spinal cord injury and its relationship to cognitive impairment. We highlight the main mechanisms that lead to the development of this neurological complication in patients with spinal cord injury.
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    Neuron-neuron attraction shapes morphology and activity of tissue engineered brain constructs
    Yevgeny Berdichevsky
    2022, 17 (12):  2655-2656.  doi: 10.4103/1673-5374.335815
    Abstract ( 128 )   PDF (630KB) ( 70 )   Save
    The propensity of neuronal stem cells to aggregate is well established. Aggregation of differentiated neurons, particularly those of the brain regions such as the cortex, has been reported more recently (Hasan et al., 2019; Ming et al., 2020). However, the tendency of these cells to aggregate may play a significant role in the brain’s response to injury, and may also be important in developing regenerative therapies to treat brain injury. Some types of injury, including stroke and trauma, result in formation of liquid-filled cavities in the brain (Kazim et al., 2011; Moreau et al., 2012). Cavities are also produced by resection surgery in patients suffering from epilepsy or by surgical brain tumor removal. Brain cavitation represents a loss of neural circuitry and therefore leads to deficits in function and behavior. Cell and tissue transplants and matrix implantation have been suggested as regenerative therapies to improve patient outcomes. The understanding of the processes occurring on cavity walls, which represent an abrupt transition between brain parenchyma and the liquid-filled interior of the cavity, is not complete. The size of the cavity can change dynamically in patients (Jarvis et al., 2012; Patel et al., 2018). This has been attributed to ongoing neuron loss after injury or cell proliferation in cancer patients. Cavity walls are characterized by gliosis, or formation of a glial cell-rich “scar” that separates neurons from liquid-filled cavity interior. This process has been attributed to injury-triggered inflammation and activation of wound healing response.
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    The role of GRP81 lactate receptor in synaptic transmission regulation: does it enhance endocytosis?
    Sergei V. Fedorovich, Tatsiana V. Waseem
    2022, 17 (12):  2657-2658.  doi: 10.4103/1673-5374.335819
    Abstract ( 96 )   PDF (645KB) ( 53 )   Save
    The brain is an expensive tissue in terms of energy consumption. It composes about 2% of body mass and consumes about 20% of all oxygen and calories (Fedorovich and Waseem, 2018). For neurons, glucose is the primary energy substrate, although they are able to use ketone bodies, pyruvate and lactate (Fedorovich and Waseem, 2018). All these compounds can be metabolized directly in the Krebs cycle, bypassing glycolysis. Hence, they are often termed non-glycolytic energy substrates. Out of all potential non-glycolytic substrates, lactate is the most physiological (Magistretti and Allaman, 2018). Ketone bodies could reach concentrations in blood plasma and cerebrospinal fluid which are sufficient to meet metabolic demands of neurons only under specific non-physiological conditions, e.g., ketogenic diet and starvation, or during suckling. In contrast, the normal plasma level of lactate is about 1.5 mM and can reach 20 mM during intensive physical exercise. This is a very high value and this compound undoubtedly contributes to energy production (Mosienko et al., 2015). The lactate concentration in cerebrospinal fluid increases up to 3 mM during brain ischemia (Mosienko et al., 2015). Therefore, the action of lactate on neurons could have certain pathophysiological consequences. In addition, the concept of astrocyte-neuron lactate shuttle has been developed. According to this concept, glycolysis occurs mainly in astrocytes but not in neurons. Lactate is imported from astrocytes to neurons wherein it is further metabolized in mitochondria. Apart from its metabolic function, lactate possesses a signaling function (Morland et al., 2015; Mosienko et al., 2015; Magistretti and Allaman, 2018).
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    Glial cells in the center of future ischemic stroke treatments
    Ivó H. Hernández, Maria José Pérez-Álvarez
    2022, 17 (12):  2659-2660.  doi: 10.4103/1673-5374.339480
    Abstract ( 119 )   PDF (3145KB) ( 71 )   Save
    In the last century, increasing knowledge about glial cells has revealed their importance in brain physiology and disease and an exciting potential target for new therapeutic interventions (Hernández et al., 2021).
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    Not only myelination: the immune-inflammatory functions of oligodendrocytes
    Marta Boccazzi, Stefano Raffaele, Marta Fumagalli
    2022, 17 (12):  2661-2663.  doi: 10.4103/1673-5374.342678
    Abstract ( 479 )   PDF (2090KB) ( 192 )   Save
    Oligodendrocytes (OLs) are highly specialized cells of the central nervous system (CNS). Their primary and most investigated role is to form myelin, a multilamellar fatty membrane that enwraps axons ensuring their insulation and the saltatory conduction of nerve impulses. The formation of myelin is a complex process during which the OL precursor cells (OPCs, also known as NG2-glia) become mature OLs through a highly regulated program of differentiation. In addition, OPCs persist in the adult grey and white matter parenchyma, representing approximately 6% of the total number of CNS cells. Beyond their role in myelin generation and turn-over, it is now clear that OPCs have the capability to control tissue homeostasis and to sense and react to inflammation which characterizes many neurological diseases.
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    Riding the rails – different modes for RNA complex transport in axons
    Ofri Abraham, Mike Fainzilber
    2022, 17 (12):  2664-2665.  doi: 10.4103/1673-5374.339478
    Abstract ( 154 )   PDF (296KB) ( 88 )   Save
    Neurons are highly polarized cells with axons that innervate distant targets. The distance of subcellular compartments from the nucleus requires sophisticated transport mechanisms and local action of vital processes for proper function and rapid responses to local stimuli (Terenzio et al., 2017). This is partially achieved by transport of mRNAs to subcellular locations and regulation of local translation for axonal growth, branching, synaptic plasticity, and regeneration, among other needs. Axonally synthesized proteins support neuronal survival, and axonal development, maintenance, and growth (Rishal and Fainzilber, 2014; Dalla Costa et al., 2021). Thus, understanding the mechanisms that promote RNA transport to subcellular locations in neurons will contribute to the development of novel strategies to enhance axon regeneration and survival.
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    Astrocytic aquaporin 4 subcellular translocation as a therapeutic target for cytotoxic edema in ischemic stroke
    Adjanie Patabendige, Ruoli Chen
    2022, 17 (12):  2666-2668.  doi: 10.4103/1673-5374.339481
    Abstract ( 101 )   PDF (1116KB) ( 61 )   Save
    Brain edema is a common feature of several brain diseases (e.g., stroke, traumatic brain injury, hydrocephalus, brain cancer, and brain infections). Brain edema leads to increased intracranial pressure and worsens outcomes in ischemic stroke patients. Conventional treatments to control brain edema, thus reducing intracranial pressure include different osmotherapeutics, hyperventilation, tromethamine, hypothermia, and barbiturate coma. However, level 1 evidence of efficacy is lacking for these treatments, with some being harmful rather than beneficial (Bardutzky and Schwab, 2007). It has been proposed aquaporin 4 (AQP4) can be a novel drug target for treating brain edema (Vandebroek and Yasui, 2020). AQP4 is a small integral membrane protein and is strongly expressed in the brain. It has a highly polarized expression towards the abluminal side of astrocytic endfeet that surrounds the brain vasculature and is also expressed on the subpial and subependymal astrocyte processes, as well as basolateral membranes of ependymal cells (Patabendige et al., 2021). AQP4 is primarily involved in bidirectional water flux, but also has diverse roles such as Ca2+ signaling, K+ buffering, neuroinflammation, and waste clearance (Verkman et al., 2017). Astroglial water movements induced by AQP4 have been shown to be a driving force contributing to the paravascular clearance of interstitial solutes like amyloid-β, thus participating in the so-called “glymphatic system” (Iliff et al., 2012).
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    Patient-derived skin fibroblasts as a model to study frontotemporal lobar degeneration
    Dorit Hoffmann, Annakaisa Haapasalo
    2022, 17 (12):  2669-2671.  doi: 10.4103/1673-5374.335814
    Abstract ( 110 )   PDF (9498KB) ( 14 )   Save
    Frontotemporal lobar degeneration (FTLD) is one of the most common causes of early-onset dementia in patients under the age of 65 years. It is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, causing atrophy in the temporal and frontal lobes of the brain. This is accompanied by progressive cognitive dysfunction, behavioral changes, difficulties in understanding or producing speech, and often also neuropsychiatric symptoms (Haapasalo and Remes, 2015). Moreover, the clinical, genetic, and neuropathological features of FTLD may overlap with those of amyotrophic lateral sclerosis (ALS). Motor dysfunction is commonly present in FTLD patients and a portion of ALS patients experience frontal and temporal lobe dysfunction (Smith et al., 2019). In addition to the sporadic forms of FTLD, which are not linked to any known mutations, approximately half of the FTLD cases are caused by different mutations in several genes, including GRN (granulin), MAPT (microtubule-associated protein tau), VCP (valosin-containing protein), TARDBP (TAR DNA-binding protein 43 kDa; TDP-43), FUS (fused in sarcoma) and C9orf72 (chromosome 9 open reading frame 72). Of these, the GGGGCC hexanucleotide repeat expansion in the C9orf72 gene (C9-HRE) is the most common genetic cause of both FTLD and ALS (Haapasalo and Remes, 2015). The expansion length can typically vary from hundreds to thousands of repeats in affected individuals.
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    Deciphering tau-related dementia using human iPSC lines: electrophysiological perspectives of future studies
    Olga Kopach
    2022, 17 (12):  2672-2674.  doi: 10.4103/1673-5374.339482
    Abstract ( 77 )   PDF (494KB) ( 98 )   Save
    To date, no disease-modifying treatment or cure is available for dementia. This disorder is becoming more common as the global population ages. There has been over several decades of extensive research focusing on how the pathology develops and progresses causing memory loss, brain damage, and eventually death – it provides the field with a deep understanding of what proteins, peptides, and signaling molecules contribute to neurodegeneration at the molecular, genetic, and cellular levels. The problem is, however, that there is a wide range of dementia types. A given disease can span heterogeneous clinical syndromes with diverse symptomatology, no matter whether it is “senile dementia” or an early-onset form; moreover, it encompasses the mixed features of many syndromes in later stages of the disease. In confirmation of this, animal models, despite being purposely designed and widely used in dementia research, usually do not fully replicate neuropathological profiles that match pathological changes found in the human brain, much less in cognitive and intellectual decline as it occurs in patients. This made it hitherto insurmountable for scientists to conceptualize the basis underlying nerve cell dysfunctions in a range of dementias.
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    Prothrombin kringle-2, a mediator of microglial activation: new insight in Alzheimer’s disease pathogenesis
    Jae Man Lee, Sang Ryong Kim
    2022, 17 (12):  2675-2676.  doi: 10.4103/1673-5374.335813
    Abstract ( 133 )   PDF (1259KB) ( 71 )   Save
    In 1907, Dr. Alois Alzheimer, a Bavarian-born German psychiatrist and neuropathologist, published an article describing the clinical and neuropathological features of an unclassified psychiatric disorder. The disorder was later named AD and is currently the most common brain disorder (Takata et al., 2021). AD involves the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau proteins in the brain, which are associated with senile plaques and neurofibrillary tangles, respectively (Vergara et al., 2019; Takata et al., 2021). AD is characterized by cognitive impairment and memory loss with hippocampal neurodegeneration (Kim et al., 2021).
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    Resolving the age-related decline in central nervous system myelin turnover and drug discovery for oligodendroglial rejuvenation
    Andrea Domenico Rivera, Arthur Morgan Butt, Kasum Azim
    2022, 17 (12):  2677-2678.  doi: 10.4103/1673-5374.338995
    Abstract ( 157 )   PDF (1578KB) ( 90 )   Save
    Just over half of the weight of an entire adult human brain is attributed to myelin, which wraps around neuronal axons and is essential for superfast axonal conduction and neuronal integrity. In the central nervous system, it is the function of specialized cells called oligodendrocytes (OLs) to make myelin, which is made up of lipids and proteins. OLs are generated throughout life by a significant population of oligodendrocyte progenitor cells (OPCs) that are responsible for the lifelong generation of OLs and myelin, essential for learning, as well as repair following pathological insults (i.e. in demyelinating diseases that include multiple sclerosis) (Simons and Nave, 2015; Philips and Rothstein, 2017). Changes in myelin content in the human brain over the lifespan of individuals have been well documented, as well as evidence of myelin loss in rodent models using classical histological approaches (Bartzokis et al., 2012; Soreq et al., 2017). During the normal course of aging, degenerative alterations in myelin (myelin thinning, formation of myelin balloons, loss of myelinated tracts) have been shown to precede overt neuronal loss and ultimately lead to negative clinical outcomes, which manifest as the dramatic decline in the speed and efficiency of neuronal networks [reviewed in Rivera et al. (2021a)]. However, a gap in our knowledge was the precise changes in OL and myelin genes at the transcriptome level, which can inform the genetic programs for targeting rejuvenation (Neumann et al., 2019; Rivera et al., 2021b).
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    The long-COVID-19 in older adults: facts and conjectures
    Tino Emanuele Poloni, Valentina Medici, Antonio Zito, Arenn Faye Carlos
    2022, 17 (12):  2679-2681.  doi: 10.4103/1673-5374.339483
    Abstract ( 160 )   PDF (1678KB) ( 75 )   Save
    The coronavirus disease-19 (COVID-19) has greatly affected the overall health of the elderly population through direct biological (infection-related) and indirect psychosocial (quarantine- and isolation-related) effects. Because the severe form of COVID-19 most frequently targets this population, the prevalence of long-term sequelae is expected to rise consequentially in people ≥ 65 years old. The prominent neuropsychiatric consequences of COVID-19 and the cognitive frailty seen in older adults can both have a negative impact on their mental health. To explore the behavioral, neurological, and psychosocial consequences of COVID-19, we conducted separate studies on different populations of older adult people residing in Lombardy – the Italian epicenter of the first pandemic wave in spring 2020. In one study, we found that behavioral changes (i.e., delirium) were a frequent symptom of COVID-19, manifesting at disease onset and preceding the typical symptoms in about 1/3 (36.8%) of cases, particularly in patients with neurocognitive disorders (NCD), such as dementia (major-NCD) or mild cognitive impairment (mild-NCD). Delirium was also associated with short-term mortality and potential long-term cognitive sequelae (Poloni et al., 2020). To uncover the neuropathology underlying behavioral changes and their possible effects over time, we compared 9 brains of elderly patients who had died of COVID-19 (with and without dementia) with 6 brains from age-matched non-COVID controls. The main finding was an excessive innate immune response, represented by microglial hyperactivation. Although we observed severe inflammatory changes especially in the brainstem, we did not find neuropathological evidence suggestive of SARS-CoV-2 replication in the brain (Gagliardi et al., 2021; Poloni et al., 2021). In a study evaluating the psychosocial consequences of the lockdown due to the pandemic (Carlos et al., 2021), we observed that those with mild-moderate dementia were unable to cope and adapt to the life changes caused by the restrictions and consequently suffered from depression and cognitive decline. Before COVID, patients with dementia normally engaged in habitual daily activities. The disruption of said routines, the inability to engage in new activities, and the incapability to use modern technologies all triggered psychological distress and some degree of cognitive and motor regression (Figure 1A). Although lockdown (the sternest form of quarantine in history) protected them from COVID-19, the social seclusion and the inability to access primary care treatment – aggravated by an unprepared and unequipped primary care health sector – caused further complications (Carlos et al., 2021). Moreover, the general effects of the pandemic in terms of loss of “individual freedom”, economic crisis, and mass media conditioning should not be overlooked due to their possible impact on mental health.
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    Cellular response against cytosolic leakage of mitochondrial DNA: insights into the pathology of Parkinson’s disease
    Akiko Sakai, Hideaki Matsui
    2022, 17 (12):  2682-2684.  doi: 10.4103/1673-5374.335816
    Abstract ( 156 )   PDF (545KB) ( 47 )   Save
    Mitochondria are important organelles for cellular metabolism and homeostasis, and their abnormalities are implicated in various diseases. Since mitochondria originate from protobacterium, their components are easily recognized by pathogen sensors called pattern-recognition receptors as foreign substances in the cytoplasm. This is prominent for mitochondrial DNA (mtDNA) which has different properties from nuclear DNA, such as low, if any, methylation status, vulnerability to oxidation due to the proximity to the oxidative phosphorylation machinery, and its circular structure. Recent studies indicate that perturbations in mitochondrial function and homeostasis cause mtDNA to leak into the cytoplasm, where it triggers the innate immune response (West and Shadel, 2017). Although inflammatory response is a cellular strategy to resist viral infections, it can also lead to undesirable outcomes by damaging own cells and tissues. Recently, we found that mtDNA leak into the cytoplasm in Parkinson’s disease (PD) models of human cells and zebrafish. Furthermore, we revealed that the leaked mtDNA is detected by a viral DNA sensor interferon gamma inducible protein 16 (IFI16), which has not been implicated in mtDNA recognition, and triggers inflammatory responses. Decreasing mtDNA sensor or overexpression of mtDNA-degrading enzymes in the PD model eliminated cytosolic mtDNA and suppressed the inflammatory response as well as neurodegeneration. Importantly, accumulation of mtDNA and IFI16 in the cytoplasm was also observed in autopsy brains of human PD patients, pointing to pathological relevance (Matsui et al., 2021). In this perspective, we will first overview the various cases and pathways by which mtDNA leakage triggers inflammatory responses, and then in particular look into how mtDNA-mediated inflammation can explain the pathogenesis of PD, discussing the ways to ameliorate the pathological conditions.
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    Implication of 14-3-3ζ-BDNF pathway in long-lasting memory enhancement and the rescue from memory deficits
    Mariam Masmudi-Martín, Irene Navarro-Lobato, Zafar U. Khan
    2022, 17 (12):  2685-2686.  doi: 10.4103/1673-5374.335817
    Abstract ( 170 )   PDF (603KB) ( 45 )   Save
    Intact memory function is critical for carrying out daily life activities, such as managing finances, remembering to take medications, driving in familiar environments, remembering a grandchild’s birthday, and learning to use a new computer. However, memory deficits not only accompany normal aging but are also comorbid with many psychiatric, neurological, and neurodegenerative diseases. Intellectual disability, autism, attention deficit disorder, learning disability, schizophrenia, and depression all have memory deficit components, as do Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and other neurodegenerative diseases (Khan et al., 2014). Therefore, a large proportion of the human population is affected by this brain disorder. In addition, according to the US Census Bureau and Eurostat estimations, the aged population (individuals over the age of 65 years) will double within three decades. Thus, the number of persons with memory deficits is expected to increase drastically, as is the social and economic burden associated with their treatment and care. Cognition-enhancing pharmacological agents are viewed as a strategy for treating memory deficits or slowing the effects of aging on memory function. Some of the most thoroughly studied examples of memory enhancers are partial agonists of the N-methyl-D-aspartic acid receptor, D-cycloserine and D-serine; synthetic ampakines that allow glutamate to exert a prolonged effect on α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptors; and stimulant drugs that inhibit monoamine reuptake, including amphetamines (Adderall), methylphenidate (Ritalin) and modafinil (Provigil); and donepezil (Aricept), which was designed to inhibit the enzyme acetylcholinesterase, which is responsible for degrading acetylcholine. These agents and other memory enhancers that have been studied to date have failed to produce consistent and invariable effects across various types of memory and have shown limited to no effect on memory deficits. Recently, we discovered that the expression of regulator of G protein signaling 14 of 414 amino acids (RGS14414) in the brain not only induced memory enhancement of multiple types of memory but also was sufficient for the rescue of recognition, spatial, and temporal memory, which are kinds of episodic memory that are primarily affected in patients or individuals with memory dysfunctions, in rodent models of aging and Alzheimer’s disease (López-Aranda et al., 2009; Masmudi-Martín et al., 2019; Navarro-Lobato et al., 2021). This RGS14414-mediated memory enhancement was facilitated through an increase in 14-3-3ζ activity (Navarro-Lobato et al., 2021).
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    Alpha-Klotho in Parkinson’s disease: a perspective on experimental evidence and potential clinical implications
    Piergiorgio Grillo, Michele Basilicata, Tommaso Schirinzi
    2022, 17 (12):  2687-2688.  doi: 10.4103/1673-5374.335820
    Abstract ( 185 )   PDF (377KB) ( 97 )   Save
    α-Klotho protein (KL) has been discovered more than 20 years ago, and immediately emerged as a master regulator of aging-related processes, which basically operates as an anti-aging factor. It is expressed through the entire human body, representing the choroid plexus and the kidney as the most active sources at the central nervous system (CNS) and periphery level respectively. To a lesser extent, also the parathyroid gland, the adipose tissue, and the liver express KL.
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    How physical and motor training affect cognitive performance: lessons from an inflammatory molecule
    Margherita Maffei, Marco Mainardi
    2022, 17 (12):  2689-2690.  doi: 10.4103/1673-5374.339486
    Abstract ( 176 )   PDF (542KB) ( 72 )   Save
    Our phenotype includes not only physical features, but also behavioral outputs such as motor schemes and learned skills, and is the result of a complex interaction between genetic background and environment. In fact, a good fraction of last decades’ biomedical efforts were dedicated to understanding how different elements (e.g., genetic polymorphisms, lifestyle components) participate in this interplay, ultimately contributing to affect a given phenotype up to the point of steering it towards pathology. Genetic and epigenetic elements are relatively easy to analyze individually using a reductionist approach, for instance via loss- or gain-of-function studies in cellular and animal models; the effects of nutrients, drugs, pollutants can be similarly tested as single specific stimuli. Not as easy is to establish in rigorous terms and to understand the molecular mechanisms through which different levels of education, social interaction, exposure to a playful environment, psychological stress, to voluntary physical activity, may impact our brain phenotype, whose combined complexity is hard to reproduce in the experimental setting. 
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    Inflammatory cytokine production in a mouse model of Aicardi-Goutieres syndrome and neuroinflammation
    Clayton A. Wiley, Qingde Wang
    2022, 17 (12):  2691-2692.  doi: 10.4103/1673-5374.335808
    Abstract ( 95 )   PDF (301KB) ( 32 )   Save
    Most neurological diseases are associated with a tissue injury that is detected by the innate immune response (IIR), leading to an inflammatory component. The IIR is activated through conserved Pattern Recognition Receptors, including membrane bound Toll like receptors (TLRs), intracellular nucleotide-binding oligomerization domain like receptors and the receptors for advanced glycation end-products (Amor et al., 2010; Heppnerrt et al., 2015). These receptors detect highly conserved structural motifs of damaged or stressed tissues (danger-associated molecular patterns (DAMP)). Cytosolic receptors of nucleic acids, such as cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and melanoma differentiation associated gene 5 (MDA-5) can also trigger IIR activation leading to interferon (IFN) and IFN stimulated gene (ISG) expression through DNA/RNA sensing signaling pathways (Yang and Li, 2020). Once bound to their cognate receptor, the recognition complexes migrate into the nucleus and initiate different signaling cascades that eventually lead to central nervous system (CNS) inflammation.
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    Cannabidiol preferentially binds TRPV2: a novel mechanism of action
    Elisa Landucci, Domenico E. Pellegrini-Giampietro, Alessandra Gianoncelli, Giovanni Ribaudo
    2022, 17 (12):  2693-2694.  doi: 10.4103/1673-5374.335821
    Abstract ( 128 )   PDF (806KB) ( 52 )   Save
    Plants from the genus Cannabis, and strains of Cannabis sativa in particular, have been used in medicine since ancient times. The Cannabis plant contains more than 500 chemical compounds, with two main phytocannabinoids consisting of Δ9-tetrahydrocannabinol (THC), the psychoactive constituent, and cannabidiol (CBD), which does not bear this effect. This paper aims at providing a perspective on the potential therapeutic effects of CBD based on its preferential interaction with transient potential receptor V2 (TRPV2).
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    Proapoptotic RECS1: a requisite gateway to lysosomal dysfunction and death
    Philippe Pihán, Mateus Milani, Claudio Hetz
    2022, 17 (12):  2695-2696.  doi: 10.4103/1673-5374.339487
    Abstract ( 137 )   PDF (826KB) ( 58 )   Save
    For a long time since their discovery by Christian de Duve in the 1950s, lysosomes have been referred to almost exclusively as passive garbage bags; the endpoint in the degradation of intra- and extracellular cargo. The catabolic function of lysosomes is accomplished by an array of more than 60 acid hydrolases, which together break down a wide variety of biological macromolecules, including proteins, lipids, carbohydrates, and nucleic acids, for reutilization in the metabolic processes of the cell. For their optimal function, these enzymes require an acidic intraluminal pH of ~4.5, which is maintained by the joint action of a proton pump, the vacuolar H+-ATPase, and several ion channels embedded in the lysosomal limiting membrane. Nowadays, lysosomes are envisioned as complex signaling hubs, integrating diverse stimuli about the cell’s metabolic status to coordinate different adaptive responses (Ballabio and Bonifacino, 2020). The lysosome can also induce cell death signals in response to certain conditions, such as infections and treatment with lysosomotropic drugs, which leads to lysosomal membrane permeabilization (LMP) and the release of cathepsins, resulting in lysosomal-mediated cell death (Figure 1A, left). Lysosomes are also important intracellular calcium reservoirs. Lysosomal calcium plays essential functions in several cellular processes, such as lysosomal fusion with other vesicles, lysosomal biogenesis, and exocytosis (Figure 1A, right). In addition, lysosomal calcium is critical for lysosomal acidification, probably through the establishment of physical contacts with the endoplasmic reticulum. As a signaling molecule, calcium release from the lysosome through the transient receptor potential cation channel, mucolipin subfamily member 1 (TRPML1) activates the autophagic signaling pathway through the transcription factor EB (TFEB), which upregulates genes involved in autophagy and lysosomal biogenesis. Only three main types of lysosomal Ca2+ channels have been identified: the transient receptor potential channels of the mucolipin family, two-pore channels (TPC), and the trimeric Ca2+ two-transmembrane channel P2X4. However, the lysosomal membrane comprises dozens of integral and peripheral proteins of unknown functions. The identification of new regulators of lysosomal biology is essential to better understand the role of lysosomes in the global regulation of adaptive and pro-dead responses, and their close connection to cell metabolism. 
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    In search for the “idyllic” animal model to evaluate ocular pathologies and translate new therapies to improve human health
    Francisco M. Nadal-Nicolás, Kiyoharu J. Miyagishima, Wei Li
    2022, 17 (12):  2697-2699.  doi: 10.4103/1673-5374.339485
    Abstract ( 119 )   PDF (29342KB) ( 32 )   Save
    The retina is a highly specialized neural tissue that encodes information of vision, a vital sensory modality for most species. Although the retina also contributes to other non‐image‐forming signals (e.g. entrainment of circadian clocks), vision chiefly enables animals to interpret and navigate their environment (despite the diverse variety of species and lifestyles; Baden et al., 2020) and also to interact with other animals. Thus, features such as high visual resolution and color discrimination are important for interactive behaviors like prey capture and also for social animals, including primates, that establish a dominance hierarchy.
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    Interferon-gamma and neuropathy: balance between pain and neuroprotection
    Valentina Ferrara, Alessandra Toti, Carla Ghelardini, Lorenzo Di Cesare Mannelli
    2022, 17 (12):  2700-2701.  doi: 10.4103/1673-5374.339484
    Abstract ( 178 )   PDF (284KB) ( 132 )   Save
    Chronic pain is sustained by a phenomenon of hyper-activation of nociceptive neurons both at peripheral (peripheral sensitization) and central (central sensitization) levels. The onset and maintenance of pain, however, is to be found in the interaction among the various cell populations in the nervous tissue including neurons and glia (Nam et al., 2016). The pathogenesis of neuropathic pain is extremely complex depending on the primary cause of nerve damage, e.g. traumatic nerve injury is associated with a robust inflammatory response while chemotherapy-induced pain is characterized by a modest phlogistic component (Di Cesare Mannelli et al., 2013). Despite these differences, a powerful common concept to explain the cellular mechanisms underlying pain is the activation of glia. The existence of a causal relationship between glia response and pain has been amply demonstrated starting from the mid 1990s (Colburn RW et al., 1999). During the development of neuropathy, a pivotal role has been imputed to microglia, whereas astrocytes are involved in the chronicization of pain (Scholz et al., 2007).
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    Sodium selenite promotes neurological function recovery after spinal cord injury by inhibiting ferroptosis
    Yi-Xin Chen, Talifu Zuliyaer, Bin Liu, Shuang Guo, De-Gang Yang, Feng Gao, Yan Yu, Ming-Liang Yang, Liang-Jie Du, Jian-Jun Li
    2022, 17 (12):  2702-2709.  doi: 10.4103/1673-5374.339491
    Abstract ( 273 )   PDF (6962KB) ( 96 )   Save
    Ferroptosis is a recently discovered form of iron-dependent cell death, which occurs during the pathological process of various central nervous system diseases or injuries, including secondary spinal cord injury. Selenium has been shown to promote neurological function recovery after cerebral hemorrhage by inhibiting ferroptosis. However, whether selenium can promote neurological function recovery after spinal cord injury as well as the underlying mechanism remain poorly understood. In this study, we injected sodium selenite (3 µL, 2.5 µM) into the injury site of a rat model of T10 vertebral contusion injury 10 minutes after spinal cord injury modeling. We found that sodium selenite treatment greatly decreased iron concentration and levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Furthermore, sodium selenite increased the protein and mRNA expression of specificity protein 1 and glutathione peroxidase 4, promoted the survival of neurons and oligodendrocytes, inhibited the proliferation of astrocytes, and promoted the recovery of locomotive function of rats with spinal cord injury. These findings suggest that sodium selenite can improve the locomotive function of rats with spinal cord injury possibly through the inhibition of ferroptosis via the specificity protein 1/glutathione peroxidase 4 pathway. 
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    Necrostatin-1 decreases necroptosis and inflammatory markers after intraventricular hemorrhage in mice
    Chang Liu, Yi Cao, Hao-Xiang Wang, Long Zhao, Ya-Xing Chen, Kun-Hong Zhong, Gao-Wei Li, Guo-Qing Wang, Ke-Ru Huang, Ai-Ping Tong, Liang-Xue Zhou
    2022, 17 (12):  2710-2716.  doi: 10.4103/1673-5374.339488
    Abstract ( 143 )   PDF (6931KB) ( 20 )   Save
    Necrostatin-1, an inhibitor of necroptosis, can effectively inhibit necrotic apoptosis in neurological diseases, which results in the inhibition of inflammation, endoplasmic reticulum stress, and reactive oxygen species production and substantial improvement of neurological function. However, the effects of necrostatin-1 on intraventricular hemorrhage (IVH) remain unknown. In this study, we established a mouse model of IVH by injecting autologous blood into the lateral ventricle of the brain. We also injected necrostatin-1 into the lateral ventricle one hour prior to IVH induction. We found that necrostatin-1 effectively reduced the expression levels of the necroptosis markers receptor-interacting protein kinase (RIP)1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphorylated (p)-RIP3, and p-MLKL and the levels of interleukin-1β , interleukin-6, and tumor necrosis factor-α in the surrounding areas of the lateral ventricle. However, necrostatin-1 did not reduce ependymal ciliary injury or brain water content. These findings suggest that necrostatin-1 can prevent local inflammation and microglial activation induced by IVH but does not greatly improve prognosis.
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    Exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation after traumatic brain injury
    Liang Wen, Ya-Dong Wang, Dong-Feng Shen, Pei-Dong Zheng, Meng-Di Tu, Wen-Dong You, Yuan-Run Zhu, Hao Wang, Jun-Feng Feng, Xiao-Feng Yang
    2022, 17 (12):  2717-2724.  doi: 10.4103/1673-5374.339489
    Abstract ( 299 )   PDF (5958KB) ( 240 )   Save
    Exosomes derived from bone marrow mesenchymal stem cells can inhibit neuroinflammation through regulating microglial phenotypes and promoting nerve injury repair. However, the underlying molecular mechanism remains unclear. In this study, we investigated the mechanism by which exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation. Our in vitro co-culture experiments showed that bone marrow mesenchymal stem cells and their exosomes promoted the polarization of activated BV2 microglia to their anti-inflammatory phenotype, inhibited the expression of proinflammatory cytokines, and increased the expression of anti-inflammatory cytokines. Our in vivo experiments showed that tail vein injection of exosomes reduced cell apoptosis in cortical tissue of mouse models of traumatic brain injury, inhibited neuroinflammation, and promoted the transformation of microglia to the anti-inflammatory phenotype. We screened some microRNAs related to neuroinflammation using microRNA sequencing and found that microRNA-181b seemed to be actively involved in the process. Finally, we regulated the expression of miR181b in the brain tissue of mouse models of traumatic brain injury using lentiviral transfection. We found that miR181b overexpression effectively reduced apoptosis and neuroinflamatory response after traumatic brain injury and promoted the transformation of microglia to the anti-inflammatory phenotype. The interleukin 10/STAT3 pathway was activated during this process. These findings suggest that the inhibitory effects of exosomes derived from bone marrow mesenchymal stem cells on neuroinflamation after traumatic brain injury may be realized by the action of miR181b on the interleukin 10/STAT3 pathway. 
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    Altered intra- and inter-network brain functional connectivity in upper-limb amputees revealed through independent component analysis
    Bing-Bo Bao, Hong-Yi Zhu, Hai-Feng Wei, Jing Li, Zhi-Bin Wang, Yue-Hua Li, Xu-Yun Hua, Mou-Xiong Zheng, Xian-You Zheng
    2022, 17 (12):  2725-2729.  doi: 10.4103/1673-5374.339496
    Abstract ( 157 )   PDF (4043KB) ( 54 )   Save
    Although cerebral neuroplasticity following amputation has been observed, little is understood about how network-level functional reorganization occurs in the brain following upper-limb amputation. The objective of this study was to analyze alterations in brain network functional connectivity (FC) in upper-limb amputees (ULAs). This observational study included 40 ULAs and 40 healthy control subjects; all participants underwent resting-state functional magnetic resonance imaging. Changes in intra- and inter-network FC in ULAs were quantified using independent component analysis and brain network FC analysis. We also analyzed the correlation between FC and clinical manifestations, such as pain. We identified 11 independent components using independent component analysis from all subjects. In ULAs, intra-network FC was decreased in the left precuneus (precuneus gyrus) within the dorsal attention network and left precentral (precentral gyrus) within the auditory network; but increased in the left Parietal_Inf (inferior parietal, but supramarginal and angular gyri) within the ventral sensorimotor network, right Cerebelum_Crus2 (crus II of cerebellum) and left Temporal_Mid (middle temporal gyrus) within the ventral attention network, and left Rolandic_Oper (rolandic operculum) within the auditory network. ULAs also showed decreased inter-network FCs between the dorsal sensorimotor network and ventral sensorimotor network, the dorsal sensorimotor network and right frontoparietal network, and the dorsal sensorimotor network and dorsal attention network. Correlation analyses revealed negative correlations between inter-network FC changes and residual limb pain and phantom limb pain scores, but positive correlations between inter-network FC changes and daily activity hours of stump limb. These results show that post-amputation plasticity in ULAs is not restricted to local remapping; rather, it also occurs at a network level across several cortical regions. This observation provides additional insights into the plasticity of brain networks after upper-limb amputation, and could contribute to identification of the mechanisms underlying post-amputation pain.
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    Epidural oscillating field stimulation increases axonal regenerative capacity and myelination after spinal cord trauma
    Maria Bacova, Katarina Bimbova, Alexandra Kisucka, Nadezda Lukacova, Jan Galik
    2022, 17 (12):  2730-2736.  doi: 10.4103/1673-5374.339497
    Abstract ( 179 )   PDF (3719KB) ( 122 )   Save
    Oscillating field stimulation (OFS) with regular alterations in the polarity of electric current is a unique, experimental approach to stimulate, support, and potentially guide the outgrowth of both sensory and motor nerve fibers after spinal cord injury (SCI). In previous experiments, we demonstrated the beneficial effects of OFS in a 4-week survival period after SCI. In this study, we observed the major behavioral, morphological, and protein changes in rats after 15 minutes of T9 spinal compression with a 40 g force, followed by long-lasting OFS (50 µA), over a 8-week survival period. Three groups of rats were analyzed: rats after T9 spinal compression (SCI group); SCI rats subjected to implantation of active oscillating field stimulator (OFS + SCI group); and SCI rats subjected to nonfunctional OFS (nOFS + SCI group). Histopathological analysis of spinal tissue indicated a strong impact of epidural OFS on the reduction of tissue and myelin loss after SCI in the segments adjacent to the lesion site. Quantitative fluorescent analysis of the most affected areas of spinal cord tissue revealed a higher number of spared axons and oligodendrocytes of rats in the OFS + SCI group, compared with rats in the SCI and nOFS + SCI groups. The protein levels of neurofilaments (NF-l), growth-associated protein-43 (marker for newly sprouted axons), and myelin basic protein in rats were signifiantly increased in the OFS + SCI group than in the nOFS + SCI and SCI groups. This suggests a supporting role of the OFS in axonal and myelin regeneration after SCI. Moreover, rats in the OFS + SCI group showed great improvements in sensory and motor functions than did rats in the nOFS + SCI and SCI groups. All these findings suggest that long-lasting OFS applied immediately after SCI can provide a good microenviroment for recovery of damaged spinal tissue by triggering regenreative processes in the acute phase of injury.
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    The mechanism by which hyperbaric oxygen treatment alleviates spinal cord injury: genome-wide transcriptome analysis
    Zhen-Cheng Sun, Fang Liang, Jing Yang, Yong Hai, Qing-Jun Su, Xue-Hua Liu
    2022, 17 (12):  2737-2742.  doi: 10.4103/1673-5374.339498
    Abstract ( 163 )   PDF (5395KB) ( 71 )   Save
    Accumulating studies have demonstrated that hyperbaric oxygen (HBO) treatment alleviates spinal cord injury (SCI). However, the underlying mechanism by which HBO alleviates SCI remains to be elucidated. In this study, we performed genome-wide transcriptional profiling of the spinal cord between SCI mice and mice that received HBO treatment by high-throughput RNA sequencing at 1 week after SCI. We also compared genome-wide transcriptional profiles from SCI mice and sham-operated mice. We found 76 differentially co-expressed genes in sham-operated mice, SCI mice, and HBO-treated SCI mice. Using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, we identified the biological characteristics of these differentially expressed genes from the perspectives of cell component, biological process, and molecular function. We also found enriched functional pathways including ferroptosis, calcium signaling pathway, serotonergic synapse, hypoxia-inducible factor-1 signaling pathway, cholinergic synapse, and neuroactive ligand-receptor interaction. We performed quantitative reverse transcription-polymerase chain reaction and validated that HBO treatment decreased the expression of Hspb1 (heat shock protein beta 1), Hmox1 (heme oxygenase 1), Ftl1 (ferritin light polypeptide 1), Tnc (tenascin C) and Igfbp3 (insulin-like growth factor binding protein 3) and increased the expression of Slc5a7 (solute carrier family 5 choline transporter member 7) after SCI. These results revealed the genome-wide transcriptional profile of the injured spinal cord after HBO treatment. Our findings contribute to a better understanding of the mechanism by which HBO treats SCI and may provide new targets for SCI intervention.
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    A multiple-tissue-specific magnetic resonance imaging model for diagnosing Parkinson’s disease: a brain radiomics study
    Xiao-Jun Guan, Tao Guo, Cheng Zhou, Ting Gao, Jing-Jing Wu, Victor Han, Steven Cao, Hong-Jiang Wei, Yu-Yao Zhang, Min Xuan, Quan-Quan Gu, Pei-Yu Huang, Chun-Lei Liu, Jia-Li Pu, Bao-Rong Zhang, Feng Cui, Xiao-Jun Xu, Min-Ming Zhang
    2022, 17 (12):  2743-2749.  doi: 10.4103/1673-5374.339493
    Abstract ( 375 )   PDF (20460KB) ( 204 )   Save
    Brain radiomics can reflect the characteristics of brain pathophysiology. However, the value of T1-weighted images, quantitative susceptibility mapping, and R2* mapping in the diagnosis of Parkinson’s disease (PD) was underestimated in previous studies. In this prospective study to establish a model for PD diagnosis based on brain imaging information, we collected high-resolution T1-weighted images, R2* mapping, and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019. According to the inclusion time, 123 PD patients and 121 healthy controls were assigned to train the diagnostic model, while the remaining 106 subjects were assigned to the external validation dataset. We extracted 1408 radiomics features, and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset. The informative features so identified were then used to construct a diagnostic model for PD. The constructed model contained 36 informative radiomics features, mainly representing abnormal subcortical iron distribution (especially in the substantia nigra), structural disorganization (e.g., in the inferior temporal, paracentral, precuneus, insula, and precentral gyri), and texture misalignment in the subcortical nuclei (e.g., caudate, globus pallidus, and thalamus). The predictive accuracy of the established model was 81.1 ± 8.0% in the training dataset. On the external validation dataset, the established model showed predictive accuracy of 78.5 ± 2.1%. In the tests of identifying early and drug-naïve PD patients from healthy controls, the accuracies of the model constructed on the same 36 informative features were 80.3 ± 7.1% and 79.1 ± 6.5%, respectively, while the accuracies were 80.4 ± 6.3% and 82.9 ± 5.8% for diagnosing middle-to-late PD and those receiving drug management, respectively. The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8 ± 6.9% and 79.1 ± 6.5%, respectively. In conclusion, the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis. 
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    Involvement of NLRP3-inflammasome pathway in noise-induced hearing loss
    Na Sai, Yuan-Yuan Yang, Long Ma, Da Liu, Qing-Qing Jiang, Wei-Wei Guo, Wei-Ju Han
    2022, 17 (12):  2750-2754.  doi: 10.4103/1673-5374.339499
    Abstract ( 176 )   PDF (8060KB) ( 56 )   Save
    The inflammasome is a multiprotein oligomer in the cell cytoplasm and is part of the innate immune system. It plays a crucial role in the pathological process of noise-induced hearing loss (NIHL). However, the mechanisms of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in NIHL have not been clearly demonstrated. In this study, miniature pigs were exposed to white noise at 120 dB(A) and auditory brainstem response measurements were used to measure their hearing function. Immunofluorescence staining, confocal laser scanning microscopy, western blot assay, and quantitative reverse transcription-polymerase chain reaction were used to analyze inflammasome-related protein distribution and expression. NLRP3, interleukin-1β, interleukin-18, and cleaved-caspase-1 were highly expressed in the cochlea after 120 dB(A) white noise exposure. Our findings suggest that NLRP3-inflammasomes in the cochlea may be activated after acoustic trauma, which may be an important mechanism of noise-induced hearing loss.
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    Interleukin-4 promotes microglial polarization toward a neuroprotective phenotype after retinal ischemia/reperfusion injury
    Di Chen, Cheng Peng, Xu-Ming Ding, Yue Wu, Chang-Juan Zeng, Li Xu, Wen-Yi Guo
    2022, 17 (12):  2755-2760.  doi: 10.4103/1673-5374.339500
    Abstract ( 214 )   PDF (3169KB) ( 94 )   Save
    Glaucoma results from irreversible loss of retinal ganglion cells (RGCs) through an unclear mechanism. Microglial polarization and neuroinflammation play an important role in retinal degeneration. Our study aimed to explore the function of microglial polarization during glaucoma progression and identify a strategy to alleviate retinal neuroinflammation. Retinal ischemia/reperfusion injury was induced in C57BL/6 mice. In a separate cohort of animals, interleukin (IL)-4 (50 ng/mL, 2 μL per injection) or vehicle was intravitreally injected after retinal ischemia/reperfusion injury. RGC loss was assessed by counting cells that were positive for the RGC marker RNA binding protein, mRNA processing factor in retinal flat mounts. The expression of classically activated (M1) and alternatively activated (M2) microglial markers were assessed by quantitative reverse transcription-polymerase chain reaction, immunofluorescence, and western blotting. The results showed that progressive RGC loss was accompanied by a continuous decrease in M2 microglia during the late phase of the 28-day period after retinal ischemia/reperfusion injury. IL-4 was undetectable in the retina at all time points, and intravitreal IL-4 administration markedly improved M2 microglial marker expression and ameliorated RGC loss in the late phase post-retinal ischemia/reperfusion injury. In summary, we observed that IL-4 treatment maintained a high number of M2 microglia after RIR and promoted RGC survival.
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    A new anterograde trans-synaptic tracer based on Sindbis virus
    Xiang-Wei Shi, Fan Jia, Pei Lyu, Fu-Qiang Xu
    2022, 17 (12):  2761-2764.  doi: 10.4103/1673-5374.339495
    Abstract ( 226 )   PDF (10552KB) ( 66 )   Save
    Mapping neural circuits is critical for understanding the structure and function of the nervous system. Engineered viruses are a valuable tool for tracing neural circuits. However, current tracers do not fully meet the needs for this approach because of various drawbacks, such as toxicity and characteristics that are difficult to modify. Therefore, there is an urgent need to develop a new tracer with low toxicity and that allows for long-term studies. In this study, we constructed an engineered Sindbis virus (SINV) expressing enhanced green fluorescent protein (EGFP) reporter gene (SINV-EGFP) and found that it had no significant difference in biological characterization compared with the wild-type Sindbis virus in BHK-21 cells and neurons in vitro. We injected the virus into the visual circuit of mouse brain and found that the virus infected neurons in the local injected site and anterogradely spread in the neural circuits. Although the efficiency of transmission was limited, the findings demonstrate that SINV can be used as a new anterograde tracer to map neural circuits in mouse brain and that it spreads exclusively in the anterograde direction. Further, use of SINV in mouse brain research will provide longer time windows for circuit tracing than is possible with herpes simplex virus and vesicular stomatitis virus tracers.
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    NR4A1 agonist cytosporone B attenuates neuroinflammation in a mouse model of multiple sclerosis
    Hai-Zhen Yu, Bing-Qing Zhu, Lin Zhu, Shuo Li, Li-Mei Wang
    2022, 17 (12):  2765-2770.  doi: 10.4103/1673-5374.339492
    Abstract ( 202 )   PDF (2602KB) ( 57 )   Save
    Nuclear receptor subfamily 4 group A1 (NR4A1) is an orphan nuclear receptor, which is expressed in the majority of cells. NR4A1 expression in peripheral blood mononuclear cells is low during the preclinical stage of multiple sclerosis. Knockout of the Nr4a1 gene in mice can aggravate the symptoms of experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. In this study, we intragastrically administered the NR4A1 agonist cytosporone B (Csn-B) to mice after inducing EAE. After treatment with Csn-B, the clinical symptoms in the EAE mice were substantially attenuated compared with that in PBS-treated control mice. The percentages of CD4+ T cells and F4/80+ cells in the central nervous system were decreased. In addition, interferon-γ and interleukin-17 production by proinflammatory Th1/Th17 cells in the central nervous system and interferon-γ levels in splenocytes were decreased after Csn-B treatment. These findings suggest that the NR4A1 agonist Csn-B can alleviate nerve injury after EAE induction, and, therefore, may be useful as a potential treatment for multiple sclerosis.
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    Interleukin 17A deficiency alleviates neuroinflammation and cognitive impairment in an experimental model of diabetic encephalopathy
    Xiao-Xia Fang, Fen-Fen Xu, Zhan Liu, Bei-Bei Cao, Yi-Hua Qiu, Yu-Ping Peng
    2022, 17 (12):  2771-2777.  doi: 10.4103/1673-5374.339490
    Abstract ( 260 )   PDF (3404KB) ( 161 )   Save
    Interleukin 17A (IL-17A) was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications. However, the role of IL-17A in diabetic encephalopathy remains poorly understood. In this study, we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a–/– mice with spontaneously diabetic Ins2Akita (Akita) mice. Blood glucose levels and body weights were monitored from 2–32 weeks of age. When mice were 32 weeks of age, behavioral tests were performed, including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory. IL-17A levels in the serum, cerebrospinal fluid, and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction. Moreover, proteins related to cognitive dysfunction (amyloid precursor protein, β-amyloid cleavage enzyme 1, p-tau, and tau), apoptosis (caspase-3 and -9), inflammation (inducible nitric oxide synthase and cyclooxygenase 2), and occludin were detected by western blot assays. Pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interferon-γ in serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays. Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining. Compared with that in wild-type mice, mice with diabetic encephalopathy had higher IL-17A levels in the serum, cerebrospinal fluid, and hippocampus; downregulation of occludin expression; lower cognitive ability; greater loss of hippocampal neurons; increased microglial activation; and higher expression of inflammatory factors in the serum and hippocampus. IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy. These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy. Furthermore, IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects. These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.
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    Acetyl-11-keto-beta-boswellic acid promotes sciatic nerve repair after injury: molecular mechanism
    Yao Wang, Zong-Liang Xiong, Xiang-Lin Ma, Chong Zhou, Mo-Han Huo, Xiao-Wen Jiang, Wen-Hui Yu
    2022, 17 (12):  2778-2784.  doi: 10.4103/1673-5374.339494
    Abstract ( 157 )   PDF (38403KB) ( 237 )   Save
    Previous studies showed that acetyl-11-keto-beta-boswellic acid (AKBA), the active ingredient in the natural Chinese medicine Boswellia, can stimulate sciatic nerve injury repair via promoting Schwann cell proliferation. However, the underlying molecular mechanism remains poorly understood. In this study, we performed genomic sequencing in a rat model of sciatic nerve crush injury after gastric AKBA administration for 30 days. We found that the phagosome pathway was related to AKBA treatment, and brain-derived neurotrophic factor expression in the neurotrophic factor signaling pathway was also highly up-regulated. We further investigated gene and protein expression changes in the phagosome pathway and neurotrophic factor signaling pathway. Myeloperoxidase expression in the phagosome pathway was markedly decreased, and brain-derived neurotrophic factor, nerve growth factor, and nerve growth factor receptor expression levels in the neurotrophic factor signaling pathway were greatly increased. Additionally, expression levels of the inflammatory factors CD68, interleukin-1β, pro-interleukin-1β, and tumor necrosis factor-α were also decreased. Myelin basic protein- and β3-tubulin-positive expression as well as the axon diameter-to-total nerve diameter ratio in the injured sciatic nerve were also increased. These findings suggest that, at the molecular level, AKBA can increase neurotrophic factor expression through inhibiting myeloperoxidase expression and reducing inflammatory reactions, which could promote myelin sheath and axon regeneration in the injured sciatic nerve.
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