Journal of Clinical Medicine

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21 pages, 26101 KiB

Open AccessArticle

Functional Heterogeneity of Mouse and Human Brain OPCs: Relevance for Preclinical Studies in Multiple Sclerosis

by Ana Bribián, Eva M. Medina-Rodríguez, Fernando Josa-Prado, Isabel García-Álvarez, Isabel Machín-Díaz, Pedro F. Esteban, Verónica Murcia-Belmonte, Lorena Vega-Zelaya, Jesús Pastor, Leoncio Garrido and Fernando de Castro

J. Clin. Med. 2020, 9(6), 1681; https://doi.org/10.3390/jcm9061681 - 02 Jun 2020

Cited by 20 | Viewed by 4727

Abstract

Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development [...] Read more.

Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development and in adulthood, yet how OPC physiological behavior is modified throughout life is not fully understood. The activity of adult human OPCs is still particularly unexplored. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In the present article, we have compared the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. By analyzing intact OPCs for the first time with 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function for their stage of maturity. Moreover, their response to Fibroblast Growth Gactor-2 (FGF-2) and anosmin-1 (two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS)) differs in relation to their developmental stage and in the function of the species. Our data reveal that the behavior of adult human and mouse OPCs differs in a very dynamic way that should be very relevant when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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20 pages, 3514 KiB

Open AccessArticle

Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

by Andrés Felipe Díaz, Sara Polo, Núria Gallardo, Sergi Leánez and Olga Pol

J. Clin. Med. 2019, 8(6), 890; https://doi.org/10.3390/jcm8060890 - 21 Jun 2019

Cited by 34 | Viewed by 4310

Abstract

Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of [...] Read more.

Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-κB (NF-κB) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of κBα (p-IκBα), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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Review

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27 pages, 1469 KiB

Open AccessReview

Glia-Derived Extracellular Vesicles in Parkinson’s Disease

by Bianca Marchetti, Loredana Leggio, Francesca L’Episcopo, Silvia Vivarelli, Cataldo Tirolo, Greta Paternò, Carmela Giachino, Salvatore Caniglia, Maria Francesca Serapide and Nunzio Iraci

J. Clin. Med. 2020, 9(6), 1941; https://doi.org/10.3390/jcm9061941 - 21 Jun 2020

Cited by 17 | Viewed by 5577

Abstract

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson’s disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) [...] Read more.

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson’s disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Notably, glial cells communicating with each other by an array of molecules, can acquire a “beneficial” or “destructive” phenotype, thereby enhancing neuronal death/vulnerability and/or exerting critical neuroprotective and neuroreparative functions, with mechanisms that are actively investigated. An important way of delivering messenger molecules within this glia-neuron cross-talk consists in the secretion of extracellular vesicles (EVs). EVs are nano-sized membranous particles able to convey a wide range of molecular cargoes in a controlled way, depending on the specific donor cell and the microenvironmental milieu. Given the dual role of glia in PD, glia-derived EVs may deliver molecules carrying various messages for the vulnerable/dysfunctional DAergic neurons. Here, we summarize the state-of-the-art of glial-neuron interactions and glia-derived EVs in PD. Also, EVs have the ability to cross the blood brain barrier (BBB), thus acting both within the CNS and outside, in the periphery. In these regards, this review discloses the emerging applications of EVs, with a special focus on glia-derived EVs as potential carriers of new biomarkers and nanotherapeutics for PD. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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26 pages, 960 KiB

Open AccessReview

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

by Valentina Cerrato

J. Clin. Med. 2020, 9(3), 757; https://doi.org/10.3390/jcm9030757 - 11 Mar 2020

Cited by 21 | Viewed by 7405

Abstract

Ataxia is a neurodegenerative syndrome, which can emerge as a major element of a disease or represent a symptom of more complex multisystemic disorders. It comprises several forms with a highly variegated etiology, mainly united by motor, balance, and speech impairments and, at [...] Read more.

Ataxia is a neurodegenerative syndrome, which can emerge as a major element of a disease or represent a symptom of more complex multisystemic disorders. It comprises several forms with a highly variegated etiology, mainly united by motor, balance, and speech impairments and, at the tissue level, by cerebellar atrophy and Purkinje cells degeneration. For this reason, the contribution of astrocytes to this disease has been largely overlooked in the past. Nevertheless, in the last few decades, growing evidences are pointing to cerebellar astrocytes as crucial players not only in the progression but also in the onset of distinct forms of ataxia. Although the current knowledge on this topic is very fragmentary and ataxia type-specific, the present review will attempt to provide a comprehensive view of astrocytes’ involvement across the distinct forms of this pathology. Here, it will be highlighted how, through consecutive stage-specific mechanisms, astrocytes can lead to non-cell autonomous neurodegeneration and, consequently, to the behavioral impairments typical of this disease. In light of that, treating astrocytes to heal neurons will be discussed as a potential complementary therapeutic approach for ataxic patients, a crucial point provided the absence of conclusive treatments for this disease. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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22 pages, 1451 KiB

Open AccessReview

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

by Davide Marangon, Marta Boccazzi, Davide Lecca and Marta Fumagalli

J. Clin. Med. 2020, 9(2), 470; https://doi.org/10.3390/jcm9020470 - 08 Feb 2020

Cited by 39 | Viewed by 7355

Abstract

Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment [...] Read more.

Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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13 pages, 736 KiB

Open AccessFeature PaperReview

GDNF, A Neuron-Derived Factor Upregulated in Glial Cells during Disease

by Marcelo Duarte Azevedo, Sibilla Sander and Liliane Tenenbaum

J. Clin. Med. 2020, 9(2), 456; https://doi.org/10.3390/jcm9020456 - 07 Feb 2020

Cited by 63 | Viewed by 8271

Abstract

In a healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons, and, in some instances, it has also been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex [...] Read more.

In a healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons, and, in some instances, it has also been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with the GDNF family receptor α1 (GFRα1), which is mainly expressed by neurons and can act in cis as a membrane-bound factor or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interactions with the “rearranged during transfection” (RET) receptor or via the neural cell adhesion molecule (NCAM) with a lower affinity. GDNF can also signal independently from GFRα1 by interacting with syndecan-3. RET, which is expressed by neurons involved in several pathways (nigro–striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc.), could be the main determinant of the specificity of GDNF’s pro-survival effect. In an injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive reactive astrocytes, and neuron/glia (NG2) positive microglia-like cells. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cell activation. Some reports also describe the upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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47 pages, 1510 KiB

Open AccessReview

Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

by Tereza Filipi, Zuzana Hermanova, Jana Tureckova, Ondrej Vanatko and Miroslava Anderova

J. Clin. Med. 2020, 9(1), 261; https://doi.org/10.3390/jcm9010261 - 18 Jan 2020

Cited by 46 | Viewed by 9005

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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16 pages, 710 KiB

Open AccessReview

Synaptic Pruning by Microglia in Epilepsy

by Megumi Andoh, Yuji Ikegaya and Ryuta Koyama

J. Clin. Med. 2019, 8(12), 2170; https://doi.org/10.3390/jcm8122170 - 09 Dec 2019

Cited by 61 | Viewed by 12390

Abstract

Structural and functional collapse of the balance between excitatory (E) and inhibitory (I) synapses, i.e., synaptic E/I balance, underlies the pathogeneses of various central nervous system (CNS) disorders. In epilepsy, the synaptic E/I balance tips toward excitation; thus, most of the existing epileptic [...] Read more.

Structural and functional collapse of the balance between excitatory (E) and inhibitory (I) synapses, i.e., synaptic E/I balance, underlies the pathogeneses of various central nervous system (CNS) disorders. In epilepsy, the synaptic E/I balance tips toward excitation; thus, most of the existing epileptic remedies have focused on how to directly suppress the activity of neurons. However, because as many as 30% of patients with epilepsy are drug resistant, the discovery of new therapeutic targets is strongly desired. Recently, the roles of glial cells in epilepsy have gained attention because glial cells manipulate synaptic structures and functions in addition to supporting neuronal survival and growth. Among glial cells, microglia, which are brain-resident immune cells, have been shown to mediate inflammation, neuronal death and aberrant neurogenesis after epileptic seizures. However, few studies have investigated the involvement of synaptic pruning—one of the most important roles of microglia—in the epileptic brain. In this review, we propose and discuss the hypothesis that synaptic pruning by microglia is enhanced in the epileptic brain, drawing upon the findings of previous studies. We further discuss the possibility that aberrant synaptic pruning by microglia induces synaptic E/I imbalance, promoting the development and aggravation of epilepsy. Full article

(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)

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