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1.
Sci Adv ; 10(28): eadk9918, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38996029

RESUMO

Cell therapy for the treatment of demyelinating diseases such as multiple sclerosis is hampered by poor survival of donor oligodendrocyte cell preparations, resulting in limited therapeutic outcomes. Excessive cell death leads to the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft to eventual rejection. Here, we engineered innovative cell-instructive shear-thinning hydrogels (STHs) with tunable viscoelasticity and bioactivity for minimally invasive delivery of primary human oligodendrocyte progenitor cells (hOPCs) to the brain of a shiverer/rag2 mouse, a model of congenital hypomyelinating disease. The STHs enabled immobilization of prosurvival signals, including a recombinantly designed bidomain peptide and platelet-derived growth factor. Notably, STHs reduced the death rate of hOPCs significantly, promoted the production of myelinating oligodendrocytes, and enhanced myelination of the mouse brain 12 weeks post-implantation. Our results demonstrate the potential of STHs loaded with biological cues to improve cell therapies for the treatment of devastating myelopathies.


Assuntos
Sobrevivência Celular , Hidrogéis , Células Precursoras de Oligodendrócitos , Remielinização , Animais , Hidrogéis/química , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/citologia , Camundongos , Humanos , Sistema Nervoso Central/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/citologia , Bainha de Mielina/metabolismo , Modelos Animais de Doenças
2.
Nat Commun ; 15(1): 5654, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969669

RESUMO

Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.


Assuntos
Bussulfano , Microglia , Progranulinas , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , Progranulinas/metabolismo , Progranulinas/genética , Camundongos , Bussulfano/farmacologia , Transplante de Células-Tronco Hematopoéticas , Aminopiridinas/farmacologia , Encéfalo/metabolismo , Pirróis/farmacologia , Camundongos Endogâmicos C57BL , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Transplante de Medula Óssea , Masculino , Sistema Nervoso Central/metabolismo , Camundongos Knockout , Condicionamento Pré-Transplante/métodos , Análise de Célula Única , Citocinas/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores
3.
Commun Biol ; 7(1): 811, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965360

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.


Assuntos
Encéfalo , Senescência Celular , Herpes Simples , Herpesvirus Humano 1 , Esclerose Múltipla , Animais , Camundongos , Encéfalo/virologia , Encéfalo/patologia , Encéfalo/metabolismo , Esclerose Múltipla/virologia , Esclerose Múltipla/patologia , Esclerose Múltipla/metabolismo , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 1/patogenicidade , Herpes Simples/virologia , Herpes Simples/patologia , Feminino , Camundongos Endogâmicos C57BL , Encefalomielite Autoimune Experimental/virologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/metabolismo , Fenótipo , Sistema Nervoso Central/virologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Medula Espinal/virologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Biomarcadores/metabolismo , Encefalite por Herpes Simples/virologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/metabolismo
4.
Sci Adv ; 10(28): eado3501, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38985859

RESUMO

Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.


Assuntos
Compostos de Quinolínio , Animais , Humanos , Compostos de Quinolínio/química , Compostos de Quinolínio/farmacocinética , Ciclosporina/química , Ciclosporina/farmacocinética , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Cristalografia por Raios X , Peptídeos/química , Peptídeos/farmacocinética , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Camundongos
5.
Int J Mol Sci ; 25(13)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-39000265

RESUMO

Rotenone, as a common pesticide and insecticide frequently found in environmental samples, may be present in aquatic habitats worldwide. Exposure to low concentrations of this compound may cause alterations in the nervous system, thus contributing to Parkinsonian motor symptoms in both vertebrates and invertebrates. However, the effects of chronic exposure to low doses of rotenone on the activity of neurotransmitters that govern motor functions and on the specific molecular mechanisms leading to movement morbidity remain largely unknown for many aquatic invertebrates. In this study, we analyzed the effects that rotenone poisoning exerts on the activity of dopamine (DA) and acetylcholine (ACh) synthesis enzymes in the central nervous system (CNS) of Asian shore crab, Hemigrapsus sanguineus (de Haan, 1835), and elucidated the association of its locomotor behavior with Parkinson's-like symptoms. An immunocytochemistry analysis showed a reduction in tyrosine hydroxylase (TH) in the median brain and the ventral nerve cord (VNC), which correlated with the subsequent decrease in the locomotor activity of shore crabs. We also observed a variation in cholinergic neurons' activity, mostly in the ventral regions of the VNC. Moreover, the rotenone-treated crabs showed signs of damage to ChAT-lir neurons in the VNC. These data suggest that chronic treatment with low doses of rotenone decreases the DA level in the VNC and the ACh level in the brain and leads to progressive and irreversible reductions in the crab's locomotor activity, life span, and changes in behavior.


Assuntos
Braquiúros , Sistema Nervoso Central , Neurônios Colinérgicos , Neurônios Dopaminérgicos , Rotenona , Animais , Rotenona/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Braquiúros/efeitos dos fármacos , Braquiúros/metabolismo , Dopamina/metabolismo , Acetilcolina/metabolismo , Inseticidas/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismo , Locomoção/efeitos dos fármacos
6.
ACS Nano ; 18(27): 17509-17520, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38918939

RESUMO

There is growing concern about the distribution of nanoplastics (NPs) in the central nervous system (CNS), whereas intrusion is poorly understood. In this study, fluorescent-labeled polystyrene NPs (PS-NPs) were microinjected into different areas of zebrafish embryo to mimic different routes of exposure. PS-NPs were observed in the brain, eyes, and spinal cord through gametal exposure. It indicated that maternally derived PS-NPs were specially distributed in the CNS of zebrafish during early development. Importantly, these NPs were stranded in the CNS but not transferred to other organs during development. Furthermore, using neuron GFP-labeled transgenic zebrafish, colocalization between NPs and the neuron cells revealed that NPs were mostly enriched in the CNS surrounded but not the neurons. Even so, the intrusion of NPs into the CNS induced the significant upregulation of some neurotransmitter receptors, leading to an inhibited effect on the movement of zebrafish larvae. This work provides insights into understanding the intrusion and distribution of NPs in the CNS and the subsequent potential adverse effects.


Assuntos
Sistema Nervoso Central , Poliestirenos , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Poliestirenos/química , Nanopartículas/química , Nanopartículas/metabolismo , Animais Geneticamente Modificados , Microplásticos/toxicidade
7.
Elife ; 122024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38904987

RESUMO

Numerous roles for the Alk receptor tyrosine kinase have been described in Drosophila, including functions in the central nervous system (CNS), however the molecular details are poorly understood. To gain mechanistic insight, we employed Targeted DamID (TaDa) transcriptional profiling to identify targets of Alk signaling in the larval CNS. TaDa was employed in larval CNS tissues, while genetically manipulating Alk signaling output. The resulting TaDa data were analyzed together with larval CNS scRNA-seq datasets performed under similar conditions, identifying a role for Alk in the transcriptional regulation of neuroendocrine gene expression. Further integration with bulk and scRNA-seq datasets from larval brains in which Alk signaling was manipulated identified a previously uncharacterized Drosophila neuropeptide precursor encoded by CG4577 as an Alk signaling transcriptional target. CG4577, which we named Sparkly (Spar), is expressed in a subset of Alk-positive neuroendocrine cells in the developing larval CNS, including circadian clock neurons. In agreement with our TaDa analysis, overexpression of the Drosophila Alk ligand Jeb resulted in increased levels of Spar protein in the larval CNS. We show that Spar protein is expressed in circadian (clock) neurons, and flies lacking Spar exhibit defects in sleep and circadian activity control. In summary, we report a novel activity regulating neuropeptide precursor gene that is regulated by Alk signaling in the Drosophila CNS.


Assuntos
Quinase do Linfoma Anaplásico , Sistema Nervoso Central , Proteínas de Drosophila , Animais , Sistema Nervoso Central/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Larva/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Neuropeptídeos/metabolismo , Neuropeptídeos/genética , Transdução de Sinais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/genética , Drosophila/genética , Drosophila/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica
9.
Transl Neurodegener ; 13(1): 32, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898538

RESUMO

The central nervous system (CNS) is integrated by glial and neuronal cells, and both release extracellular vesicles (EVs) that participate in CNS homeostasis. EVs could be one of the best candidates to operate as nanosized biological platforms for analysing multidimensional bioactive cargos, which are protected during systemic circulation of EVs. Having a window into the molecular level processes that are happening in the CNS could open a new avenue in CNS research. This raises a particular point of interest: can CNS-derived EVs in blood serve as circulating biomarkers that reflect the pathological status of neurological diseases? L1 cell adhesion molecule (L1CAM) is a widely reported biomarker to identify CNS-derived EVs in peripheral blood. However, it has been demonstrated that L1CAM is also expressed outside the CNS. Given that principal data related to neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease were obtained using L1CAM-positive EVs, efforts to overcome present challenges related to its specificity are required. In this sense, other surface biomarkers for CNS-derived EVs, such as glutamate aspartate transporter (GLAST) and myelin oligodendrocyte glycoprotein (MOG), among others, have started to be used. Establishing a panel of EV biomarkers to analyse CNS-derived EVs in blood could increase the specificity and sensitivity necessary for these types of studies. This review covers the main evidence related to CNS-derived EVs in cerebrospinal fluid and blood samples of patients with neurological diseases, focusing on the reported biomarkers and the technical possibilities for their isolation. EVs are emerging as a mirror of brain physiopathology, reflecting both localized and systemic changes. Therefore, when the technical hindrances for EV research and clinical applications are overcome, novel disease-specific panels of EV biomarkers would be discovered to facilitate transformation from traditional medicine to personalized medicine.


Assuntos
Biomarcadores , Sistema Nervoso Central , Vesículas Extracelulares , Doenças Neurodegenerativas , Humanos , Vesículas Extracelulares/metabolismo , Biomarcadores/sangue , Sistema Nervoso Central/metabolismo , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Animais
10.
Biomolecules ; 14(6)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38927082

RESUMO

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Oximas , Triazóis , Oximas/química , Oximas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Humanos , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Estilbenos/química , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Estilbenos/síntese química , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/uso terapêutico , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo
11.
Int J Mol Sci ; 25(12)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38928271

RESUMO

Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl-, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets.


Assuntos
Sistema Nervoso Central , Canais Iônicos , Lisossomos , Humanos , Lisossomos/metabolismo , Animais , Canais Iônicos/metabolismo , Canais Iônicos/genética , Sistema Nervoso Central/metabolismo , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Homeostase
12.
Int J Mol Sci ; 25(11)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38892158

RESUMO

Neuroinflammatory conditions in the central nervous system (CNS) are implicated in the pathogenesis of several neuroimmune disorders such as acquired demyelinating syndromes, autoimmune encephalopathies, acute or chronic bacterial and viral CNS infections as well as multiple sclerosis (MS) [...].


Assuntos
Doenças Neuroinflamatórias , Humanos , Doenças Neuroinflamatórias/imunologia , Animais , Esclerose Múltipla/terapia , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/tratamento farmacológico , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/imunologia , Inflamação
13.
Insect Biochem Mol Biol ; 171: 104149, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38871133

RESUMO

The central nervous system (CNS) plays a critical role in signal integration in animals and allows the orchestration of life processes to maintain homeostasis. Current research clearly shows that inflammatory processes can also be modulated by the CNS via the neuroendocrine system. One of the neuropeptide families that participate in vertebrates in this process is orexins (OXs). Interestingly, our previous results suggested that a similar dependency may also exist between neuropeptides and immune system activity in insects. Due to the structural homology of orexin and allatotropin receptors and the functional similarity between these two neuropeptide families, the main aim of this research was to perform a complex analysis of the relationships between allatotropin (AT) and the insect immune response. Our results revealed functional similarities between vertebrate OXs and insect ATs. Similar effects were observed in the profile of the expression level of the gene encoding the AT precursor in the Tenebrio molitor nervous system and in the general action of Tenmo-AT on selected immune parameters of the tested beetles. Moreover, for the first time in insects, we confirmed the role of cytokines in the modulation of neuroendocrine system by determining the effect of Spätzle-like protein injection on the expression of genes encoding AT precursor and receptor. All these results are important for understanding the evolutionary basis of hormonal regulation of the immune response.


Assuntos
Hormônios de Inseto , Neuropeptídeos , Animais , Neuropeptídeos/metabolismo , Neuropeptídeos/genética , Hormônios de Inseto/metabolismo , Orexinas/metabolismo , Tenebrio/imunologia , Tenebrio/genética , Tenebrio/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Fatores Imunológicos/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo
14.
Yi Chuan ; 46(6): 478-489, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38886151

RESUMO

Metronidazole (MTZ), a commonly used anti-infective drug in clinical practice, has also been employed as a prodrug in cell-targeted ablation systems in scientific research, exhibiting significant application value. However, it has been demonstrated that MTZ can induce neurotoxic symptoms to some extent during its use, and there is currently a lack of effective means to circumvent its toxicity in both clinical and research settings, which limits its application. Therefore, exploring the specific mechanisms underlying MTZ-induced neurotoxic symptoms and elucidating countermeasures will enhance the practical value of MTZ. In this study, using a zebrafish spinal cord injury regeneration model, we confirmed that MTZ neurotoxicity leads to impaired axon regeneration in the central nervous system. By overexpressing il34 in the central nervous system of zebrafish, we eliminated the inhibitory effect of MTZ on axonal regeneration and demonstrated that the pro-regenerative effect against MTZ neurotoxicity is not caused by excessive macrophages/microglia chemoattracted by interleukin 34(Il34). Transcriptome sequencing analysis and GO enrichment analysis of differentially expressed genes between groups revealed that Il34 may counteract MTZ neurotoxicity and promote spinal cord injury repair through biological processes that enhance cellular adhesion and cell location. In summary, our work uncovers a possible cause of MTZ neurotoxicity and provides a new perspective for eliminating MTZ toxicity.


Assuntos
Metronidazol , Traumatismos da Medula Espinal , Regeneração da Medula Espinal , Peixe-Zebra , Animais , Metronidazol/farmacologia , Metronidazol/efeitos adversos , Regeneração da Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
15.
J Integr Neurosci ; 23(6): 119, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38940087

RESUMO

OBJECTIVES: The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica immunoglobulin G antibodies (NMO-IgG)]. Although NMO-IgG can induce pathological changes in the central nervous system (CNS), the immunological changes in the CNS and peripheral tissue remain largely unknown. We investigated whether NMO-IgG binds to tissue expressing AQP4 and induces immunological changes in the peripheral tissue and CNS. METHODS: C57BL/6 female mice were assigned into an NMOSD or control group. Pathological and immunological changes in peripheral tissue and CNS were measured by immunostaining and flow cytometry, respectively. Motor impairment was measured by open-field test. RESULTS: We found that NMO-IgG did bind to astrocyte- and AQP4-expressing peripheral tissue, but induced glial fibrillary acidic protein and AQP4 loss only in the CNS. NMO-IgG induced the activation of microglia and modulated microglia polarization toward the classical (M1) phenotype, but did not affect innate or adaptive immune cells in the peripheral immune system, such as macrophages, neutrophils, Th17/Th1, or IL-10-producing B cells. In addition, NMOSD mice showed significantly less total distance traveled and higher immobility time in the open field. CONCLUSIONS: We found that injection of human NMO-IgG led to astrocytopathic lesions with microglial activation in the CNS. However, there were no significant pathological or immunological changes in the peripheral tissues.


Assuntos
Aquaporina 4 , Imunoglobulina G , Camundongos Endogâmicos C57BL , Neuromielite Óptica , Animais , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Aquaporina 4/imunologia , Feminino , Humanos , Camundongos , Modelos Animais de Doenças , Microglia/metabolismo , Microglia/imunologia , Microglia/efeitos dos fármacos , Autoanticorpos/imunologia , Astrócitos/imunologia , Astrócitos/metabolismo , Astrócitos/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia
16.
Cell Rep Med ; 5(7): 101622, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38917802

RESUMO

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4+ and CD8+ T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.


Assuntos
Movimento Celular , Sistema Nervoso Central , Quimiocinas , Leucoencefalopatia Multifocal Progressiva , Humanos , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Quimiocinas/metabolismo , Quimiocinas/genética , Movimento Celular/genética , Sistema Nervoso Central/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/imunologia , Linfócitos T CD8-Positivos/imunologia , Masculino , Feminino , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Pessoa de Meia-Idade , Idoso
17.
eNeuro ; 11(7)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38871457

RESUMO

CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function and can be combined with genetically encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific editing across the nervous system. Expressing Cre-dependent Cas9 from a genomic locus affords space to package guide RNAs for gene editing together with Cre-dependent, genetically encoded tools to manipulate, map, or monitor neurons using a single virus. We validated this strategy with three common tools in neuroscience: ChRonos, a channelrhodopsin, for studying synaptic transmission using optogenetics, GCaMP8f for recording Ca2+ transients using photometry, and mCherry for tracing axonal projections. We tested these tools in multiple brain regions and cell types, including GABAergic neurons in the nucleus accumbens, glutamatergic neurons projecting from the ventral pallidum to the lateral habenula, dopaminergic neurons in the ventral tegmental area, and proprioceptive neurons in the periphery. This flexible approach could help identify and test the function of novel genes affecting synaptic transmission, circuit activity, or morphology with a single viral injection.


Assuntos
Sistemas CRISPR-Cas , Dependovirus , Edição de Genes , Vetores Genéticos , Animais , Dependovirus/genética , Edição de Genes/métodos , Camundongos , Optogenética/métodos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Periférico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Feminino , Camundongos Transgênicos
18.
Eur J Med Res ; 29(1): 317, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38849920

RESUMO

The brain-bone axis has emerged as a captivating field of research, unveiling the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This comprehensive review delves into the current state of knowledge surrounding the brain-bone axis, exploring the complex mechanisms, key players, and potential clinical implications of this fascinating area of study. The review discusses the neural regulation of bone metabolism, highlighting the roles of the sympathetic nervous system, hypothalamic neuropeptides, and neurotransmitters in modulating bone remodeling. In addition, it examines the influence of bone-derived factors, such as osteocalcin and fibroblast growth factor 23, on brain function and behavior. The therapeutic potential of targeting the brain-bone axis in the context of skeletal and neurological disorders is also explored. By unraveling the complex interplay between the CNS and skeletal metabolism, this review aims to provide a comprehensive resource for researchers, clinicians, and students interested in the brain-bone axis and its implications for human health and disease.


Assuntos
Osso e Ossos , Encéfalo , Sistema Nervoso Central , Humanos , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiologia , Animais , Remodelação Óssea/fisiologia , Sistema Nervoso Simpático/fisiologia , Sistema Nervoso Simpático/metabolismo
19.
J Neuroinflammation ; 21(1): 151, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840215

RESUMO

BACKGROUND: Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes. METHODS: 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated. RESULTS: The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established. CONCLUSIONS: Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.


Assuntos
Caspase 1 , Dieta Cetogênica , Camundongos Transgênicos , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Caspase 1/metabolismo , Dieta Cetogênica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/farmacologia , Sistema Nervoso Central/metabolismo , Microbioma Gastrointestinal/fisiologia , Camundongos Endogâmicos C57BL
20.
Int Immunopharmacol ; 134: 112246, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759372

RESUMO

BACKGROUND: A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE. METHODS: We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1-/- and Ahr-/- mice. RESULTS: Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4+ T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4+ T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes. CONCLUSIONS: Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4+ T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.


Assuntos
Encefalomielite Autoimune Experimental , Inibidores de Histona Desacetilases , Indolamina-Pirrol 2,3,-Dioxigenase , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios , Fator de Transcrição STAT3 , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Camundongos , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Feminino , Medula Espinal/patologia , Medula Espinal/metabolismo , Medula Espinal/imunologia , Medula Espinal/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Progressão da Doença , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Fragmentos de Peptídeos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Interleucina-6/metabolismo , Interleucina-6/genética
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