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Article ; Online: Nutritional interventions for spinal cord injury: preclinical efficacy and molecular mechanisms.

Campos, Jonas / Silva, Nuno A / Salgado, António J

2021 Volume 80, Issue 5, Page(s) 1206–1221

Abstract: Spinal cord injury (SCI) is a debilitating condition that leads to motor, sensory, and autonomic impairments. Its intrinsic pathophysiological complexity has hindered the establishment of effective treatments for decades. Nutritional interventions (NIs) ... ...

Abstract	Spinal cord injury (SCI) is a debilitating condition that leads to motor, sensory, and autonomic impairments. Its intrinsic pathophysiological complexity has hindered the establishment of effective treatments for decades. Nutritional interventions (NIs) for SCI have been proposed as a route to circumvent some of the problems associated with this condition. Results obtained in animal models point to a more holistic effect, rather than to specific modulation, of several relevant SCI pathophysiological processes. Indeed, published data have shown NI improves energetic imbalance, oxidative damage, and inflammation, which are promoters of improved proteostasis and neurotrophic signaling, leading ultimately to neuroprotection and neuroplasticity. This review focuses on the most well-documented Nis. The mechanistic implications and their translational potential for SCI are discussed.
MeSH term(s)	Animals ; Humans ; Neuronal Plasticity/physiology ; Spinal Cord Injuries/therapy
Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	82067-2
ISSN	1753-4887 ; 0029-6643
ISSN (online)	1753-4887
ISSN	0029-6643
DOI	10.1093/nutrit/nuab068
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Article: Adipose tissue derived stem cell secretome induces motor and histological gains after complete spinal cord injury in

Assunção-Silva, Rita C / Pinho, Andreia / Cibrão, Jorge R / Pereira, Inês M / Monteiro, Susana / Silva, Nuno A / Campos, Jonas / Rebelo, Ana L / Schlosser, Gerhard / Pinto, Luisa / Pandit, Abhay / Salgado, António J

Journal of tissue engineering

2024 Volume 15, Page(s) 20417314231203824

Abstract: Mesenchymal stem cell-based therapies have been studied for spinal cord injury (SCI) treatment due to their paracrine action upon damaged tissues. MSCs neuroregenerative role may relate to the contents of their secretome in anti-inflammatory cytokines ... ...

Abstract	Mesenchymal stem cell-based therapies have been studied for spinal cord injury (SCI) treatment due to their paracrine action upon damaged tissues. MSCs neuroregenerative role may relate to the contents of their secretome in anti-inflammatory cytokines and growth-permissive factors. We propose using the secretome of MSCs isolated from the adipose tissue-adipose tissue-derived stem cells (ASCs) as a cell-free based therapy for SCI. In vivo studies were conducted in two SCI models,
Language	English
Publishing date	2024-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2573915-3
ISSN	2041-7314
ISSN	2041-7314
DOI	10.1177/20417314231203824
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Article ; Online: In vitro neuronal and glial response to magnetically stimulated piezoelectric poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV)/cobalt ferrite (CFO) microspheres.

Pinho, Tiffany S / Cibrão, Jorge Ribeiro / Silva, Deolinda / Barata-Antunes, Sandra / Campos, Jonas / Afonso, João L / Sampaio-Marques, Belém / Ribeiro, Clarisse / Macedo, André S / Martins, Pedro / Cunha, Cristiana B / Lanceros-Mendez, Senentxu / Salgado, António J

Biomaterials advances

2024 Volume 159, Page(s) 213798

Abstract: Polymer biomaterials are being considered for tissue regeneration due to the possibility of resembling different extracellular matrix characteristics. However, most current scaffolds cannot respond to physical-chemical modifications of the cell ... ...

Abstract	Polymer biomaterials are being considered for tissue regeneration due to the possibility of resembling different extracellular matrix characteristics. However, most current scaffolds cannot respond to physical-chemical modifications of the cell microenvironment. Stimuli-responsive materials, such as electroactive smart polymers, are increasingly gaining attention once they can produce electrical potentials without external power supplies. The presence of piezoelectricity in human tissues like cartilage and bone highlights the importance of electrical stimulation in physiological conditions. Although poly(vinylidene fluoride) (PVDF) is one of the piezoelectric polymers with the highest piezoelectric response, it is not biodegradable. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) is a promising copolymer of poly(hydroxybutyrate) (PHB) for tissue engineering and regeneration applications. It offers biodegradability, piezoelectric properties, biocompatibility, and bioactivity, making it a superior option to PVDF for biomedical purposes requiring biodegradability. Magnetoelectric polymer composites can be made by combining magnetostrictive particles and piezoelectric polymers to further tune their properties for tissue regeneration. These composites convert magnetic stimuli into electrical stimuli, generating local electrical potentials for various applications. Cobalt ferrites (CFO) and piezoelectric polymers have been combined and processed into different morphologies, maintaining biocompatibility for tissue engineering. The present work studied how PHBV/CFO microspheres affected neural and glial response in spinal cord cultures. It is expected that the electrical signals generated by these microspheres due to their magnetoelectric nature could aid in tissue regeneration and repair. PHBV/CFO microspheres were not cytotoxic and were able to impact neurite outgrowth and promote neuronal differentiation. Furthermore, PHBV/CFO microspheres led to microglia activation and induced the release of several bioactive molecules. Importantly, magnetically stimulated microspheres ameliorated cell viability after an in vitro ROS-induced lesion of spinal cord cultures, which suggests a beneficial effect on tissue regeneration and repair.
MeSH term(s)	Humans ; Tissue Scaffolds/chemistry ; Microspheres ; Polymers ; Cobalt ; Hydroxybutyrates/pharmacology ; Polyesters/pharmacology ; Ferric Compounds ; Fluorocarbon Polymers ; Polyvinyls
Chemical Substances	poly(hydroxybutyrate-co-hydroxyvalerate) ; polyvinylidene fluoride (24937-79-9) ; cobalt ferrite ; Polymers ; Cobalt (3G0H8C9362) ; Hydroxybutyrates ; Polyesters ; Ferric Compounds ; Fluorocarbon Polymers ; Polyvinyls
Language	English
Publishing date	2024-02-10
Publishing country	Netherlands
Document type	Journal Article
ISSN	2772-9508
ISSN (online)	2772-9508
DOI	10.1016/j.bioadv.2024.213798
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Article ; Online: Secretome of bone marrow mesenchymal stromal cells cultured in a dynamic system induces neuroprotection and modulates microglial responsiveness in an α-synuclein overexpression rat model.

Marques, Cláudia Raquel / Campos, Jonas / Sampaio-Marques, Belém / Antunes, Filipa Ferreira / Dos Santos Cunha, Raquel Medina / Silva, Deolinda / Barata-Antunes, Sandra / Lima, Rui / Fernandes-Platzgummer, Ana / da Silva, Cláudia L / Sousa, Rui Amandi / Salgado, António José

Cytotherapy

2024

Abstract: Background aims: Parkinson's disease (PD) is the second most common neurodegenerative disorder. The etiology of the disease remains largely unknown, but evidence have suggested that the overexpression and aggregation of alpha-synuclein (α-syn) play key ... ...

Abstract	Background aims: Parkinson's disease (PD) is the second most common neurodegenerative disorder. The etiology of the disease remains largely unknown, but evidence have suggested that the overexpression and aggregation of alpha-synuclein (α-syn) play key roles in the pathogenesis and progression of PD. Mesenchymal stromal cells (MSCs) have been earning attention in this field, mainly due to their paracrine capacity. The bioactive molecules secreted by MSCs, i.e. their secretome, have been associated with enhanced neuronal survival as well as a strong modulatory capacity of the microenvironments where the disease develops. The selection of the appropriate animal model is crucial in studies of efficacy assessment. Given the involvement of α-syn in the pathogenesis of PD, the evidence generated from the use of animal models that develop a pathologic phenotype due to the action of this protein is extremely valuable. Therefore, in this work, we established an animal model based on the viral vector-mediated overexpression of A53T α-syn and studied the impact of the secretome of bone marrow mesenchymal stromal cells MSC(M) as a therapeutic strategy. Methods: Adult male rats were subjected to α-syn over expression in the nigrostriatal pathway to model dopaminergic neurodegeneration. The impact of locally administered secretome treatment from MSC(M) was studied. Motor impairments were assessed throughout the study coupled with whole-region (striatum and substantia nigra) confocal microscopy evaluation of histopathological changes associated with dopaminergic neurodegeneration and glial cell reactivity. Results: Ten weeks after lesion induction, the animals received secretome injections in the substantia nigra pars compacta (SNpc) and striatum (STR). The secretome used was produced from bone marrow mesenchymal stromal cells MSC(M) expanded in a spinner flask (SP) system. Nine weeks later, animals that received the viral vector containing the gene for A53T α-syn and treated with vehicle (Neurobasal-A medium) presented dopaminergic cell loss in the SNpc and denervation in the STR. The treatment with secretome significantly reduced the levels of α-syn in the SNpc and protected the dopaminergic neurons (DAn) within the SNpc and STR. Conclusions: Our results are aligned with previous studies in both α-syn Caenorhabditis elegans models, as well as 6-OHDA rodent model, revealing that secretome exerted a neuroprotective effect. Moreover, these effects were associated with a modulation of microglial reactivity supporting an immunomodulatory role for the factors contained within the secretome. This further supports the development of new studies exploring the effects and the mechanism of action of secretome from MSC(M) against α-syn-induced neurotoxicity.
Language	English
Publishing date	2024-02-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2024.02.008
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Article ; Online: Cerebral Malaria Model Applying Human Brain Organoids.

Silva-Pedrosa, Rita / Campos, Jonas / Fernandes, Aline Marie / Silva, Miguel / Calçada, Carla / Marote, Ana / Martinho, Olga / Veiga, Maria Isabel / Rodrigues, Ligia R / Salgado, António José / Ferreira, Pedro Eduardo

Cells

2023 Volume 12, Issue 7

Abstract: Neural injuries in cerebral malaria patients are a significant cause of morbidity and mortality. Nevertheless, a comprehensive research approach to study this issue is lacking, so herein we propose an in vitro system to study human cerebral malaria using ...

Abstract	Neural injuries in cerebral malaria patients are a significant cause of morbidity and mortality. Nevertheless, a comprehensive research approach to study this issue is lacking, so herein we propose an in vitro system to study human cerebral malaria using cellular approaches. Our first goal was to establish a cellular system to identify the molecular alterations in human brain vasculature cells that resemble the blood-brain barrier (BBB) in cerebral malaria (CM). Through transcriptomic analysis, we characterized specific gene expression profiles in human brain microvascular endothelial cells (HBMEC) activated by the
MeSH term(s)	Humans ; Malaria, Cerebral/metabolism ; Malaria, Cerebral/parasitology ; Malaria, Cerebral/pathology ; Endothelial Cells/metabolism ; Reproducibility of Results ; Brain/pathology ; Plasmodium falciparum ; Organoids/metabolism
Language	English
Publishing date	2023-03-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12070984
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Article: Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury.

Sousa, Carla S / Lima, Rui / Cibrão, Jorge R / Gomes, Eduardo D / Fernandes, Luís S / Pinho, Tiffany S / Silva, Deolinda / Campos, Jonas / Salgado, António J / Silva, Nuno A

Pharmaceutics

2023 Volume 15, Issue 5

Abstract: The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is ... ...

Abstract	The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration but also leads to further damage. One of the most promising approaches for promoting axonal regeneration is to maintain the levels of cyclic adenosine monophosphate (cAMP), specifically by a phosphodiesterase-4 (PDE4) inhibitor expressed in neural tissues. Therefore, in our study, we evaluated the therapeutic effect of an FDA-approved PDE4 inhibitor, Roflumilast (Rof), in a thoracic contusion rat model. Results indicate that the treatment was effective in promoting functional recovery. Rof-treated animals showed improvements in both gross and fine motor function. Eight weeks post-injury, the animals significantly recovered by achieving occasional weight-supported plantar steps. Histological assessment revealed a significant decrease in cavity size, less reactive microglia, as well as higher axonal regeneration in treated animals. Molecular analysis revealed that IL-10 and IL-13 levels, as well as VEGF, were increased in the serum of Rof-treated animals. Overall, Roflumilast promotes functional recovery and supports neuroregeneration in a severe thoracic contusion injury model and may be important in SCI treatment.
Language	English
Publishing date	2023-05-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15051556
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Article: Neurodifferentiation and Neuroprotection Potential of Mesenchymal Stromal Cell-Derived Secretome Produced in Different Dynamic Systems.

Marques, Cláudia Raquel / Fuzeta, Miguel de Almeida / Dos Santos Cunha, Raquel Medina / Pereira-Sousa, Joana / Silva, Deolinda / Campos, Jonas / Teixeira-Castro, Andreia / Sousa, Rui Amandi / Fernandes-Platzgummer, Ana / da Silva, Cláudia L / Salgado, António José

Biomedicines

2023 Volume 11, Issue 5

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta, leading to a loss of DA in the basal ganglia. The presence of ... ...

Abstract	Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta, leading to a loss of DA in the basal ganglia. The presence of aggregates of alpha-synuclein (α-synuclein) is seen as the main contributor to the pathogenesis and progression of PD. Evidence suggests that the secretome of mesenchymal stromal cells (MSC) could be a potential cell-free therapy for PD. However, to accelerate the integration of this therapy in the clinical setting, there is still the need to develop a protocol for the large-scale production of secretome under good manufacturing practices (GMP) guidelines. Bioreactors have the capacity to produce large quantities of secretomes in a scalable manner, surpassing the limitations of planar static culture systems. However, few studies focused on the influence of the culture system used to expand MSC, on the secretome composition. In this work, we studied the capacity of the secretome produced by bone marrow-derived mesenchymal stromal cells (BMSC) expanded in a spinner flask (SP) and in a Vertical-Wheel™ bioreactor (VWBR) system, to induce neurodifferentiation of human neural progenitor cells (hNPCs) and to prevent dopaminergic neuron degeneration caused by the overexpression of α-synuclein in one
Language	English
Publishing date	2023-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11051240
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Article ; Online: Preclinical Comparison of Stem Cells Secretome and Levodopa Application in a 6-Hydroxydopamine Rat Model of Parkinson's Disease.

Teixeira, Fábio G / Vilaça-Faria, Helena / Domingues, Ana V / Campos, Jonas / Salgado, António J

Cells

2020 Volume 9, Issue 2

Abstract: Parkinson's Disease (PD) is characterized by the massive loss of dopaminergic neurons, leading to the appearance of several motor impairments. Current pharmacological treatments, such as the use of levodopa, are yet unable to cure the disease. Therefore, ...

Abstract	Parkinson's Disease (PD) is characterized by the massive loss of dopaminergic neurons, leading to the appearance of several motor impairments. Current pharmacological treatments, such as the use of levodopa, are yet unable to cure the disease. Therefore, there is a need for novel strategies, particularly those that can combine in an integrated manner neuroprotection and neuroregeneration properties. In vitro and in vivo models have recently revealed that the secretome of mesenchymal stem cells (MSCs) holds a promising potential for treating PD, given its effects on neural survival, proliferation, differentiation. In the present study, we aimed to access the impact of human bone marrow MSCs (hBM-MSCs) secretome in 6-hydroxydopamine (6-OHDA) PD model when compared to levodopa administration, by addressing animals' motor performance, and substantia nigra (SN), and striatum (STR) histological parameters by tyrosine hydroxylase (TH) expression. Results revealed that hBM-MSCs secretome per se appears to be a modulator of the dopaminergic system, enhancing TH-positive cells expression (e.g., dopaminergic neurons) and terminals both in the SN and STR when compared to the untreated group 6-OHDA. Such finding was positively correlated with a significant amelioration of the motor outcomes of 6-OHDA PD animals (assessed by the staircase test). Thus, the present findings support hBM-MSCs secretome administration as a potential therapeutic tool in treating PD, and although we suggest candidate molecules (Trx1, SEMA7A, UCHL1, PEDF, BDNF, Clusterin, SDF-1, CypA, CypB, Cys C, VEGF, DJ-1, Gal-1, GDNF, CDH2, IL-6, HSP27, PRDX1, UBE3A, MMP-2, and GDN) and possible mechanisms of hBM-MSCs secretome-mediated effects, further detailed studies are needed to carefully and clearly define which players may be responsible for its therapeutic actions. By doing so, it will be reasonable to presume that potential treatments that can, per se, or in combination modulate or slow PD may lead to a rational design of new therapeutic or adjuvant strategies for its functional modeling and repair.
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Levodopa/administration & dosage ; Levodopa/therapeutic use ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/metabolism ; Motor Activity ; Neostriatum/pathology ; Neostriatum/physiopathology ; Oxidopamine ; Parkinson Disease/drug therapy ; Parkinson Disease/pathology ; Parkinson Disease/physiopathology ; Phenotype ; Rats, Sprague-Dawley ; Reproducibility of Results ; Substantia Nigra/pathology ; Substantia Nigra/physiopathology
Chemical Substances	Levodopa (46627O600J) ; Oxidopamine (8HW4YBZ748)
Language	English
Publishing date	2020-01-28
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9020315
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Article ; Online: Treating Parkinson's Disease with Human Bone Marrow Mesenchymal Stem Cell Secretome: A Translational Investigation Using Human Brain Organoids and Different Routes of In Vivo Administration.

Mendes-Pinheiro, Bárbara / Campos, Jonas / Marote, Ana / Soares-Cunha, Carina / Nickels, Sarah L / Monzel, Anna S / Cibrão, Jorge R / Loureiro-Campos, Eduardo / Serra, Sofia C / Barata-Antunes, Sandra / Duarte-Silva, Sara / Pinto, Luísa / Schwamborn, Jens C / Salgado, António J

Cells

2023 Volume 12, Issue 21

Abstract: Parkinson's disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the ... ...

Abstract	Parkinson's disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells (MSCs) are one of the most extensively studied cell sources for regenerative medicine applications, particularly due to the release of soluble factors and vesicles, known as secretome. The main goal of this work was to address the therapeutic potential of the secretome collected from bone-marrow-derived MSCs (BM-MSCs) using different models of the disease. Firstly, we took advantage of an optimized human midbrain-specific organoid system to model PD in vitro using a neurotoxin-induced model through 6-hydroxydopamine (6-OHDA) exposure. In vivo, we evaluated the effects of BM-MSC secretome comparing two different routes of secretome administration: intracerebral injections (a two-site single administration) against multiple systemic administration. The secretome of BM-MSCs was able to protect from dopaminergic neuronal loss, these effects being more evident in vivo. The BM-MSC secretome led to motor function recovery and dopaminergic loss protection; however, multiple systemic administrations resulted in larger therapeutic effects, making this result extremely relevant for potential future clinical applications.
MeSH term(s)	Humans ; Parkinson Disease/drug therapy ; Secretome ; Brain ; Oxidopamine ; Organoids ; Mesenchymal Stem Cells
Chemical Substances	Oxidopamine (8HW4YBZ748)
Language	English
Publishing date	2023-11-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12212565
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Article ; Online: Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado-Joseph Disease.

Campos, Ana Bela / Duarte-Silva, Sara / Fernandes, Bruno / Coimbra, Bárbara / Campos, Jonas / Monteiro-Fernandes, Daniela / Teixeira-Castro, Andreia / Ambrósio, António Francisco / Maciel, Patrícia

Cells

2022 Volume 11, Issue 13

Abstract: Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder (ND). While most research in NDs has been following a neuron-centric point of view, microglia are now recognized as ... ...

Abstract	Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder (ND). While most research in NDs has been following a neuron-centric point of view, microglia are now recognized as crucial in the brain. Previous work revealed alterations that point to an increased activation state of microglia in the brain of CMVMJD135 mice, a MJD mouse model that replicates the motor symptoms and neuropathology of the human condition. Here, we investigated the extent to which microglia are actively contributing to MJD pathogenesis and symptom progression. For this, we used PLX3397 to reduce the number of microglia in the brain of CMVMJD135 mice. In addition, a set of statistical and machine learning models were further implemented to analyze the impact of PLX3397 on the morphology of the surviving microglia. Then, a battery of behavioral tests was used to evaluate the impact of microglial depletion on the motor phenotype of CMVMJD135 mice. Although PLX3397 treatment substantially reduced microglia density in the affected brain regions, it did not affect the motor deficits seen in CMVMJD135 mice. In addition to reducing the number of microglia, the treatment with PLX3397 induced morphological changes suggestive of activation in the surviving microglia, the microglia of wild-type animals becoming similar to those of CMVMJD135 animals. These results suggest that microglial cells are not key contributors for MJD progression. Furthermore, the impact of PLX3397 on microglial activation should be taken into account in the interpretation of findings of ND modification seen upon treatment with this CSF1R inhibitor.
MeSH term(s)	Animals ; Ataxin-3/genetics ; Disease Models, Animal ; Disease Progression ; Machado-Joseph Disease/genetics ; Machado-Joseph Disease/pathology ; Mice ; Microglia/pathology
Chemical Substances	Ataxin-3 (EC 3.4.19.12)
Language	English
Publishing date	2022-06-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11132022
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