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1.
J Neuroinflammation ; 22(1): 31, 2025 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-39894839

RESUMO

Parkinson's disease (PD) is a progressive degenerative disease of the central nervous system associated with neuroinflammation and microglial cell activation. Chemokine signaling regulates neuron-glia communication and triggers a microglial inflammatory profile. Herein, we identified the neuronal chemokine CCL21 as a major cause of microglial cell imbalance through the CCR7 receptor pathway with therapeutic implications for PD. In humans, we found that CCL21 transcript expression was increased in dopaminergic neurons (DANs) of the substantia nigra in PD patients. CCL21 and CCR7 expressions were spatially associated with brain regional vulnerability to synucleinopathies, as well as with the expression of microglial activation, neuroinflammation, and degeneration-related genes. Also, in mouse models of PD, we showed that CCL21 was overexpressed in DANs in vivo and in vitro. Mechanistically, neuronal CCL21 was shown to regulate microglial cell migration, proliferation, and activation in a CCR7-dependent manner through both canonical (PI3K/AKT) and non-canonical (ERK1/2/JNK) signaling pathways. Finally, we demonstrated that navarixin, a clinically relevant chemokine inhibitor with high affinity for the CCR7 receptor, could block CCL21 effects on microglia and prevent neurodegeneration and behavioral deficits in two mouse models of PD induced with either α-synuclein oligomers (αSynO) or 3,4-dihydroxyphenylacetaldehyde (DOPAL). Altogether, our data indicate that navarixin blocks CCL21/CCR7-mediated neuron-microglia communication and could be used as a therapeutic strategy against PD.


Assuntos
Quimiocina CCL21 , Doenças Neuroinflamatórias , Doença de Parkinson , Receptores CCR7 , Animais , Camundongos , Receptores CCR7/metabolismo , Receptores CCR7/genética , Humanos , Quimiocina CCL21/metabolismo , Quimiocina CCL21/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Modelos Animais de Doenças , Microglia/efeitos dos fármacos , Microglia/metabolismo , Degeneração Neural/patologia , Degeneração Neural/tratamento farmacológico , Feminino , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Camundongos Transgênicos
2.
Int J Mol Sci ; 26(1)2025 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-39796167

RESUMO

Schizophrenia (SZ), a complex psychiatric disorder of neurodevelopment, is characterised by a range of symptoms, including hallucinations, delusions, social isolation and cognitive deterioration. One of the hypotheses that underlie SZ is related to inflammatory events which could be partly responsible for symptoms. However, it is unknown how inflammatory molecules can contribute to cognitive decline in SZ. This review summarises and exposes the possible contribution of the imbalance between pro-inflammatory and anti-inflammatory interleukins like IL-1beta, IL-4 and TNFalfa among others on cognitive impairment. We discuss how this inflammatory imbalance affects microglia and astrocytes inducing the disruption of the blood-brain barrier (BBB) in SZ, which could impact the prefrontal cortex or associative areas involved in executive functions such as planning and working tasks. We also highlight that inflammatory molecules generated by intestinal microbiota alterations, due to dysfunctional microbial colonisers or the use of some anti-psychotics, could impact the central nervous system. Finally, the question arises as to whether it is possible to modulate or correct the inflammatory imbalance that characterises SZ, and if an immunomodulatory strategy can be incorporated into conventional clinical treatments, either alone or in complement, to be applied in specific phases, such as prodromal or in the first-episode psychosis.


Assuntos
Disfunção Cognitiva , Doenças Neuroinflamatórias , Esquizofrenia , Humanos , Esquizofrenia/metabolismo , Disfunção Cognitiva/etiologia , Doenças Neuroinflamatórias/etiologia , Animais , Barreira Hematoencefálica/metabolismo , Microglia/metabolismo , Microglia/patologia , Inflamação/patologia , Microbioma Gastrointestinal
3.
Molecules ; 30(1)2025 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-39795214

RESUMO

Glioblastomas (GBM) are malignant tumours with poor prognosis. Treatment involves chemotherapy and/or radiotherapy; however, there is currently no standard treatment for recurrence, and prognosis remains unfavourable. Inflammatory mediators and microRNAs (miRNAs) influence the aggressiveness of GBM, being involved in the communication with the cells of the tumour parenchyma, including microglia/macrophages, and maintaining an immunosuppressive microenvironment. Hence, the modulation of miRNAs and inflammatory factors may improve GBM treatments. In this study, we investigated the effects of agathisflavone, a biflavonoid purified from Cenostigma pyramidale (Tul.), on the growth and migration of GBM cells, on the expression of inflammatory cytokines and microRNAs, as well on the response of microglia. Agathisflavone (5-30 µM) induced a dose- and time-dependent reduction in the viability of both human GL-15 and rat C6 cells, as determined by the MTT test, and reduced cell migration, as determined by cell scratch assay. RT-qPCR analysis revealed that agathisflavone (5 µM) down-regulated the expression of miR-125b and miR-155 in the secretome derived from GL-15 cells, which was associated with upregulation of the mRNA expression of IL-6 and arginase-1 immunoregulatory factors. Exposure of human microglia/macrophage to the secretome from GL-15 GMB cells modulated proliferation and morphology, effects that were modulated by agathisflavone treatment. These results demonstrate the effect of flavonoids on the growth of GBM cells, which impacts cells in the microenvironment and can be considered for preclinical studies for adjuvant treatments.


Assuntos
Arginase , Biflavonoides , Sobrevivência Celular , Glioblastoma , Interleucina-6 , MicroRNAs , Microglia , MicroRNAs/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/genética , Humanos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Arginase/genética , Arginase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ratos , Interleucina-6/metabolismo , Interleucina-6/genética , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Animais , Ativação de Macrófagos/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proliferação de Células/efeitos dos fármacos
4.
Int J Dev Neurosci ; 85(1): e10414, 2025 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39873286

RESUMO

Most of the malformations of the polymicrogyria spectrum are caused by destructive lesions of the neocortex during the third trimester of pregnancy, triggered by hypoxic-ischemic, hemorrhagic or infectious events, with neuroinflammation as a common pathophysiological mechanism. Our study investigated hydrocortisone treatment in attenuating inflammation, malformations development and seizures predisposition in mice subjected to neonatal transcranial freeze lesion. Our results show attenuation of malformation and predisposition to febrile seizures, with concomitant reduction of macrophages/microglia after neonatal freeze lesion, polarizing them towards an anti-inflammatory profile. Thus, we have identified a promising treatment to minimize the development of cortical developmental malformations.


Assuntos
Hidrocortisona , Polimicrogiria , Animais , Camundongos , Hidrocortisona/uso terapêutico , Hidrocortisona/farmacologia , Polimicrogiria/tratamento farmacológico , Feminino , Anti-Inflamatórios/uso terapêutico , Malformações do Desenvolvimento Cortical/tratamento farmacológico , Animais Recém-Nascidos , Convulsões Febris/tratamento farmacológico , Convulsões Febris/prevenção & controle , Microglia/efeitos dos fármacos , Microglia/patologia , Gravidez
5.
Nutrients ; 16(23)2024 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-39683446

RESUMO

BACKGROUND: Reactive astrogliosis and microgliosis are coordinated responses to CNS insults and are pathological hallmarks of traumatic brain injury (TBI). In these conditions, persistent reactive gliosis can impede tissue repopulation and limit neurogenesis. Thus, modulating this phenomenon has been increasingly recognized as potential therapeutic approach. METHODS: In this study, we investigated the potential of the flavonoid agathisflavone to modulate astroglial and microglial injury responses and promote neurogenesis in the subventricular zone (SVZ) neurogenic niche. Agathisflavone, or the vehicle in controls, was administered directly into the lateral ventricles in postnatal day (P)8-10 mice by twice daily intracerebroventricular (ICV) injections for 3 days, and brains were examined at P11. RESULTS: In the controls, ICV injection caused glial reactivity along the needle track, characterised immunohistochemically by increased astrocyte expression of glial fibrillary protein (GFAP) and the number of Iba-1+ microglia at the lesion site. Treatment with agathisflavone decreased GFAP expression, reduced both astrocyte reactivity and the number of Iba-1+ microglia at the core of the lesion site and the penumbra, and induced a 2-fold increase on the ratio of anti-inflammatory CD206+ to pro-inflammatory CD16/32+ microglia. Notably, agathisflavone increased the population of neuroblasts (GFAP+ type B cells) in all SVZ microdomains by up to double, without significantly increasing the number of neuronal progenitors (DCX+). CONCLUSIONS: Although future studies should investigate the underlying molecular mechanisms driving agathisflavone effects on microglial polarization and neurogenesis at different timepoints, these data indicate that agathisflavone could be a potential adjuvant treatment for TBI or central nervous system disorders that have reactive gliosis as a common feature.


Assuntos
Astrócitos , Lesões Encefálicas Traumáticas , Flavonoides , Gliose , Ventrículos Laterais , Microglia , Neurogênese , Animais , Gliose/tratamento farmacológico , Camundongos , Neurogênese/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/metabolismo , Ventrículos Laterais/efeitos dos fármacos , Flavonoides/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Astrócitos/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Flavonas/farmacologia , Masculino , Modelos Animais de Doenças , Proteína Duplacortina , Biflavonoides
6.
Elife ; 132024 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-39535032

RESUMO

Microgliosis plays a critical role in diet-induced hypothalamic inflammation. A few hours after a high-fat diet (HFD), hypothalamic microglia shift to an inflammatory phenotype, and prolonged fat consumption leads to the recruitment of bone marrow-derived cells to the hypothalamus. However, the transcriptional signatures and functions of these cells remain unclear. Using dual-reporter mice, this study reveals that CX3CR1-positive microglia exhibit minimal changes in response to a HFD, while significant transcriptional differences emerge between microglia and CCR2-positive recruited myeloid cells, particularly affecting chemotaxis. These recruited cells also show sex-specific transcriptional differences impacting neurodegeneration and thermogenesis. The chemokine receptor CXCR3 is emphasized for its role in chemotaxis, displaying notable differences between recruited cells and resident microglia, requiring further investigation. Central immunoneutralization of CXCL10, a ligand for CXCR3, resulted in increased body mass and decreased energy expenditure, especially in females. Systemic chemical inhibition of CXCR3 led to significant metabolic changes, including increased body mass, reduced energy expenditure, elevated blood leptin, glucose intolerance, and decreased insulin levels. This study elucidates the transcriptional differences between hypothalamic microglia and CCR2-positive recruited myeloid cells in diet-induced inflammation and identifies CXCR3-expressing recruited immune cells as protective in metabolic outcomes linked to HFD consumption, establishing a new concept in obesity-related hypothalamic inflammation.


Assuntos
Dieta Hiperlipídica , Hipotálamo , Microglia , Células Mieloides , Receptores CXCR3 , Animais , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Hipotálamo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos , Células Mieloides/metabolismo , Microglia/metabolismo , Masculino , Feminino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Aumento de Peso , Metabolismo Energético , Receptores CCR2/metabolismo , Receptores CCR2/genética
7.
Toxicon ; 252: 108182, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39579879

RESUMO

Our previous studies have demonstrated the analgesic effects of botulinum toxin type A (BoNT/A) in a pre-clinical model of rheumatoid arthritis of the temporomandibular joint, where we proposed that BoNT/A decreases the neurogenic milieu after reaching the subnucleus caudalis. However, it is unknown whether BoNT/A directly regulates microglial cell activity. Therefore, the present study investigates the effects of BoNT/A on a microglial murine cell lineage (BV-2) in different inflammatory conditions. Cellular viability and proliferation were carried out with different concentrations of BoNT/A (ranging from 0.3125 to 20 U/mL) for 24 h. Cells were primed with carrageenan (300 µg/mL) or Lipopolysaccharides (LPS) (20 ng/mL). The gene expression of IL-1ß, IL-6, IL-18, TNF-α, Ikkß, p65, Iba1 were quantified using PCR-RT. The supernatant was used to determine IL-1ß, IL-6, and TNF-α levels. For all data, the significance level was set at 5%. Overall, data analysis revealed that BoNT/A 1.25 U/mL exhibited the greatest effect cell viability and proliferation. In addition, genes associated with inflammatory response in both stimuli (carrageenan and LPS) were downregulated in the presence of BoNT/A. Lastly, BoNT/A mitigates the protein levels of IL-1ß and TNF-α in a time and dose-dependent manner. In conclusion, our results revealed that BoNT/A directly modulates the microglial cells' activities in an inflammatory context, opening new perspectives for using BoNT/A, considering its potential immunomodulatory effect.


Assuntos
Toxinas Botulínicas Tipo A , Sobrevivência Celular , Inflamação , Lipopolissacarídeos , Microglia , Toxinas Botulínicas Tipo A/farmacologia , Animais , Microglia/efeitos dos fármacos , Camundongos , Lipopolissacarídeos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Carragenina , Citocinas/metabolismo
8.
Viruses ; 16(11)2024 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-39599837

RESUMO

The purpose of this study was to examine the relationship between demyelination and cellular reactions in the cerebellum of Canine Distemper Virus (CDV)-infected dogs. We subdivided the disease staging by adding the degree of demyelination determined by Luxol Fast Blue staining to the previously reported disease staging from the acute stage to the chronic stage, and investigated the relationship between demyelination in the cerebellum and the number and histological changes in astroglia, microglia, and Purkinje cells in each stage. Reactions of astrocytes and microglia were observed at an early stage when demyelination was not evident. Changes progressed with demyelination. Demyelination initially began in the medulla adjoining the fourth ventricle and gradually spread to the entire cerebellum, including the lobes. CDV immune-positive granules were seen from the early stage, and inclusion bodies also appeared at the same time. CDV immune-positive reaction and inclusion bodies were observed in astrocytes, microglia, neurons, ependymal cells, and even leptomeningeal mononuclear cells. On the other hand, infiltration of CDV-immunoreactive particles from the pia mater to the gray matter and further into the white matter through the granular layer was observed from an early stage. Purkinje cells decreased from the intermediate stage, and a decrease in cells in the granular layer was also observed. There was no clear association between age and each stage, and the stages did not progress with age.


Assuntos
Astrócitos , Cerebelo , Doenças Desmielinizantes , Vírus da Cinomose Canina , Cinomose , Microglia , Animais , Cães , Cinomose/virologia , Cinomose/patologia , Vírus da Cinomose Canina/patogenicidade , Doenças Desmielinizantes/virologia , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/veterinária , Cerebelo/patologia , Cerebelo/virologia , Astrócitos/virologia , Astrócitos/patologia , Microglia/virologia , Microglia/patologia , Células de Purkinje/patologia , Células de Purkinje/virologia , Masculino , Feminino
9.
Front Immunol ; 15: 1429157, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39469711

RESUMO

Background: Pneumococcal meningitis (PM) triggers apoptotic neuronal and progenitor cell death in the hippocampal dentate gyrus (DG), resulting in subsequent cognitive impairment. Microglia play a crucial role in PM-induced hippocampal damage. While the lasting effects of neonatal nutrition on health are well documented, the influence of early-life overfeeding on the host response to neuroinfections remains uncertain. This study aimed to examine whether neonatal overfeeding affects the outcome of PM in the hippocampus (HC). Material and methods: Overfeeding was induced by adjusting litter size immediately after birth. On the eleventh day of life, rats were intracisternally injected with Streptococcus pneumoniae or saline, followed by euthanasia after 24 hours for brain dissection. Histological analysis evaluated apoptosis in the DG and the extent of inflammatory infiltrate in the hippocampal fissure, while microgliosis was assessed by immunohistochemistry. The hippocampal transcriptome was analyzed using RNAseq, and the mRNA levels of specific inflammatory biomarkers were evaluated via RT-qPCR. Results: Overfed rats exhibited 40.5% greater body mass compared to their normal-fed counterparts. Intriguingly, PM-induced apoptosis in the DG was 50% lower in overfed rats. This effect was accompanied by significant alterations in the hippocampal transcriptional profile, particularly the lack of activation of the Programmed cell death pathway in overfed infected animals. RT-qPCR analysis of Aif1 and examination of Iba1-immunostained cells revealed mild microgliosis in the HC of infected-overfed animals. This reduced microglial reaction may be attributed to the diminished activation of interferon signaling pathways, as disclosed by the transcriptome analysis, potentially preventing microglial priming. Additionally, evidence of reduced neuroinflammation in overfed rats with PM was observed through the milder activation of pathways associated with Toll-like receptors, interleukins, and chemokine signaling. Furthermore, overfed animals exhibited increased transcription of proinflammatory Il6 and anti-inflammatory Il10 genes, with the latter showing higher expression even in the absence of PM, suggesting a priming effect of overfeeding on hippocampal immune cells. Conclusion: This study sheds light on the complex interplay between early-life overfeeding, immune response, and neuroprotection in infant rats with PM. The findings demonstrate the neuroprotective impact of early-life overfeeding in the context of PM, linked to the modulation of microglial function.


Assuntos
Animais Recém-Nascidos , Modelos Animais de Doenças , Gliose , Hipocampo , Meningite Pneumocócica , Microglia , Animais , Meningite Pneumocócica/imunologia , Meningite Pneumocócica/patologia , Ratos , Hipocampo/patologia , Hipocampo/metabolismo , Hipernutrição/complicações , Streptococcus pneumoniae , Masculino , Apoptose , Feminino , Ratos Wistar
10.
Front Immunol ; 15: 1392077, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39295865

RESUMO

Microglia are highly dynamic cells that have been mainly studied under pathological conditions. The present review discusses the possible implication of microglia as modulators of neuronal electrical responses in physiological conditions and hypothesizes how these cells might modulate hypothalamic circuits in health and during obesity. Microglial cells studied under physiological conditions are highly diverse, depending on the developmental stage and brain region. The evidence also suggests that neuronal electrical activity modulates microglial motility to control neuronal excitability. Additionally, we show that the expression of genes associated with neuron-microglia interaction is down-regulated in obese mice compared to control-fed mice, suggesting an alteration in the contact-dependent mechanisms that sustain hypothalamic arcuate-median eminence neuronal function. We also discuss the possible implication of microglial-derived signals for the excitability of hypothalamic neurons during homeostasis and obesity. This review emphasizes the importance of studying the physiological interplay between microglia and neurons to maintain proper neuronal circuit function. It aims to elucidate how disruptions in the normal activities of microglia can adversely affect neuronal health.


Assuntos
Núcleo Arqueado do Hipotálamo , Homeostase , Microglia , Neurônios , Microglia/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Humanos , Neurônios/metabolismo , Neurônios/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Camundongos
11.
Adv Neurobiol ; 37: 83-121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39207688

RESUMO

Microglial cells are the most receptive cells in the central nervous system (CNS), expressing several classes of receptors reflecting their immune heritage and newly acquired neural specialisation. Microglia possess, depending on the particular context, receptors to neurotransmitters and neuromodulators as well as immunocompetent receptors. This rich complement allows microglial cells to monitor the functional status of the nervous system, contribute actively to the regulation of neural activity and plasticity and homeostasis, and guard against pathogens as well as other challenges to the CNS's integrity and function.


Assuntos
Microglia , Microglia/metabolismo , Humanos , Animais , Sistema Nervoso Central/metabolismo , Plasticidade Neuronal/fisiologia
12.
Adv Neurobiol ; 37: 287-302, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39207698

RESUMO

Microglia are specialized immune cells that reside in the central nervous system (CNS) and play a crucial role in maintaining the homeostasis of the brain microenvironment. While traditionally regarded as a part of the innate immune system, recent research has highlighted their role in adaptive immunity. The CNS is no longer considered an immune-privileged organ, and increasing evidence suggests bidirectional communication between the immune system and the CNS. Microglia are sensitive to systemic immune signals and can respond to systemic inflammation by producing various inflammatory cytokines and chemokines. This response is mediated by activating pattern recognition receptors (PRRs), which recognize pathogen- and danger-associated molecular patterns in the systemic circulation. The microglial response to systemic inflammation has been implicated in several neurological conditions, including depression, anxiety, and cognitive impairment. Understanding the complex interplay between microglia and systemic immunity is crucial for developing therapeutic interventions to modulate immune responses in the CNS.


Assuntos
Imunidade Inata , Microglia , Microglia/imunologia , Microglia/metabolismo , Humanos , Animais , Imunidade Inata/imunologia , Inflamação/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Imunidade Adaptativa/imunologia , Encéfalo/imunologia
13.
Adv Neurobiol ; 37: 379-395, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39207703

RESUMO

Aging is the greatest risk factor for neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system (CNS), playing key roles in its normal functioning, and as mediators for age-dependent changes of the CNS, condition at which they generate a hostile environment for neurons. Transforming Growth Factor ß1 (TGFß1) is a regulatory cytokine involved in immuneregulation and neuroprotection, affecting glial cell inflammatory activation, neuronal survival, and function. TGFß1 signaling undergoes age-dependent changes affecting the regulation of microglial cells and can contribute to the pathophysiology of neurodegenerative diseases. This chapter focuses on assessing the role of age-related changes on the regulation of microglial cells and their impact on neuroinflammation and neuronal function, for understanding age-dependent changes of the nervous system.


Assuntos
Envelhecimento , Microglia , Doenças Neuroinflamatórias , Microglia/metabolismo , Humanos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neurodegenerativas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Sistema Nervoso Central/metabolismo , Neurônios/metabolismo , Transdução de Sinais
14.
J Immunol Methods ; 532: 113727, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-38997100

RESUMO

Resident macrophages are tissue-specific innate immune cells acting as sentinels, constantly patrolling their assigned tissue to maintain homeostasis, and quickly responding to pathogenic invaders or molecular danger signals molecules when necessary. Adenosine triphosphate (ATP), when released to the extracellular medium, acts as a danger signal through specific purinergic receptors. Interaction of ATP with the purinergic receptor P2X7 activates macrophages and microglial cells in different pathological conditions, triggering inflammation. The highly expressed P2X7 receptor in these cells induces cell membrane permeabilization, inflammasome activation, cell death, and the production of inflammatory mediators, including cytokines and nitrogen and oxygen-reactive species. This review explores the techniques to evaluate the functional and molecular aspects of the P2X7 receptor, particularly in macrophages and microglial cells. Polymerase chain reaction (PCR), Western blotting, and immunocytochemistry or immunohistochemistry are essential for assessing gene and protein expression in these cell types. Evaluation of P2X7 receptor function involves the use of ATP and selective agonists and antagonists and diverse techniques, including electrophysiology, intracellular calcium measurements, ethidium bromide uptake, and propidium iodide cell viability assays. These techniques are crucial for studying the role of P2X7 receptors in immune responses, neuroinflammation, and various pathological conditions. Therefore, a comprehensive understanding of the functional and molecular aspects of the P2X7 receptor in macrophages and microglia is vital for unraveling its involvement in immune modulation and its potential as a therapeutic target. The methodologies presented and discussed herein offer valuable tools for researchers investigating the complexities of P2X7 receptor signaling in innate immune cells in health and disease.


Assuntos
Trifosfato de Adenosina , Macrófagos , Microglia , Receptores Purinérgicos P2X7 , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/imunologia , Microglia/metabolismo , Microglia/imunologia , Humanos , Trifosfato de Adenosina/metabolismo , Animais , Macrófagos/imunologia , Macrófagos/metabolismo , Imuno-Histoquímica , Transdução de Sinais
15.
Mar Drugs ; 22(6)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38921546

RESUMO

Neurodegenerative diseases involve neuroinflammation and a loss of neurons, leading to disability and death. Hence, the research into new therapies has been focused on the modulation of the inflammatory response mainly by microglia/macrophages. The extracts and metabolites of marine sponges have been presented as anti-inflammatory. This study evaluated the toxicity of an extract and purified compound from the Brazilian marine sponge Aplysina fulva as well as its neuroprotection against inflammatory damage associated with the modulation of microglia response. PC12 neuronal cells and neonatal rat microglia were treated with the methanolic extract of A. fulva (AF-MeOH, 0.1-200 µg/mL) or with its purified dimethyl ketal of 3,5-dibromoverongiaquinol (AF-H1, 0.1-100 µM). Cytotoxicity was determined by MTT tetrazolium, Trypan blue, and propidium iodide; microglia were also treated with the conditioned medium (CM) from PC12 cells in different conditions. The microglia phenotype was determined by the expression of Iba-1 and CD68. AF-MeOH and AF-H1 were not toxic to PC12 or the microglia. Inflammatory damage with Escherichia coli lipopolysaccharide (LPS, 5 µg/mL) was not observed in the PC12 cells treated with AF-MeOH (1-10 µg/mL) or AF-H1 (1-10 µM). Microglia subjected to the CM from PC12 cells treated with LPS and AF-MeOH or AF-H1 showed the control phenotype-like (multipolar, low-CD68), highlighting the anti-neuroinflammatory and neuroprotective effect of components of this marine sponge.


Assuntos
Microglia , Fármacos Neuroprotetores , Poríferos , Animais , Microglia/efeitos dos fármacos , Ratos , Poríferos/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Células PC12 , Brasil , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Hidrocarbonetos Bromados/farmacologia , Inflamação/tratamento farmacológico
16.
Molecules ; 29(12)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38930790

RESUMO

Seven new abietane diterpenoids, comprising medusanthol A-G (1-3, 5, 7-9) and two previously identified analogs (4 and 6), were isolated from the hexane extract of the aerial parts of Medusantha martiusii. The structures of the compounds were elucidated by HRESIMS, 1D/2D NMR spectroscopic data, IR spectroscopy, NMR calculations with DP4+ probability analysis, and ECD calculations. The anti-neuroinflammatory potential of compounds 1-7 was evaluated by determining their ability to inhibit the production of nitric oxide (NO) and the proinflammatory cytokine TNF-α in BV2 microglia stimulated with LPS and IFN-γ. Compounds 1-4 and 7 exhibited decreased NO levels at a concentration of 12.5 µM. Compound 1 demonstrated strong activity with an IC50 of 3.12 µM, and compound 2 had an IC50 of 15.53 µM; both compounds effectively reduced NO levels compared to the positive control quercetin (IC50 11.8 µM). Additionally, both compounds significantly decreased TNF-α levels, indicating their potential as promising anti-neuroinflammatory agents.


Assuntos
Abietanos , Anti-Inflamatórios , Microglia , Óxido Nítrico , Abietanos/farmacologia , Abietanos/química , Abietanos/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Animais , Óxido Nítrico/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Linhagem Celular , Estrutura Molecular , Lipopolissacarídeos , Componentes Aéreos da Planta/química
17.
Neuroscience ; 549: 65-75, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38750924

RESUMO

Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Sintomas Prodrômicos , Substância Negra , Animais , Masculino , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Doenças Neuroinflamatórias/patologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/etiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia
18.
Biol Res ; 57(1): 28, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750549

RESUMO

BACKGROUND: The activated microglia have been reported as pillar factors in neuropathic pain (NP) pathology, but the molecules driving pain-inducible microglial activation require further exploration. In this study, we investigated the effect of dorsal root ganglion (DRG)-derived exosomes (Exo) on microglial activation and the related mechanism. METHODS: A mouse model of NP was generated by spinal nerve ligation (SNL), and DRG-derived Exo were extracted. The effects of DRG-Exo on NP and microglial activation in SNL mice were evaluated using behavioral tests, HE staining, immunofluorescence, and western blot. Next, the differentially enriched microRNAs (miRNAs) in DRG-Exo-treated microglia were analyzed using microarrays. RT-qPCR, RNA pull-down, dual-luciferase reporter assay, and immunofluorescence were conducted to verify the binding relation between miR-16-5p and HECTD1. Finally, the effects of ubiquitination modification of HSP90 by HECTD1 on NP progression and microglial activation were investigated by Co-IP, western blot, immunofluorescence assays, and rescue experiments. RESULTS: DRG-Exo aggravated NP resulting from SNL in mice, promoted the activation of microglia in DRG, and increased neuroinflammation. miR-16-5p knockdown in DRG-Exo alleviated the stimulating effects of DRG-Exo on NP and microglial activation. DRG-Exo regulated the ubiquitination of HSP90 through the interaction between miR-16-5p and HECTD1. Ubiquitination alteration of HSP90 was involved in microglial activation during NP. CONCLUSIONS: miR-16-5p shuttled by DRG-Exo regulated the ubiquitination of HSP90 by interacting with HECTD1, thereby contributing to the microglial activation in NP.


Assuntos
Exossomos , Gânglios Espinais , Proteínas de Choque Térmico HSP90 , MicroRNAs , Microglia , Neuralgia , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Exossomos/metabolismo , Gânglios Espinais/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Neuralgia/metabolismo , Neuralgia/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
19.
Sci Rep ; 14(1): 11435, 2024 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-38763939

RESUMO

Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic acid (VPA), males typically display reduced sociability, while females are less affected. Although both males and females exhibit VPA effects on neuroinflammatory parameters, these effects are sex-specific. Notably, females exposed to VPA show increased microglia and astrocyte density during the juvenile period. We hypothesized that these distinct neuroinflammatory patterns contribute to the resilience of females to VPA. To investigate this hypothesis, we treated juvenile animals with intraperitoneal bacterial lipopolysaccharides (LPS), a treatment known to elicit brain neuroinflammation. We thus evaluated the impact of juvenile LPS-induced inflammation on adult sociability and neuroinflammation in female mice prenatally exposed to VPA. Our results demonstrate that VPA-LPS females exhibit social deficits in adulthood, overriding the resilience observed in VPA-saline littermates. Repetitive behavior and anxiety levels were not affected by either treatment. We also evaluated whether the effect on sociability was accompanied by heightened neuroinflammation in the cerebellum and hippocampus. Surprisingly, we observed reduced astrocyte and microglia density in the cerebellum of VPA-LPS animals. These findings shed light on the complex interactions between prenatal insults, juvenile inflammatory stimuli, and sex-specific vulnerability in ASD-related social deficits, providing insights into potential therapeutic interventions for ASD.


Assuntos
Transtorno do Espectro Autista , Lipopolissacarídeos , Efeitos Tardios da Exposição Pré-Natal , Comportamento Social , Ácido Valproico , Animais , Feminino , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Gravidez , Camundongos , Ácido Valproico/efeitos adversos , Masculino , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/etiologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Camundongos Endogâmicos C57BL
20.
Biol Res ; 57(1): 18, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38671534

RESUMO

BACKGROUND: Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. RESULTS: IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNFα levels, respectively. TNFα released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNFα also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation. CONCLUSIONS: All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.


Assuntos
Cerebelo , Hiperamonemia , Microglia , Ratos Wistar , Receptores de Interleucina-17 , Animais , Hiperamonemia/metabolismo , Microglia/metabolismo , Cerebelo/metabolismo , Masculino , Ratos , Receptores de Interleucina-17/metabolismo , Doenças Neuroinflamatórias/metabolismo , Interleucina-17/metabolismo , Encefalopatia Hepática/metabolismo , Transdução de Sinais , Modelos Animais de Doenças
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