Topical Collection "Collection on Molecular and Cellular Neuroscience"

A topical collection in Brain Sciences (ISSN 2076-3425). This collection belongs to the section "Molecular and Cellular Neuroscience".

Editor

Dr. Andrew Clarkson
E-Mail Website
Collection Editor
Department of Anatomy, University of Otago, Dunedin, New Zealand
Interests: stroke; ageing; drug delivery; neuroprotection; neurorepair; learning and memory; behavioural neuroscience; neuropharmacology; CNS diseases; neuroinflammation; epilepsy; extracellular matrix; glial biology
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Topical Collection Information

Dear Colleagues,

The mission of the collection on Molecular and Cellular Neuroscience is to publish cutting-edge original articles and critical reviews on the molecular and cellular basis of neurological disorders. In particular, the journal covers all aspects of molecular and cellular neuroscience, from genetic analyses of human populations to tissue culture and animal models of neurological disorders. Coverage includes experimental analyses of molecular and cellular events underpinning both developmental and adult plasticity mechanisms of the normal nervous system and occurring as a consequence of neurological dysfunction and in neuronal degeneration and repair. In particular, in relation to the latter subject, this journal section focuses on synaptic maintenance, synaptic de- and reorganization, neuron–glia communication, de- and regenerative neurobiology, molecular genetics, signal transduction, synaptic plasticity, and cell death. Of particular interest are studies using animal models of disease with translational prospects and experimental approaches utilising a bedside-to-bench approach to validate disease signatures from human patients.

Dr. Andrew Clarkson
Collection Editor

Manuscript Submission Information

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Published Papers (16 papers)

2021

Jump to: 2020, 2019

Article
Bayesian Network as a Decision Tool for Predicting ALS Disease
Brain Sci. 2021, 11(2), 150; https://doi.org/10.3390/brainsci11020150 - 23 Jan 2021
Viewed by 876
Abstract
Clinical diagnosis of amyotrophic lateral sclerosis (ALS) is difficult in the early period. But blood tests are less time consuming and low cost methods compared to other methods for the diagnosis. The ALS researchers have been used machine learning methods to predict the [...] Read more.
Clinical diagnosis of amyotrophic lateral sclerosis (ALS) is difficult in the early period. But blood tests are less time consuming and low cost methods compared to other methods for the diagnosis. The ALS researchers have been used machine learning methods to predict the genetic architecture of disease. In this study we take advantages of Bayesian networks and machine learning methods to predict the ALS patients with blood plasma protein level and independent personal features. According to the comparison results, Bayesian Networks produced best results with accuracy (0.887), area under the curve (AUC) (0.970) and other comparison metrics. We confirmed that sex and age are effective variables on the ALS. In addition, we found that the probability of onset involvement in the ALS patients is very high. Also, a person’s other chronic or neurological diseases are associated with the ALS disease. Finally, we confirmed that the Parkin level may also have an effect on the ALS disease. While this protein is at very low levels in Parkinson’s patients, it is higher in the ALS patients than all control groups. Full article
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2020

Jump to: 2021, 2019

Article
Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition
Brain Sci. 2021, 11(1), 12; https://doi.org/10.3390/brainsci11010012 - 24 Dec 2020
Viewed by 549
Abstract
(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual [...] Read more.
(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the ‘light’ synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed. Full article
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Communication
Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons
Brain Sci. 2020, 10(12), 958; https://doi.org/10.3390/brainsci10120958 - 09 Dec 2020
Cited by 1 | Viewed by 731
Abstract
O-GlcNAc transferase (OGT) is a ubiquitous enzyme that regulates the addition of β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of target proteins. Autophagy is a cellular process of self-digestion, in which cytoplasmic resources, such as aggregate proteins, toxic compounds, damaged organelles, mitochondria, and [...] Read more.
O-GlcNAc transferase (OGT) is a ubiquitous enzyme that regulates the addition of β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of target proteins. Autophagy is a cellular process of self-digestion, in which cytoplasmic resources, such as aggregate proteins, toxic compounds, damaged organelles, mitochondria, and lipid molecules, are degraded and recycled. Here, we examined how three different OGT inhibitors, alloxan, BXZ2, and OSMI-1, modulate O-GlcNAcylation in rat cortical neurons, and their autophagic effects were determined by immunoblot and immunofluorescence assays. We found that the treatment of cortical neurons with an OGT inhibitor decreased O-GlcNAcylation levels and increased LC3-II expression. Interestingly, the pre-treatment with rapamycin, an mTOR inhibitor, further increased the expression levels of LC3-II induced by OGT inhibition, implicating the involvement of mTOR signaling in O-GlcNAcylation-dependent autophagy. In contrast, OGT inhibitor-mediated autophagy was significantly attenuated by 3-methyladenine (3-MA), a blocker of autophagosome formation. However, when pre-treated with chloroquine (CQ), a lysosomotropic agent and a late-stage autophagy inhibitor, OGT inhibitors significantly increased LC3-II levels along with LC3 puncta formation, indicating the stimulation of autophagic flux. Lastly, we found that OGT inhibitors significantly decreased the levels of the autophagy substrate p62/SQSTM1 while increasing the expression of lysosome-associated membrane protein 1 (LAMP1). Together, our study reveals that the modulation of O-GlcNAcylation by OGT inhibition regulates mTOR-dependent autophagy in rat cortical neurons. Full article
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Article
Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes
Brain Sci. 2020, 10(9), 611; https://doi.org/10.3390/brainsci10090611 - 05 Sep 2020
Cited by 2 | Viewed by 1328
Abstract
Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining [...] Read more.
Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining genomic integrity in the central nervous system (CNS). However, the impact of cocaine-mediated epigenetic changes in astrocytes has not yet been elucidated. In this study, we explored the neuroprotective effect of piracetam against cocaine-induced epigenetic changes in DNA methylation in astrocytes. To study our hypothesis, we exposed human astrocytes to cocaine alone or in combination with the nootropic drug piracetam. We examined the expression of the DNA methyltransferases (DNMTs) DNMT-1, DNMT-3A, and DNMT-3B; global DNA methylation levels of 5-methycytosine (5-mC); and induction of ten–eleven translocation (TET) enzymes in astrocytes. In addition, we analyzed mtDNA methylation by targeted next-generation bisulfite sequencing. Our data provide evidence that cocaine impairs DNMT activity and thereby has impacts on mtDNA, which might contribute to the neurodegeneration observed in cocaine users. These effects might be at least partially prevented by piracetam, allowing neuronal function to be maintained. Full article
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Article
Localization of ZIP14 and ZIP8 in HIBCPP Cells
Brain Sci. 2020, 10(8), 534; https://doi.org/10.3390/brainsci10080534 - 08 Aug 2020
Cited by 2 | Viewed by 1015
Abstract
The blood–cerebrospinal fluid barrier (BCB) is important in maintaining brain manganese (Mn) homeostasis. This barrier consists of a single layer of epithelial cells, connected by tight junctions, that restrict the passage of nutrients to only allow molecules to be carried through the membrane [...] Read more.
The blood–cerebrospinal fluid barrier (BCB) is important in maintaining brain manganese (Mn) homeostasis. This barrier consists of a single layer of epithelial cells, connected by tight junctions, that restrict the passage of nutrients to only allow molecules to be carried through the membrane by a transporter. These epithelial cells are polarized with asymmetrical blood-facing and cerebrospinal fluid-facing sides. Here, we have established a polarized model of a human choroid plexus papilloma cell line, HIBCPP. For the first time, Mn importers ZIP14 and ZIP8 were identified in HIBCPP cells and were found to be enriched at the basolateral and apical sides of the cell monolayer, respectively. The localization of each ZIP protein adds to the understanding of Mn transport across the HIBCPP BCB model to help understand the mechanism of Mn homeostasis within the brain. Full article
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Article
Proliferation, Adult Neuronal Stem Cells and Cells Migration in Pallium during Constitutive Neurogenesis and after Traumatic Injury of Telencephalon of Juvenile Masu Salmon, Oncorhynchus masou
Brain Sci. 2020, 10(4), 222; https://doi.org/10.3390/brainsci10040222 - 08 Apr 2020
Cited by 2 | Viewed by 1244
Abstract
A study of the lateral pallium in zebrafish and the visual tectum of the medaka revealed a population of adult neuroepithelial (NE) cells supported from the early stage of development to various postembryonic stages of ontogenesis. These data emphasize the importance of non-radial [...] Read more.
A study of the lateral pallium in zebrafish and the visual tectum of the medaka revealed a population of adult neuroepithelial (NE) cells supported from the early stage of development to various postembryonic stages of ontogenesis. These data emphasize the importance of non-radial glial stem cells in the neurogenesis of adult animals, in particular fish. However, the distribution, cell cycle features, and molecular markers of NE cells and glial progenitors in fish are still poorly understood at the postembryonic stages of ontogenesis. Fetalization predominates in the ontogenetic development of salmon fish, which is associated with a delay in development and preservation of the features of the embryonic structure of the brain during the first year of life. In the present work, we studied the features of proliferation and the migration of neuronal precursors in the pallial proliferative zone of juvenile Oncorhynchus masou. The aim of the study is a comparative analysis of the distribution of glial-type aNSCs markers, such as vimentin and glial fibrillar acid protein GFAP, as well as the proliferation marker BrdU and migratory neuronal precursor doublecortin, in the pallial zone of the intact telencephalon in juvenile O. masou normal and after mechanical injury. The immunohistochemical IHC labeling with antibodies to vimentin, GFAP and doublecortin in the pallium of intact fish revealed single, small, round and oval immunopositive cells, that correspond to a persistent pool of neuronal and/or glial progenitors. After the injury, heterogeneous cell clusters, radial glia processes, single and small intensely labeled GFAP+ cells in the parenchyma of Dd and lateral part of pallium (Dl) appeared, corresponding to reactive neurogenic niches containing glial aNSCs. A multifold increase in the pool of Vim+ neuronal precursor cells (NPCs) resulting from the injury was observed. Vim+ cells of the neuroepithelial type in Dd and Dm and cells of the glial type were identified in Dl after the injury. Doublecortine (Dc) immunolabeling after the injury revealed the radial migration of neuroblasts into Dm from the neurogenic zone of the pallium. The appearance of intensely labeled Dc+ cells in the brain parenchyma might indicate the activation of resident aNSCs as a consequence of the traumatic process. Full article
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Article
Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone
Brain Sci. 2020, 10(4), 193; https://doi.org/10.3390/brainsci10040193 - 25 Mar 2020
Viewed by 1836
Abstract
Acute restraint stress (ARS) is an unavoidable stress situation and may be encountered in different clinical situations. The aim of the current study was to investigate the effects of ARS on the hippocampus and cerebellum, assess the impact of these effects on the [...] Read more.
Acute restraint stress (ARS) is an unavoidable stress situation and may be encountered in different clinical situations. The aim of the current study was to investigate the effects of ARS on the hippocampus and cerebellum, assess the impact of these effects on the behavior and cognitive function, and determine whether pretreatment with ceftriaxone would attenuate the damages produced by ARS on the hippocampus and cerebellum. Four groups of male mice were included in this study: The control group, ARS group, ceftriaxone group, and ARS + ceftriaxone group. Tail suspension test, Y-maze task, and open field tests were used to assess depression, working spatial memory, and anxiety. The biochemical analyses included measurements of serum cortisol, tumor necrotic factor (TNF), interleukin-6, hippocampal expression of bone morphogenetic protein 9 (BMP9), lysosomal-associated membrane protein 1 (LAMP1), glutamate transporter 1 (GLT1), heat shock protein 90, cerebellar expression of S100 protein, glutamic acid decarboxylase (GAD), and carbon anhydrase. Histopathological examination of the brain sections was conducted on the hippocampus and cerebellum by hematoxylin and eosin stains in addition to ultrastructure evaluation using electron microscopy. Our results suggested that ceftriaxone had neuroprotective properties by attenuating the effects of ARS on the hippocampus and cerebellum in mice. This effect was demonstrated by the improvement in the cognitive and behavioral tests as well as by the preservation of the hippocampal and cerebellar architecture. Full article
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Article
Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease
Brain Sci. 2020, 10(2), 68; https://doi.org/10.3390/brainsci10020068 - 27 Jan 2020
Cited by 1 | Viewed by 1234
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in [...] Read more.
Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions. Full article
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Article
Neural Stem Cells/Neuronal Precursor Cells and Postmitotic Neuroblasts in Constitutive Neurogenesis and After ,Traumatic Injury to the Mesencephalic Tegmentum of Juvenile Chum Salmon, Oncorhynchus keta
Brain Sci. 2020, 10(2), 65; https://doi.org/10.3390/brainsci10020065 - 25 Jan 2020
Cited by 2 | Viewed by 1061
Abstract
The proliferation of neural stem cells (NSCs)/neuronal precursor cells (NPCs) and the occurrence of postmitotic neuroblasts in the mesencephalic tegmentum of intact juvenile chum salmon, Oncorhynchus keta, and at 3 days after a tegmental injury, were studied by immunohistochemical labeling. BrdU+ constitutive [...] Read more.
The proliferation of neural stem cells (NSCs)/neuronal precursor cells (NPCs) and the occurrence of postmitotic neuroblasts in the mesencephalic tegmentum of intact juvenile chum salmon, Oncorhynchus keta, and at 3 days after a tegmental injury, were studied by immunohistochemical labeling. BrdU+ constitutive progenitor cells located both in the periventricular matrix zone and in deeper subventricular and parenchymal layers of the brain are revealed in the tegmentum of juvenile chum salmon. As a result of traumatic damage to the tegmentum, the proliferation of resident progenitor cells of the neuroepithelial type increases. Nestin-positive and vimentin-positive NPCs and granules located in the periventricular and subventricular matrix zones, as well as in the parenchymal regions of the tegmentum, are revealed in the mesencephalic tegmentum of juvenile chum salmon, which indicates a high level of constructive metabolism and constitutive neurogenesis. The expression of vimentin and nestin in the extracellular space, as well as additionally in the NSCs and NPCs of the neuroepithelial phenotype, which do not express nestin in the control animals, is enhanced during the traumatic process. As a result of the proliferation of such cells in the post-traumatic period, local Nes+ and Vim+ NPCs clusters are formed and become involved in the reparative response. Along with the primary traumatic lesion, which coincides with the injury zone, additional Nes+ and Vim+ secondary lesions are observed to form in the adjacent subventricular and parenchymal zones of the tegmentum. In the lateral tegmentum, the number of doublecortin-positive cells is higher compared to that in the medial tegmentum, which determines the different intensities and rates of neuronal differentiation in the sensory and motor regions of the tegmentum, respectively. In periventricular regions remote from the injury, the expression of doublecortin in single cells and their groups significantly increases compared to that in the damage zone. Full article
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2019

Jump to: 2021, 2020

Article
Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway
Brain Sci. 2019, 9(12), 378; https://doi.org/10.3390/brainsci9120378 - 15 Dec 2019
Cited by 3 | Viewed by 1426
Abstract
Phenothiazine treatment has been shown to reduce post-stroke ischemic injury, though the underlying mechanism remains unclear. This study sought to confirm the neuroprotective effects of phenothiazines and to explore the role of the NOX (nicotinamide adenine dinucleotide phosphate oxidase)/Akt/PKC (protein kinase C) pathway [...] Read more.
Phenothiazine treatment has been shown to reduce post-stroke ischemic injury, though the underlying mechanism remains unclear. This study sought to confirm the neuroprotective effects of phenothiazines and to explore the role of the NOX (nicotinamide adenine dinucleotide phosphate oxidase)/Akt/PKC (protein kinase C) pathway in cerebral apoptosis. Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) for 2 h and were randomly divided into 3 different cohorts: (1) saline, (2) 8 mg/kg chlorpromazine and promethazine (C+P), and (3) 8 mg/kg C+P as well as apocynin (NOX inhibitor). Brain infarct volumes were examined, and cell death/NOX activity was determined by assays. Western blotting was used to assess protein expression of kinase C-δ (PKC-δ), phosphorylated Akt (p-Akt), Bax, Bcl-XL, and uncleaved/cleaved caspase-3. Both C+P and C+P/NOX inhibitor administration yielded a significant reduction in infarct volumes and cell death, while the C+P/NOX inhibitor did not confer further reduction. In both treatment groups, anti-apoptotic Bcl-XL protein expression generally increased, while pro-apoptotic Bax and caspase-3 proteins generally decreased. PKC protein expression was decreased in both treatment groups, demonstrating a further decrease by C+P/NOX inhibitor at 6 and 24 h of reperfusion. The present study confirms C+P-mediated neuroprotection and suggests that the NOX/Akt/PKC pathway is a potential target for efficacious therapy following ischemic stroke. Full article
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Article
Neuronal Transmembrane Chloride Transport Has a Time-Dependent Influence on Survival of Hippocampal Cultures to Oxygen-Glucose Deprivation
Brain Sci. 2019, 9(12), 360; https://doi.org/10.3390/brainsci9120360 - 06 Dec 2019
Cited by 3 | Viewed by 1388
Abstract
Neuronal ischemia results in chloride gradient alterations which impact the excitatory–inhibitory balance, volume regulation, and neuronal survival. Thus, the Na+/K+/Cl co-transporter (NKCC1), the K+/ Cl co-transporter (KCC2), and the gamma-aminobutyric acid A (GABAA) [...] Read more.
Neuronal ischemia results in chloride gradient alterations which impact the excitatory–inhibitory balance, volume regulation, and neuronal survival. Thus, the Na+/K+/Cl co-transporter (NKCC1), the K+/ Cl co-transporter (KCC2), and the gamma-aminobutyric acid A (GABAA) receptor may represent therapeutic targets in stroke, but a time-dependent effect on neuronal viability could influence the outcome. We, therefore, successively blocked NKCC1, KCC2, and GABAA (with bumetanide, DIOA, and gabazine, respectively) or activated GABAA (with isoguvacine) either during or after oxygen-glucose deprivation (OGD). Primary hippocampal cultures were exposed to a 2-h OGD or sham normoxia treatment, and viability was determined using the resazurin assay. Neuronal viability was significantly reduced after OGD, and was further decreased by DIOA treatment applied during OGD (p < 0.01) and by gabazine applied after OGD (p < 0.05). Bumetanide treatment during OGD increased viability (p < 0.05), while isoguvacine applied either during or after OGD did not influence viability. Our data suggests that NKCC1 and KCC2 function has an important impact on neuronal viability during the acute ischemic episode, while the GABAA receptor plays a role during the subsequent recovery period. These findings suggest that pharmacological modulation of transmembrane chloride transport could be a promising approach during stroke and highlight the importance of the timing of treatment application in relation to ischemia-reoxygenation. Full article
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Perspective
Human Periapical Cyst-Derived Stem Cells Can Be A Smart “Lab-on-A-Cell” to Investigate Neurodegenerative Diseases and the Related Alteration of the Exosomes’ Content
Brain Sci. 2019, 9(12), 358; https://doi.org/10.3390/brainsci9120358 - 05 Dec 2019
Cited by 4 | Viewed by 1680
Abstract
Promising researches have demonstrated that the alteration of biological rhythms may be consistently linked to neurodegenerative pathologies. Parkinson’s disease (PD) has a multifactorial pathogenesis, involving both genetic and environmental and/or molecular co-factors. Generally, heterogeneous alterations in circadian rhythm (CR) are a typical finding [...] Read more.
Promising researches have demonstrated that the alteration of biological rhythms may be consistently linked to neurodegenerative pathologies. Parkinson’s disease (PD) has a multifactorial pathogenesis, involving both genetic and environmental and/or molecular co-factors. Generally, heterogeneous alterations in circadian rhythm (CR) are a typical finding in degenerative processes, such as cell aging and death. Although numerous genetic phenotypes have been discovered in the most common forms of PD, it seems that severe deficiencies in synaptic transmission and high vesicular recycling are frequently found in PD patients. Neuron-to-neuron interactions are often ensured by exosomes, a specific type of extracellular vesicle (EV). Neuron-derived exosomes may carry several active compounds, including miRNAs: Several studies have found that circulating miRNAs are closely associated with an atypical oscillation of circadian rhythm genes, and they are also involved in the regulation of clock genes, in animal models. In this context, a careful analysis of neural-differentiated Mesenchymal Stem Cells (MSCs) and the molecular and genetic characterization of their exosome content, both in healthy cells and in PD-induced cells, could be a strategic field of investigation for early diagnosis and better treatment of PD and similar neurodegenerative pathologies. A novel MSC population, called human periapical cyst–mesenchymal stem cells (hPCy–MSCs), has demonstrated that it naively expresswa the main neuronal markers, and may differentiate towards functional neurons. Therefore, hPCy–MSCs can be considered of particular interest for testing of in vitro strategies to treat neurological diseases. On the other hand, the limitations of using stem cells is an issue that leads researchers to perform experimental studies on the exosomes released by MCSs. Human periapical cyst-derived mesenkymal stem cells can be a smart “lab-on-a-cell” to investigate neurodegenerative diseases and the related exosomes’ content alteration. Full article
Article
Assessing the Effects of Cytoprotectants on Selective Neuronal Loss, Sensorimotor Deficit and Microglial Activation after Temporary Middle Cerebral Occlusion
Brain Sci. 2019, 9(10), 287; https://doi.org/10.3390/brainsci9100287 - 22 Oct 2019
Cited by 1 | Viewed by 949
Abstract
Although early reperfusion after stroke salvages the still-viable ischemic tissue, peri-infarct selective neuronal loss (SNL) can cause sensorimotor deficits (SMD). We designed a longitudinal protocol to assess the effects of cytoprotectants on SMD, microglial activation (MA) and SNL, and specifically tested whether the [...] Read more.
Although early reperfusion after stroke salvages the still-viable ischemic tissue, peri-infarct selective neuronal loss (SNL) can cause sensorimotor deficits (SMD). We designed a longitudinal protocol to assess the effects of cytoprotectants on SMD, microglial activation (MA) and SNL, and specifically tested whether the KCa3.1-blocker TRAM-34 would prevent SNL. Spontaneously hypertensive rats underwent 15 min middle-cerebral artery occlusion and were randomized into control or treatment group, which received TRAM-34 intraperitoneally for 4 weeks starting 12 h after reperfusion. SMD was assessed longitudinally using the sticky-label test. MA was quantified at day 14 using in vivo [11C]-PK111195 positron emission tomography (PET), and again across the same regions-of-interest template by immunofluorescence together with SNL at day 28. SMD recovered significantly faster in the treated group (p = 0.004). On PET, MA was present in 5/6 rats in each group, with no significant between-group difference. On immunofluorescence, both SNL and MA were present in 5/6 control rats and 4/6 TRAM-34 rats, with a non-significantly lower degree of MA but a significantly (p = 0.009) lower degree of SNL in the treated group. These findings document the utility of our longitudinal protocol and suggest that TRAM-34 reduces SNL and hastens behavioural recovery without marked MA blocking at the assessed time-points. Full article
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Article
Pre- and Post-Treatment with Novel Antiepileptic Drug Oxcarbazepine Exerts Neuroprotective Effect in the Hippocampus in a Gerbil Model of Transient Global Cerebral Ischemia
Brain Sci. 2019, 9(10), 279; https://doi.org/10.3390/brainsci9100279 - 17 Oct 2019
Cited by 6 | Viewed by 1235
Abstract
Oxcarbazepine, an antiepileptic drug, has been reported to modulate voltage-dependent sodium channels, and it is commonly used in epilepsy treatment. In this study, we investigated the neuroprotective effect of oxcarbazepine in the hippocampus after transient ischemia in gerbils. Gerbils randomly received oxcarbazepine 100 [...] Read more.
Oxcarbazepine, an antiepileptic drug, has been reported to modulate voltage-dependent sodium channels, and it is commonly used in epilepsy treatment. In this study, we investigated the neuroprotective effect of oxcarbazepine in the hippocampus after transient ischemia in gerbils. Gerbils randomly received oxcarbazepine 100 or 200 mg/kg before and after transient ischemia. We examined its neuroprotective effect in the cornu ammonis 1 subfield of the gerbil hippocampus at 5 days after transient ischemia by using cresyl violet staining, neuronal nuclei immunohistochemistry and Fluoro-Jade B histofluorescence staining for neuroprotection, and by using glial fibrillary protein and ionized calcium-binding adapter molecule 1 immunohistochemistry for reaction of astrocytes and microglia, respectively. Pre- and post-treatment with 200 mg/kg of oxcarbazepine, but not 100 mg/kg of oxcarbazepine, protected pyramidal neurons of the cornu ammonis 1 subfield from transient ischemic damage. In addition, pre- and post-treatment with oxcarbazepine (200 mg/kg) significantly ameliorated astrocytes and microglia activation in the ischemic cornu ammonis 1 subfield. In brief, our current results indicate that post-treatment as well as pre-treatment with 200 mg/kg of oxcarbazepine can protect neurons from ischemic insults via attenuation of the glia reaction. Full article
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Article
Effects of Stathmin 1 Gene Knockout on Behaviors and Dopaminergic Markers in Mice Exposed to Social Defeat Stress
Brain Sci. 2019, 9(9), 215; https://doi.org/10.3390/brainsci9090215 - 26 Aug 2019
Cited by 1 | Viewed by 1704
Abstract
Stathmin (STMN), a microtubule-destabilizing factor, can regulate fear, anxiety, and learning. Social defeat stress (SDS) has detrimental effects on mental health and increases the risk of various psychiatric diseases. This study investigated the effects of STMN1 gene knockout (KO) on behavioral [...] Read more.
Stathmin (STMN), a microtubule-destabilizing factor, can regulate fear, anxiety, and learning. Social defeat stress (SDS) has detrimental effects on mental health and increases the risk of various psychiatric diseases. This study investigated the effects of STMN1 gene knockout (KO) on behavioral parameters and dopaminergic markers using an SDS mouse model. The STMN1 KO mice showed anxious hyperactivity, impaired object recognition, and decreased levels of neutral and social investigating behaviors at baseline compared to wild-type (WT) mice. The impact of SDS on neutral, social investigating and dominant behaviors differed markedly between the STMN1 WT and KO mice. In addition, different levels of total DARPP-32 and pDARPP-32 Thr75 expression were observed among the control, unsusceptible, and susceptible groups of STMN1 KO mice. Our results show that STMN1 has specific roles in locomotion, object recognition, and social interactions. Moreover, SDS had differential impacts on social interactions and dopaminergic markers between STMN1 WT and KO mice. Full article
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Article
Pro-Nerve Growth Factor Induces Activation of RhoA Kinase and Neuronal Cell Death
Brain Sci. 2019, 9(8), 204; https://doi.org/10.3390/brainsci9080204 - 19 Aug 2019
Cited by 5 | Viewed by 1596
Abstract
We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by [...] Read more.
We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75NTR receptors. ProNGF is the precursor form of NGF, binds to p75NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75NTR expression and activation of RhoA, leading to neuronal cell death. Full article
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