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15 December 2020, Volume 15 Issue 12 Previous Issue    Next Issue

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Dopamine: an immune transmitter Sarah Thomas Broome, Krystal Louangaphay, Kevin A. Keay, Gian Marco Leggio, Giuseppe Musumeci, Alessandro Castorina 2020, 15 (12):  2173-2185.  doi: 10.4103/1673-5374.284976 Abstract ( 217 )   PDF (1739KB) ( 182 )   Save The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies. Related Articles | Metrics

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The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis Adriana Delice Foster, Sarah Lyn Rea 2020, 15 (12):  2186-2194.  doi: 10.4103/1673-5374.284977 Abstract ( 211 )   PDF (659KB) ( 186 )   Save Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic, pathological and clinical overlap. One such overlap is the presence of SQSTM1/p62 mutations. While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget’s disease of bone, mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system, and also regulates cell survival via the Nrf2 antioxidant response pathway, the nuclear factor-kappa B signaling pathway and apoptosis. Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis. In this review we discuss the role of p62 in these pathways, the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1, in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis. Related Articles | Metrics

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Mounting evidence of FKBP12 implication in neurodegeneration Gabriella Caminati, Piero Procacci 2020, 15 (12):  2195-2202.  doi: 10.4103/1673-5374.284980 Abstract ( 159 )   PDF (1604KB) ( 238 )   Save Intrinsically disordered proteins, such as tau or α-synuclein, have long been associated with a dysfunctional role in neurodegenerative diseases. In Alzheimer’s and Parkinson’s’ diseases, these proteins, sharing a common chemical-physical pattern with alternating hydrophobic and hydrophilic domains rich in prolines, abnormally aggregate in tangles in the brain leading to progressive loss of neurons. In this review, we present an overview linking the studies on the implication of the peptidyl-prolyl isomerase domain of immunophilins, and notably FKBP12, to a variety of neurodegenerative diseases, focusing on the molecular origin of such a role. The involvement of FKBP12 dysregulation in the aberrant aggregation of disordered proteins pinpoints this protein as a possible therapeutic target and, at the same time, as a predictive biomarker for early diagnosis in neurodegeneration, calling for the development of reliable, fast and cost-effective detection methods in body fluids for community-based screening campaigns. Related Articles | Metrics

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Using antifibrinolytics to tackle neuroinflammation Stanimir Atsev, Nikola Tomov 2020, 15 (12):  2203-2206.  doi: 10.4103/1673-5374.284979 Abstract ( 96 )   PDF (348KB) ( 127 )   Save Plasmin is generally known as a promotor of inflammation. Recent advancement suggests that it has a complex role as immunity modulator. Pharmacological inhibition of plasmin production and activity has been proven to improve neurological outcomes in traumatic brain injury and subarachnoid hemorrhage, most probably by preventing re-bleeding. The immune-modulatory properties of antifibrinolytics, however, suggest that they probably have effects unrelated to fibrinolysis inhibition, which are currently not adequately harnessed. The present work aims to give an account of the existing data regarding antifibrinolytics as agents influencing neuroinflammation. Preclinical and clinical studies on the possible influence of antifibrinolytics on neuroinflammation are scarce. However, the emerging evidence suggests that inhibition of plasmin(ogen) activity can ameliorate neuroinflammation to some extent. This data demonstrate that plasmin(ogen) is not exclusively involved in fibrinolysis, but also has other substrates and can precipitate in inflammatory processes. Investigation on the role of plasmin as the factor for the development of neuroinflammation shows the significant potential of antifibrinolytics as pharmacotherapy of neuroinflammationm, which is worthy of further exploration. Related Articles | Metrics

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Medicinal plants and natural products as neuroprotective agents in age-related macular degeneration Francisco Bosch-Morell, Victoria Villagrasa, Teresa Ortega, Nuria Acero, Dolores Muñoz-Mingarro, M. Eugenia González-Rosende, Encarna Castillo, M. Amparo Sanahuja, Pilar Soriano, Isabel Martínez-Solís 2020, 15 (12):  2207-2216.  doi: 10.4103/1673-5374.284978 Abstract ( 126 )   PDF (748KB) ( 173 )   Save The retina may suffer neurodegenerative damages, as other tissues of the central nervous system do, and serious eye diseases may develop. One of them is age-related macular degeneration, which causes progressive loss of vision due to retina degeneration. Treatment of age-related macular degeneration focuses on antioxidant agents and anti-vascular endothelial growth factor compounds, among others, that prevent/ diminish oxidative stress and reduce neovascularisation respectively. The phytochemicals, medicinal plants and/or plant-diet supplements might be a useful adjunct in prevention or treatment of age-related macular degeneration owing to their antioxidant and anti-vascular endothelial growth factor properties. This review article presents the most investigated plants and natural products in relation to age-related macular degeneration, such as saffron, ginkgo, bilberry and blueberry, curcuma or turmeric, carotenoids, polyphenols, and vitamins C and E. This study provides up-to-date information on the effects, treatments, safety and efficiency of these phytotherapy products. Related Articles | Metrics

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Nafamostat mesylate attenuates the pathophysiologic sequelae of neurovascular ischemia George Zaki Ghali, Michael George Zaki Ghali 2020, 15 (12):  2217-2234.  doi: 10.4103/1673-5374.284981 Abstract ( 156 )   PDF (1889KB) ( 234 )   Save Nafamostat mesylate, an apparent soi-disant panacea of sorts, is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass, mitigate the inflammatory response in patients diagnosed with acute pancreatitis, and reverse the coagulopathy of patients experiencing the commonly preterminal disseminated intravascular coagulation in the Far East. The serine protease inhibitor nafamostat mesylate exhibits significant neuroprotective effects in the setting of neurovascular ischemia. Nafamostat mesylate generates neuroprotective effects by attenuating the enzymatic activity of serine proteases, neuroinflammatory signaling cascades, and the endoplasmic reticulum stress responses, downregulating excitotoxic transient receptor membrane channel subfamily 7 cationic currents, modulating the activity of intracellular signal transduction pathways, and supporting neuronal survival (brain-derived neurotrophic factor/TrkB/ERK1/2/CREB, nuclear factor kappa B. The effects collectively reduce neuronal necrosis and apoptosis and prevent ischemia mediated disruption of blood-brain barrier microarchitecture. Investigational clinical applications of these compounds may mitigate ischemic reperfusion injury in patients undergoing cardiac, hepatic, renal, or intestinal transplant, preventing allograft rejection, and treating solid organ malignancies. Neuroprotective effects mediated by nafamostat mesylate support the wise conduct of randomized prospective controlled trials in Western countries to evaluate the clinical utility of this compound. Related Articles | Metrics

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Engineering mesenchymal stromal/ stem cell-derived extracellular vesicles with improved targeting and therapeutic efficiency for the treatment of central nervous system disorders Alexandra M. Iavorovschi, Aijun Wang 2020, 15 (12):  2235-2236.  doi: 10.4103/1673-5374.284982 Abstract ( 108 )   PDF (334KB) ( 137 )   Save Treatment for central nervous system (CNS) disorders is known to be limited by the low regenerative potential of neurons, and thus neurodegenerative insults became known as nearly irreversible ailments. Functional recovery for acquired CNS disorders, such as spinal cord injury (SCI), traumatic brain injury, ischemic stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS), and for congenital CNS abnormalities, such as spina bifida, is not spontaneous and effective treatments are limited to non-existent. Related Articles | Metrics

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Adaptable retinal ganglion cell function: assessing autoregulation of inner retina pathways Tsung-Han Chou, Vittorio Porciatti 2020, 15 (12):  2237-2238.  doi: 10.4103/1673-5374.284984 Abstract ( 105 )   PDF (295KB) ( 681 )   Save RGCs are extremely high-maintenance neurons connecting the eye to the brain trough the optic nerve. In order to produce and propagate action potentials along the unmyelinated RGC axons and support axonal transport of materials back and forth from the eye to the brain, RGC require large amounts of energy. Therefore, RGCs are under considerable metabolic stress when healthy and become particularly vulnerable in disease, resulting in blindness Related Articles | Metrics

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Prion-like domain disease-causing mutations and misregulation of alternative splicing relevance in limb-girdle muscular dystrophy (LGMD) 1G Cristina Batlle, Salvador Ventura 2020, 15 (12):  2239-2240.  doi: 10.4103/1673-5374.284988 Abstract ( 136 )   PDF (389KB) ( 235 )   Save Human prion-like proteins often correspond to nucleic acid binding proteins, displaying both globular domains and long intrinsically disordered regions (IDRs) (Harrison and Shorter, 2017). Their IDRs are of low complexity and resemble in amino acid composition to the disordered yeast prion domains, being usually enriched in Gln and Asn residues and depleted in hydrophobic and charged residues. Accordingly, these sequence stretches are named prion-like domains (PrLDs). Prion-like proteins can aggregate into amyloid fibrils, which can accommodate incoming protein monomers, propagating thus the polymeric fold, both processes being driven by their PrLDs. Human prion-like proteins are attracting attention because they are found in the insoluble inclusions identified in an increasing number of neurodegenerative diseases (Harrison and Shorter, 2017). Some well-characterized examples are FUS, TDP43, TAF15, EWSR1, TIA1, hnRNPA1, and hnRNPA2 proteins. Importantly, mutations in the genes that encode for these polypeptides are connected with degenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal dementia or multisystem proteinopathy. A significant proportion of these mutations map in the PrLD of the prion-like protein, and often they result in their accelerated aggregation, both in vitro and in vivo. These proteins shuttle between the nucleus and the cytoplasm and are involved in the formation of membraneless organelles, like stress granules, through liquid-liquid phase separation (LLPS) (Boeynaems et al., 2018). Their aggregation typically occurs after protein mislocalization to the cytoplasm, where they form the insoluble inclusions observed in patients. It has been hypothesized that LLPS, which creates a high local protein density, is the first step towards a liquid-to-solid state transition that initiates aggregation. Membraneless organelles are highly dynamic in order to sense environmental changes and generate adequate adaptative responses. This property obeys to the fact that prion-like proteins phase separate via transient and weak non-covalent interactions. Nevertheless, genetic mutations can strengthen LLPS interactions, increasing the kinetic barrier for dissociation, leading to the population of an irreversible aberrant state, which resolves into the aggregates observed in the above-described diseases. Thus, mutations in these prion-like proteins have been suggested to result in a gain of toxic function phenotype similar to the one occurring in the brain of patients with neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases Related Articles | Metrics

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Neurotrophin-3-mediated locomotor recovery: a novel therapeutic strategy targeting lumbar neural circuitry after spinal cord injury Qi Han, Xiao-Ming Xu 2020, 15 (12):  2241-2242.  doi: 10.4103/1673-5374.284985 Abstract ( 124 )   PDF (418KB) ( 136 )   Save Traumatic spinal cord injury (SCI) leads to chronic locomotor impairment and disability. Unfortunately, there are no effective treatments currently available for SCI patients (Bradbury and Burnside, 2019). Developing novel repair interventions to mitigate the devastating nature of SCI and translating them clinically are urgent medical needs to improve the quality of life of patients with SCI. The lumbar spinal motoneurons (MNs) are the final common pathway for hindlimb locomotion since all neural activities that influence hindlimb movement converging upon these neurons. With above-level (cervical and thoracic) SCIs, the lumbar MNs are not directly injured by the initial mechanical impact, but they undergo profound degeneration with dendritic atrophy and synaptic stripping due to a trauma-induced decrease of supraspinal and propriospinal innervations, leading to impaired locomotor function (Figure 1A; Wang et al., 2018). While most SCI studies have been focused on the neuroregeneration or neuroprotection of injured spinal cord at the lesion site, few studies have explored the potential benefit of modulating lumbar motor circuitry for locomotor recovery after an above-level SCI. Filling this gap is an important task for developing the care and treatment of SCI. Related Articles | Metrics

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How and why does photobiomodulation change brain activity? John Mitrofanis, Luke A. Henderson 2020, 15 (12):  2243-2244.  doi: 10.4103/1673-5374.284989 Abstract ( 115 )   PDF (594KB) ( 166 )   Save The concept that certain wavelengths of light can change regional brain activity as well as influencing the functional connectivity between different brain centers, is rather striking. Such a concept goes beyond that of a function for light stimulating specialized retinal ganglion cells to entrain circadian rhythms but extends this to include light having a direct influence on all neurons to potentially influence a range of core higher-order brain activities. In this perspective, we explore how light may influence such core brain activities, together with why it should do so in the first place. We propose that the effect of light on brain activity has evolutionary links, relating to a basic survival strategy against any potentially dangerous situation. Related Articles | Metrics

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Activation of tyrosine phosphatases in the progression of Alzheimer’s disease Alexandre F. R. Stewart, Hsiao-Huei Chen 2020, 15 (12):  2245-2246.  doi: 10.4103/1673-5374.284986 Abstract ( 130 )   PDF (242KB) ( 158 )   Save Patients with Alzheimer’s disease (AD) have progressive memory loss, inability to reason, and display anxiety that accelerates disease progression. Evidence points to two deficits: 1) the brain fails to respond to insulin that regulates the formation of neuron connections required to store memories, and 2) deficits arise in the brain’s endogenous cannabinoid signaling that regulates mood and prevents anxiety (Aso and Ferrer, 2014). In addition, leptin signaling, important in regulating hypothalamic synaptic plasticity and cognitive function is also affected in AD (McGregor and Harvey, 2018). Until now, no single treatment targeting these three signaling deficits has been proposed. The tyrosine phosphatase PTP1B (Ptpn1) blocks brain insulin and leptin signaling (Pandey et al., 2013) and prevents endogenous cannabinoid production (Qin et al., 2015b) and is elevated in the brain of AD mice (Ricke et al., 2020). Thus, PTP1B is a plausible target for AD. Related Articles | Metrics

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Targeting cannabidiol to specifc areas of the brain: an ultrasound-based strategy Jacopo Junio Valerio Branca , Donatello Carrino, Alessandra Pacini 2020, 15 (12):  2247-2248.  doi: 10.4103/1673-5374.284992 Abstract ( 112 )   PDF (577KB) ( 151 )   Save Brain diseases, ranging from central nervous system (CNS) dis- orders to brain cancers, are some of the most prevalent pathol- ogies in the world. Despite the high incidence, many of these diseases lack successful treatments because of inadequate drug development in comparison to other therapeutic areas. In par- ticular, even if many drugs have shown the potential to tackle some neurological disorders including Alzheimer’s and Parkin- son’s diseases and many other associated CNS pathologies, their delivery in specifc brain areas and in adequate concentrations represent the real obstacle to the treatment of these pathologies. Related Articles | Metrics

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Remote ischemic conditioning: the brain’s endogenous defense against stroke Caleb J. Heiberger, Tej Mehta, Jae Kim, Divyajot S. Sandhu 2020, 15 (12):  2249-2250.  doi: 10.4103/1673-5374.284987 Abstract ( 128 )   PDF (443KB) ( 171 )   Save In 1986, Murray built upon a se- ries of accumulated works to demonstrated that brief ischemic “training” episodes fortified cardiac tissue against impending prolonged infarction (Murry et al., 1986). This discovery altered the dogmatic understanding of ischemia, highlighting that time-dependent tissue compromise during infarction was bimodal, not linear, in nature. Instead of being invariably deleterious, an organ’s response to ischemia is dependent upon both the duration of the infarction as well as adaptions from previous, transient isch- emic episodes. Related Articles | Metrics

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Targeting the transferrin receptor to develop erythropoietin for Alzheimer’s disease Rachita K. Sumbria 2020, 15 (12):  2251-2252.  doi: 10.4103/1673-5374.284994 Abstract ( 117 )   PDF (465KB) ( 129 )   Save Alzheimer’s disease (AD) is the sixth leading cause of death in the United States with approximately 5.8 million Americans currently living with AD. Due to the lack of a disease modifying treatment for AD and the aging baby boomer generation, this number is pro- jected to grow to 13.8 million by 2050 (Gaugler et al., 2019). Amy- loid-beta (Aβ) plaque accumulation, one of the major pathological hallmarks of AD, can begin > 20 years before clinical symptoms of AD. By the time AD is clinically diagnosed, neuronal loss and neu- ropathological lesions (Aβ plaques and tau tangles) have already occurred in many brain regions (Gaugler et al., 2019). AD demen- tia correlates highly with neuronal loss, and therefore, reduction of neuropathological lesions in the AD brain at the time of clinical diagnosis alone cannot reverse AD dementia. We propose that a therapy that combines a reduction of neuropathological lesions of AD along with neuronal repair and neurogenesis may be required to treat AD dementia. Related Articles | Metrics

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Recent advances on the role of long non-coding RNAs in Alzheimer’s disease Kyle Doxtater, Manish K. Tripathi, Mohammad Moshahid Khan 2020, 15 (12):  2253-2254.  doi: 10.4103/1673-5374.284990 Abstract ( 166 )   PDF (357KB) ( 203 )   Save Dementia is a progressive cognitive impairment that affects the activities of daily living. Alzheimer’s disease (AD) is the most common form of the dementia worldwide accounting for 60–80% of all dementia cases. With an estimated cost exceeding $290 billion in the USA, understanding and devel- opment of future therapeutic strategies is vital. In this perspective, we will be examining the current thinking of AD research and therapeutic strate- gies, while proposing a possible new direction for diagnosis, understanding, and treatment targets. Non-coding RNA accounts for the largest popu- lation of the human transcriptome. Long noncoding RNA (lncRNA) is a recent molecule of interest in the biomedical research which is non protein coding and is of length greater than 200 nucleotides. LncRNAs have been shown to play diverse roles within the cells such as posttranscriptional and posttranslational regulation, chromatin modulation, and protein complex organization. Given the fexible and diverse role in disease pathophysiology, lncRNAs may serve as novel therapeutic targets for diagnosis and treatment. Evidently, recent studies showed that dysregulation of lncRNA infuences the clinical course of tumorigenesis, neurological disorders, cardiovascular disease, diabetes, and acquired immunodefciency syndrome (Kazimierczyk et al., 2020). Tis indicates that lncRNA can provide a unique avenue of re- search and possible therapeutic targets in AD. Related Articles | Metrics

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Whole-brain three-dimensional imaging for quantifcation of drug targets and treatment efects in mouse models of neurodegenerative diseases Henrik H. Hansen, Urmas Roostalu, Jacob Hecksher-Sørensen 2020, 15 (12):  2255-2257.  doi: 10.4103/1673-5374.284983 Abstract ( 130 )   PDF (656KB) ( 109 )   Save Altered brain functionality in neurodegenerative diseases, including Par- kinson’s disease (PD) and Alzheimer’s disease (AD), involve com- plex pathological changes and molecular mechanisms which poses a major challenge for development of effective drug treatments. Progressive loss of specifc neuron types and projections are hall- marks of PD and AD and proper histological evaluation of relevant disease models therefore requires highly reliable cell detection and quantification methods. Immunohistochemistry is the prevail- ing method of choice to visualize and quantify histopathological changes in brain tissue sections. Although stereology applied to se- rially sampled sections is considered the gold standard for unbiased three-dimensional (3D) estimation of histomorphometric changes and therapeutic efects in neurodegeneration models, the elaborate sequence of histological processing steps can be time-intensive and limit analyses to a few preselected brain areas. Whereas physical tis- sue sections may provide higher structural resolution for any given 2D plane, the advantage of volume imaging is to facilitate 3D inves- tigation of brain structures and cell populations in the intact brain. In this respect, clinical whole-brain 3D imaging has continued to provide valuable insights in early detection, diagnosis and interpre- tation of PD and AD in humans, yet it has remained challenging to establish in preclinical research and drug discovery. Related Articles | Metrics

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Activation of β2 adrenergic receptors promotes adult hippocampal neurogenesis Valeria Bortolotto, Mariagrazia Grilli 2020, 15 (12):  2258-2259.  doi: 10.4103/1673-5374.284991 Abstract ( 121 )   PDF (112KB) ( 182 )   Save Te subgranular zone (SGZ) of the hippocampal dentate gyrus is one of the few central nervous system regions where genera- tion of adult born neurons occurs physiologically. Tis process, referred to as adult hippocampal neurogenesis (ahN), relies on the presence of neural progenitor cells (NPC) in the SGZ neu- rogenic niche. NPC, in response to appropriate cues and sig- nals, give rise to neuroblasts migrating to the granular cell layer (GCL) where they mature into neurons functionally integrated into the hippocampal circuit (Toda et al., 2019). Although the functional role of adult born hippocampal neurons is not fully understood, a vast array of experimental evidence suggest that these cells are involved in crucial hippocampal-dependent func- tions like specifc types of learning and memory and emotional responses (Toda et al., 2019). Intriguingly, deregulated ahN has been associated with several neurodegenerative and neuropsy- chiatric diseases. Major depression, in particular, is one of the disorders where dysregulated ahN has been more extensively studied Related Articles | Metrics

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Small molecules to prevent the neurodegeneration caused by α-synuclein aggregation Samuel Peña-Díaz, Jordi Pujols, Salvador Ventura 2020, 15 (12):  2260-2261.  doi: 10.4103/1673-5374.284993 Abstract ( 131 )   PDF (422KB) ( 175 )   Save Parkinson’s disease (PD) is a neurodegenerative disorder belonging to a group of human pathologies known as synucleinopathies, which includes multiple system atrophy or dementia with Lewy bodies (Spill- antini et al., 1998). Tese diseases share a common neuropathological feature, the presence of α-synuclein (α-Syn) deposits, although they difer in the cellular and anatomical compartment in which α-Syn in- clusions accumulate. PD afects more than 1% of people over 60 years of age, thus being the second most prevalent neurodegenerative disease in the world and the most common synucleinopathy. Te loss of do- paminergic neurons in the substantia nigra pars compacta during PD progression induces a pronounced dopamine concentration decrease in the synaptic area, which translates into motor symptoms such as bradykinesia, rigidity or resting tremor (Martí et al., 2003). Damaged neurons were reported to have large proteinaceous inclusions, named Lewy’s bodies and neurites, which constitute the major histopathologi- cal hallmark in PD. Amyloid fbrils of α-Syn were identifed as the main component of these inclusions (Spillantini et al., 1997). Te detection of genetic mutations (Polymeropoulos et al., 1997) and multiplications in the SNCA gene (Singleton et al., 2003), which encodes for α-Syn, linked to the early onset and higher penetrance of PD, provide evidence for the connection between the aggregation of this particular protein and PD. Related Articles | Metrics

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Hub genes and key pathways of traumatic brain injury: bioinformatics analysis and in vivo validation Yun-Liang Tang, Long-Jun Fang, Ling-Yang Zhong, Jian Jiang, Xiao-Yang Dong, Zhen Feng 2020, 15 (12):  2262-2269.  doi: 10.4103/1673-5374.284996 Abstract ( 574 )   PDF (2544KB) ( 430 )   Save Te exact mechanisms associated with secondary brain damage following traumatic brain injury (TBI) remain unclear; therefore, identify- ing the critical molecular mechanisms involved in TBI is essential. Te mRNA expression microarray GSE2871 was downloaded from the Gene Expression Omnibus (GEO) repository. GSE2871 comprises a total of 31 cerebral cortex samples, including two post-TBI time points. Te microarray features eight control and seven TBI samples, from 4 hours post-TBI, and eight control and eight TBI samples from 24 hours post-TBI. In this bioinformatics-based study, 109 and 66 diferentially expressed genes (DEGs) were identifed in a Sprague-Dawley (SD) rat TBI model, 4 and 24 hours post-TBI, respectively. Functional enrichment analysis showed that the identifed DEGs were signif- cantly enriched in several terms, such as positive regulation of nuclear factor-κB transcription factor activity, mitogen-activated protein kinase signaling pathway, negative regulation of apoptotic process, and tumor necrosis factor signaling pathway. Moreover, the hub genes with high connectivity degrees were primarily related to infammatory mediators. To validate the top fve hub genes, a rat model of TBI was established using the weight-drop method, and real-time quantitative polymerase chain reaction analysis of the cerebral cortex was per- formed. Te results showed that compared with control rats, Tnf-α, c-Myc, Spp1, Cxcl10, Ptprc, Egf, Mmp9, and Lcn2 were upregulated, and Fn1 was downregulated in TBI rats. Among these hub genes, Fn1, c-Myc, and Ptprc may represent novel biomarkers or therapeutic targets for TBI. Tese identifed pathways and key genes may provide insights into the molecular mechanisms of TBI and provide potential treat- ment targets for patients with TBI. Tis study was approved by the Experimental Animal Ethics Committee of the First Afliated Hospital of Nanchang University, China (approval No. 003) in January 2016. Related Articles | Metrics

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Enzyme-digested Colla Corii Asini (E’jiao) prevents hydrogen peroxide-induced cell death and accelerates amyloid beta clearance in neuronal-like PC12 cells Li Xiao, Feng Liao, Ryoji Ide, Tetsuro Horie, Yumei Fan, Chikako Saiki, Nobuhiko Miwa 2020, 15 (12):  2270-2277.  doi: 10.4103/1673-5374.285000 Abstract ( 170 )   PDF (1767KB) ( 265 )   Save As an aging-associated degenerative disease, Alzheimer’s disease is characterized by the deposition of am- yloid beta (Aβ), oxidative stress, infammation, dysfunction and loss of cholinergic neurons. Colla Corii Asini (CCA) is a traditional Chinese medicine which has been used for feebleness-related diseases and anti-aging. CCA might delay aging-induced degenerative changes in neurons. In the present study, we eval- uated antioxidant activity, cytoprotective efects, and Aβ removability of enzyme-digested Colla Corii Asini (CCAD). Oxygen radical absorbance capacity (ORAC) activity assay showed that, as compared to gelatins from the skin of porcine, bovine and cold water fsh, CCA exhibited the highest ORAC activity. Te ORAC activity of CCA and CCAD was increased gradually by the length of time in storage. Ultrastructure analysis by scanning electron microscopy showed that among CCA manufactured in 2008, 2013, 2017 and gelatin from cold water fsh skin, CCA manufactured in 2008 presented the smoothest surface structure. We fur- ther tested the protective efects of CCAD (manufactured in 2008) and enzyme-digested gelatin from cold water fsh skin (FGD) on hydrogen peroxide (H2O2)-induced cell death in nerve growth factor-diferenti- ated neuronal-like PC12 cells. Presto blue assay showed that both FGD and CCAD at 0.5 mg/mL increased cell viability in H2O2-treated neuronal-like PC12 cells. Te protection of CCAD was signifcantly superior to that of FGD. Acetylcholinesterase (AchE) assay showed that both FGD and CCAD inhibited AchE activ- ity in nerve growth factor-diferentiated neuronal-like PC12 cells to 89.1% and 74.5% of that in non-treated cells, respectively. Te data suggest that CCAD might be able to increase the neurotransmitter acetylcho- line. Although CCAD inhibited AchE activity in neuronal-like PC12 cells, CCAD prevented H2O2-induced abnormal deterioration of AchE. ELISA and neprilysin activity assay results indicated that CCAD reduced amyloid beta accumulation and increased neprilysin activity in Aβ1–42-treated neuronal-like PC12 cells, sug- gesting that CCAD can enhance Aβ clearance. Our results suggest that CCA might be useful for preventing and treating Alzheimer’s disease. Related Articles | Metrics

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An appropriate level of autophagy reduces emulsifed isofurane-induced apoptosis in fetal neural stem cells Ze-Yong Yang, Lei Zhou, Qiong Meng, Hong Shi, Yuan-Hai Li 2020, 15 (12):  2278-2285.  doi: 10.4103/1673-5374.285004 Abstract ( 117 )   PDF (2077KB) ( 190 )   Save Autophagy plays essential roles in cell survival. However, the functions and regulation of the autophagy-related proteins Atg5, LC3B, and Beclin 1 during anesthetic-induced developmental neurotoxicity remain unclear. Tis study aimed to understand the autophagy pathways and mechanisms that afect neurotoxicity, induced by the anesthetic emulsifed isofurane, in rat fetal neural stem cells. Fetal neural stem cells were cultured, in vitro, and neurotoxicity was induced by emulsifed isofurane treatment. Te efects of pretreatment with the auto- phagy inhibitors 3-methyladenine and baflomycin and the efects of transfection with small interfering RNA against ATG5 (siRNA-Atg5) were observed. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assessed using fow cytometry. Ultrastructural changes were analyzed through transmission electron microscopy. Te levels of the autophagy-related proteins LC3B, Beclin 1, Atg5, and P62 and the pro-apoptosis-related protein caspase-3 were analyzed using western blot assay. Te inhibition of cell proliferation and that of apoptosis rate increased afer treatment with emulsifed isofurane. Autophagoly- sosomes, monolayer membrane formation due to lysosomal degradation, were observed. Te autophagy-related proteins LC3B, Beclin 1, Atg5, and P62 and caspase-3 were upregulated. Tese results confrm that emulsifed isofurane can induce toxicity and autophagy in fetal neural stem cells. Pre-treatment with 3-methyladenine and baflomycin increased the apoptosis rate in emulsifed isofurane-treated fetal neural stem cells, which indicated that the complete inhibition of autophagy does not alleviate emulsifed isofurane-induced fetal neural stem cell toxicity. Atg5 expression was decreased significantly by siRNA-Atg5 transfection, and cell proliferation was inhibited. These results verify that the Atg5 autophagy pathway can be regulated to maintain appropriate levels of autophagy, which can inhibit the neuro- toxicity induced by emulsifed isofurane anesthetic in fetal neural stem cells. Related Articles | Metrics

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Mechanism of delayed encephalopathy afer acute carbon monoxide poisoning Yan-Qing Huang, Zheng-Rong Peng, Fang-Ling Huang, A-Li Yang 2020, 15 (12):  2286-2295.  doi: 10.4103/1673-5374.284995 Abstract ( 289 )   PDF (3978KB) ( 244 )   Save Many hypotheses exist regarding the mechanism underlying delayed encephalopathy afer acute carbon monoxide poisoning (DEACMP), including the infammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis; however, no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP. Leucine-rich repeat and immunoglobulin-like domain-containing protein-1 (LINGO-1) activates the Ras homolog gene family member A (RhoA)/ Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway, which negatively regulates oligodendrocyte myelin- ation, axonal growth, and neuronal survival, causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases. However, whether LINGO-1 is involved in DEACMP remains unclear. A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes, followed by 3000 ppm carbon monoxide gas for an additional 20 minutes. Te results showed that compared with control rats, DEACMP rats showed signifcantly increased water maze latency and increased protein and mRNA expression levels of LINGO-1, RhoA, and ROCK2 in the brain. Compared with normal rats, signifcant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats. From days 1 to 21 afer DEACMP, the intraperitoneal injection of retinoic acid (10 mg/kg), which can inhibit LINGO-1 expression, was able to improve the above changes observed in the DEACMP model. Terefore, the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning, activating the RhoA/ROCK2 signaling pathway, which may be an important pathophys- iological mechanism underlying DEACMP. Tis study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital (approval No. 201612684) on December 26, 2016. Related Articles | Metrics

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Neuroprotective efects of ZL006 in Aβ1–42-treated neuronal cells Wen-Yuan Tao, Lin-Jie Yu, Su Jiang, Xiang Cao, Jian Chen, Xin-Yu Bao, Fei Li, Yun Xu, Xiao-Lei Zhu 2020, 15 (12):  2296-2305.  doi: 10.4103/1673-5374.285006 Abstract ( 153 )   PDF (3797KB) ( 189 )   Save Amyloid beta (Aβ)-induced neurotoxicity and oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). ZL006 is shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke by interrupting the interaction of neuronal nitric oxide synthase and postsynaptic density protein 95. However, few studies are reported on the role of ZL006 in AD. To investigate whether ZL006 exerted neuroprotective effects in AD, we used Aβ 1–42 to treat primary cortical neurons and N2a neuroblastoma cells as an in vitro model of AD. Cortical neurons were incubated with ZL006 or dimethyl sulfoxide for 2 hours and treated with Aβ 1–42 or NH3•H 2 O for another 24 hours. The results of cell counting Kit-8 (CCK-8) assay and calcein-acetoxymethylester/propidium iodide staining showed that ZL006 pretreatment rescued the neuronal death induced by Aβ 1–42 . Fluorescence and western blot assay were used to detect oxidative stress and apoptosis-related proteins in each group of cells. Results showed that ZL006 pretreatment decreased neuronal apoptosis and oxidative stress induced by Aβ 1–42 . The results of CCK8 assay showed that inhibition of Akt or NF-E2-related factor 2 (Nrf2) in cortical neu- rons abolished the protective effects of ZL006. Moreover, similar results were also observed in N2a neuroblastoma cells. ZL006 inhibited N2a cell death and oxidative stress induced by Aβ 1–42 , while inhibition of Akt or Nrf2 abolished the protective effect of ZL006. These results demonstrated that ZL006 reduced Aβ 1–42 -induced neuronal damage and oxidative stress, and the mechanisms might be associated with the activation of Akt/Nrf2/heme oxygenase-1 signaling pathways. Related Articles | Metrics

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Human adipose tissue- and umbilical cord-derived stem cells: which is a better alternative to treat spinal cord injury? Ai-Mei Liu, Bo-Li Chen, Ling-Tai Yu, Tao Liu, Ling-Ling Shi, Pan-Pan Yu, Yi-Bo Qu, Kwok-Fai So, Li-Bing Zhou 2020, 15 (12):  2306-2317.  doi: 10.4103/1673-5374.284997 Abstract ( 159 )   PDF (9332KB) ( 38 )   Save Multiple types of stem cells have been proposed for the treatment of spinal cord injury, but their comparative information remains elusive. In this study, a rat model of T10 contusion spinal cord injury was established by the impactor method. Human umbilical cord-derived mesen- chymal stem cells (UCMSCs) or human adipose tissue-derived mesenchymal stem cells (ADMSCs) (2.5 μL/injection site, 1 × 10 5 cells/μL) was injected on rostral and caudal of the injury segment on the ninth day after injury. Rats injected with mesenchymal stem cell culture medium were used as controls. Our results show that although transplanted UCMSCs and ADMSCs failed to differentiate into neurons or glial cells in vivo, both significantly improved motor and sensory function. After spinal cord injury, UCMSCs and ADMSCs similarly promoted spinal neuron survival and axonal regeneration, decreased glial scar and lesion cavity formation, and reduced numbers of active macrophages. Bio- Plex analysis of spinal samples showed a specific increase of interleukin-10 and decrease of tumor necrosis factor α in the ADMSC group, as well as a downregulation of macrophage inflammatory protein 3α in both UCMSC and ADMSC groups at 3 days after cell transplantation. Upregulation of interleukin-10 and interleukin-13 was observed in both UCMSC and ADMSC groups at 7 days after cell transplantation. Isobaric tagging for relative and absolute quantitation proteomics analyses showed that UCMSCs and ADMSCs induced changes of multiple genes related to axonal regeneration, neurotrophy, and cell apoptosis in common and specific manners. In conclusion, UCMSC and ADMSC transplants yielded quite similar contributions to motor and sensory recovery after spinal cord injury via anti-inflammation and improved axonal growth. However, there were some differences in cytokine and gene expression induced by these two types of transplanted cells. Animal experiments were approved by the Laboratory Animal Ethics Committee at Jinan University (approval No. 20180228026) on February 28, 2018, and the application of human stem cells was approved by the Medical Ethics Committee of Medical College of Jinan University of China (approval No. 2016041303) on April 13, 2016. Related Articles | Metrics

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Pentraxin 3 contributes to neurogenesis after traumatic brain injury in mice Chao Zhou, Hong Chen, Jian-Feng Zheng, Zong-Duo Guo, Zhi-Jian Huang, Yue Wu, Jian-Jun Zhong, Xiao-Chuan Sun, Chong-Jie Cheng 2020, 15 (12):  2318-2326.  doi: 10.4103/1673-5374.285001 Abstract ( 118 )   PDF (4583KB) ( 190 )   Save Emerging evidence indicates that pentraxin 3 is an acute-phase protein that is linked with the immune response to inflammation. It is also a newly discovered marker of anti-inflammatory A2 reactive astrocytes, and potentially has multiple protective effects in stroke; however, its role in the adult brain after traumatic brain injury is unknown. In the present study, a moderate model of traumatic brain injury in mice was established using controlled cortical impact. The models were intraventricularly injected with recombinant pentraxin 3 (the recom- binant pentraxin 3 group) or an equal volume of vehicle (the control group). The sham-operated mice underwent craniotomy, but did not undergo the controlled cortical impact. The potential neuroprotective and neuroregenerative roles of pentraxin 3 were investigated on days 14 and 21 after traumatic brain injury. Western blot assay showed that the expression of endogenous pentraxin 3 was increased after trau- matic brain injury in mice. Furthermore, the neurological severity test and wire grip test revealed that recombinant pentraxin 3 treatment reduced the neurological severity score and increased the wire grip score, suggesting an improved recovery of sensory-motor functions. The Morris water maze results demonstrated that recombinant pentraxin 3 treatment reduced the latency to the platform, increased the time spent in the correct quadrant, and increased the number of times traveled across the platform, thus suggesting an improved recovery of cognitive function. In addition, to investigate the effects of pentraxin 3 on astrocytes, specific markers of A2 astrocytes were detect- ed in primary astrocyte cultures in vitro using western blot assay. The results demonstrated that pentraxin 3 administration activates A2 astrocytes. To explore the protective mechanisms of pentraxin 3, immunofluorescence staining was used. Intraventricular injection of recombinant pentraxin 3 increased neuronal maintenance in the peri-injured cortex and ipsilateral hippocampus, increased the number of doublecortin-positive neural progenitor cells in the subventricular and subgranular zones, and increased the number of bromodeoxy- uridine (proliferation) and neuronal nuclear antigen (mature neuron) double-labeled cells in the hippocampus and peri-injured cortex. Pentraxin 3 administration also increased the number of neurospheres and the number of bromodeoxyuridine and doublecortin double-la- beled cells in neurospheres, and enhanced the proliferation of neural progenitor cells in primary neural progenitor cell cultures in vitro. In conclusion, recombinant pentraxin 3 administration activated A2 astrocytes, and consequently improved the recovery of neural function by increasing neuronal survival and enhancing neurogenesis. All experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China on March 1, 2016. Related Articles | Metrics

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Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice Xin Wang, Zhao-Xiang Meng, Ying-Zhu Chen, Yu-Ping Li, Hong-Yu Zhou, Man Yang, Ting-Ting Zhao, Yu-Lai Gong, Yi Wu, Tao Liu 2020, 15 (12):  2327-2334.  doi: 10.4103/1673-5374.285005 Abstract ( 160 )   PDF (823KB) ( 135 )   Save The mechanisms of age-associated memory impairment may be associated with glutamate receptor function and chromatin modification. To observe the effect of an enriched environment on the cognitive function of mice with age-associated memory impairment, 3-month- old C57BL/6 male mice (“young” mice) were raised in a standard environment, while 24-month-old C57BL/6 male mice with memory impairment (“age-associated memory impairment” mice) were raised in either a standard environment or an enriched environment. The enriched environment included a variety of stimuli involving movement and sensation. A water maze test was then used to measure cog- nitive function in the mice. Furthermore, quantitative real-time polymerase chain reaction and western blot assays were used to detect right hippocampal GluN2B mRNA as well as protein expression of GluN2B and CREB binding protein in all mice. In addition, chromatin immunoprecipitation was used to measure the extent of histone acetylation of the hippocampal GluN2B gene promoters. Compared with the young mice, the water maze performance of age-associated memory impairment mice in the standard environment was significantly decreased. In addition, there were significantly lower levels of total histone acetylation and expression of CREB binding protein in the hippocampus of age-associated memory impairment mice in the standard environment compared with the young mice. There were also significantly lower levels of histone acetylation, protein expression, and mRNA expression of GluN2B in the hippocampus of these mice. In contrast, in the age-associated memory impairment mice with the enriched environment intervention, the water maze performance and molecular biological indexes were significantly improved. These data confirm that an enriched environment can improve cognitive dys- function in age-associated memory impairment mice, and suggest that the mechanisms may be related to the increased expression of CREB binding protein and the increased degree of total histone acetylation in the hippocampus of age-associated memory impairment mice, which may cause the increase of histone acetylation of GluN2B gene promoter and the enhancement of GluN2B mRNA transcription and protein expression in hippocampus. The animal experiment was approved by the Animal Ethics Committee of Yangzhou University, China (approval No. 20170312001) in March 2017. Related Articles | Metrics

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Insulin-like growth factor 1 partially rescues early developmental defects caused by SHANK2 knockdown in human neurons Shu-Ting Chen, Wan-Jing Lai, Wei-Jia Zhang, Qing-Pei Chen, Li-Bing Zhou, Kwok-Fai So, Ling-Ling Shi 2020, 15 (12):  2335-2343.  doi: 10.4103/1673-5374.285002 Abstract ( 211 )   PDF (4905KB) ( 218 )   Save SHANK2 is a scaffold protein that serves as a protein anchor at the postsynaptic density in neurons. Genetic variants of SHANK2 are strongly associated with synaptic dysfunction and the pathophysiology of autism spectrum disorder. Recent studies indicate that early neuronal developmental defects play a role in the pathogenesis of autism spectrum disorder, and that insulin-like growth factor 1 has a positive effect on neurite development. To investigate the effects of SHANK2 knockdown on early neuronal development, we generated a sparse culture system using human induced pluripotent stem cells, which then differentiated into neural progenitor cells after 3–14 days in culture, and which were dissociated into single neurons. Neurons in the experimental group were infected with shSHANK2 lentivirus car- rying a red fluorescent protein reporter (shSHANK2 group). Control neurons were infected with scrambled shControl lentivirus carrying a red fluorescent protein reporter (shControl group). Neuronal somata and neurites were reconstructed based on the lentiviral red fluo- rescent protein signal. Developmental dendritic and motility changes in VGLUT1 + glutamatergic neurons and TH + dopaminergic neurons were then evaluated in both groups. Compared with shControl VGLUT1 + neurons, the dendritic length and arborizations of shSHANK2 VGLUT1 + neurons were shorter and fewer, while cell soma speed was higher. Furthermore, dendritic length and arborization were sig- nificantly increased after insulin-like growth factor 1 treatment of shSHANK2 neurons, while cell soma speed remained unaffected. These results suggest that insulin-like growth factor 1 can rescue morphological defects, but not the change in neuronal motility. Collectively, our findings demonstrate that SHANK2 deficiency perturbs early neuronal development, and that IGF1 can partially rescue the neuronal defects caused by SHANK2 knockdown. All experimental procedures and protocols were approved by the Laboratory Animal Ethics Com- mittee of Jinan University, China (approval No. 20170228010) on February 28, 2017. Related Articles | Metrics

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Lycium barbarum polysaccharides related RAGE and Aβ levels in the retina of mice with acute ocular hypertension and promote maintenance of blood retinal barrier Xue-Song Mi, Qian Feng, Amy Cheuk Yin Lo, Raymond Chuen-Chung Chang, Sookja Kim Chung, Kwok-Fai So 2020, 15 (12):  2344-2352.  doi: 10.4103/1673-5374.284998 Abstract ( 196 )   PDF (3869KB) ( 193 )   Save Our previous study verified the protective effects of Lycium barbarum polysaccharides (LBP) on retinal neurons and blood vessels in acute ocular hypertension (AOH) mice. To investigate the effect of LBP on the reactivity of retinal glial cells, an AOH mouse model was estab- lished in one eye by maintaining ocular hypertension of 90 mmHg for 60 minutes. Either LBP solution (1 mg/kg) or phosphate-buffered saline was administrated to the mice by gavage daily, starting 7 days before the AOH insult and continuing until the mice were sacrificed for specimen collection on day 4 post-insult. After AOH insult, increased numbers of astrocytes and microglia were observed, together with decreased expression of the following glial cell biomarkers in the retinal ganglion cells of AOH mice: glial fibrillary acidic protein, glutamine synthetase, aquaporin-4, S-100 proteins, ionized calcium-binding adaptor molecule 1, amyloid precursor protein and receptor of advanced glycosylation end-products. After intervention with LBP, the above changes were significantly reduced. Remarkably, morpho- logical remodeling of blood vessel-associated retinal astrocytes, marked by glial fibrillary acidic protein, was also observed. These results, taken together, suggest that LBP regulated the production of amyloid-β and expression of receptor of advanced glycosylation end-products, as well as mediating the activity of retinal glial cells, which may lead to the promotion of better maintenance of the blood-retinal barrier and improved neuronal survival in AOH insult. This study was approved by the Committee for the Use of Live Animals in Teaching and Research (approval No. CULTRA-#1664-08). Related Articles | Metrics

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FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury Jovan C.D. Hasmatali, Jolly De Guzman, Jayne M. Johnston, Hossein Noyan, Bernhard H. Juurlink, Vikram Misra, Valerie M.K. Verge 2020, 15 (12):  2353-2361.  doi: 10.4103/1673-5374.284999 Abstract ( 138 )   PDF (2848KB) ( 195 )   Save Emerging evidence supports that the stress response to peripheral nerve injury extends beyond the injured neuron, with alterations in associated transcription factors detected both locally and remote to the lesion. Stress-induced nuclear translocation of the transcription factor forkhead class box O3a (FOXO3a) was ini- tially linked to activation of apoptotic genes in many neuronal subtypes. However, a more complex role of FOXO3a has been suggested in the injury response of sensory neurons, with the injured neuron expressing less FOXO3a. To elucidate this response and test whether non-injured sensory neurons also alter FOXO3a expression, the temporal impact of chronic unilateral L4–6 spinal nerve transection on FOXO3a expres- sion and nuclear localization in adult rat dorsal root ganglion neurons ipsilateral, contralateral or remote to injury relative to naïve controls was examined. In naïve neurons, high cytoplasmic and nuclear levels of FOXO3a colocalized with calcitonin gene related peptide, a marker of the nociceptive subpopulation. One hour post-injury, an acute increase in nuclear FOXO3a in small size injured neurons occurred followed by a significant decrease after 1, 2 and 4 days, with levels increasing toward pre-injury levels by 1 week post-in- jury. A more robust biphasic response to the injury was observed in uninjured neurons contralateral to and those remote to injury. Nuclear levels of FOXO3a peaked at 1 day, decreased by 4 days, then increased by 1 week post-injury, a response mirrored in C4 dorsal root ganglion neurons remote to injury. This altered expression contralateral and remote to injury supports that spinal nerve damage has broader systemic impacts, a response we recently reported for another stress transcription factor, Luman/CREB3. The early decreased expression and nuclear localization of FOXO3a in the injured neuron implicate these changes in the cell body response to injury that may be protective. Finally, the broader systemic changes support the existence of stress/injury-induced humeral factor(s) influencing transcriptional and potentially behavioral changes in uninjured dorsal root ganglion neurons. Approval to conduct this study was obtained from the University of Saskatchewan Animal Research Ethics Board (protocol #19920164). Related Articles | Metrics

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Neuroprotective mechanisms of DNA methyltransferase in a mouse hippocampal neuronal cell line after hypoxic preconditioning Na Liu, Xiao-Lu Zhang, Shu-Yuan Jiang, Jing-Hua Shi, Jun-He Cui, Xiao-Lei Liu, Li-Hong Han, Ke-Rui Gong, Shao-Chun Yan, Wei Xie, Chun-Yang Zhang, Guo Shao 2020, 15 (12):  2362-2368.  doi: 10.4103/1673-5374.285003 Abstract ( 125 )   PDF (1885KB) ( 332 )   Save Hypoxic preconditioning has been shown to improve hypoxic tolerance in mice, accompanied by the downregulation of DNA methyltrans- ferases (DNMTs) in the brain. However, the roles played by DNMTs in the multiple neuroprotective mechanisms associated with hypoxic preconditioning remain poorly understood. This study aimed to establish an in vitro model of hypoxic preconditioning, using a cultured mouse hippocampal neuronal cell line (HT22 cells), to examine the effects of DNMTs on the endogenous neuroprotective mechanisms that occur during hypoxic preconditioning. HT22 cells were divided into a control group, which received no exposure to hypoxia, a hypoxia group, which was exposed to hypoxia once, and a hypoxic preconditioning group, which was exposed to four cycles of hypoxia. To test the ability of hypoxic preadaptation to induce hypoxic tolerance, cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-5(3-car- boxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. Cell viability improved in the hypoxic preconditioning group compared with that in the hypoxia group. The effects of hypoxic preconditioning on the cell cycle and apoptosis in HT22 cells were examined by west- ern blot assay and flow cytometry. Compared with the hypoxia group, the expression levels of caspase-3 and spectrin, which are markers of early apoptosis and S-phase arrest, respectively, noticeably reduced in the hypoxic preconditioning group. Finally, enzyme-linked im- munosorbent assay, real-time polymerase chain reaction, and western blot assay were used to investigate the changes in DNMT expression and activity during hypoxic preconditioning. The results showed that compared with the control group, hypoxic preconditioning down- regulated the expression levels of DNMT3A and DNMT3B mRNA and protein in HT22 cells and decreased the activities of total DNMTs and DNMT3B. In conclusion, hypoxic preconditioning may exert anti-hypoxic neuroprotective effects, maintaining HT22 cell viability and inhibiting cell apoptosis. These neuroprotective mechanisms may be associated with the inhibition of DNMT3A and DNMT3B. Related Articles | Metrics