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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(5): 788-795, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34728041

RESUMO

Alzheimer's disease(AD)is a chronic neurodegenerative disease whose cause remains unclear.The ß-amyloid plaques in the brain are one of the major pathological features of AD.However,the drugs targeting extracellular ß-amyloid plaques have failed to cure the disease.Innate immunity and neuroinflammation play a role in the pathogenesis and progression of AD.As the macrophages existing in the central nervous system,microglia are related with extracellular ß-amyloid deposition,intracellular neurofibrillary tangle formation,and neuron injury.Accumulating evidence demonstrates that the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome in microglia plays a role in AD,suggesting new therapeutic target for AD in this signaling pathway.This article reviewed the studies about the activation and regulation of NLRP3 inflammasome in the pathogenesis and progression of AD as well as the development of AD therapies targeting this pathway,aiming to provide reference for further studies in this field.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Inflamassomos , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nucleotídeos , Domínio Pirina
2.
Alzheimers Res Ther ; 13(1): 184, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749800

RESUMO

BACKGROUND: The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer's disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function. METHODS: Immunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer's disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). RESULTS: In a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids. CONCLUSIONS: The results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.


Assuntos
Canabinoides , Microglia , Receptores de Canabinoides , Receptores de N-Metil-D-Aspartato , Animais , Hipocampo/metabolismo , Humanos , Camundongos , Microglia/metabolismo , N-Metilaspartato , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
3.
Neurologia (Engl Ed) ; 36(9): 673-680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34752345

RESUMO

INTRODUCTION: Chronic exposure to low doses of ozone causes oxidative stress and loss of regulation of the inflammatory response, leading to progressive neurodegeneration. OBJECTIVE: We studied the effect of chronic exposure to low doses of ozone on IL-17A concentration and expression in neurons, microglia, astrocytes, and T cells in the rat hippocampus. METHODS: We used 72 Wistar rats, divided into 6 groups (n=12): a control group (no ozone exposure) and 5 groups exposed to ozone (0.25ppm, 4h daily) for 7, 15, 30, 60, and 90 days. We processed 6 rats from each group to quantify IL-17A by ELISA; the remaining 6 were processed for immunohistochemistry (against IL-17A and GFAP, Iba1, NeuN, and CD3). RESULTS: The ELISA study data showed a significant increase in IL-17A concentrations in the 7-, 15-, 30-, and 60-day exposure groups, with regard to the control group (P<.05). Furthermore, they indicate that hippocampal neurons were the cells showing greatest immunoreactivity against IL-17A between 60 and 90 days of exposure to ozone; we also observed an increase in activated astrocytes in the 30- and 60-day exposure groups. CONCLUSION: Exposure to ozone in rats induces an increase in IL-17A expression, mainly in hippocampal neurons, accompanied by hippocampal astrocyte activation during chronic neurodegeneration, similar to that observed in Alzheimer disease in humans.


Assuntos
Hipocampo , Interleucina-17 , Ozônio , Animais , Hipocampo/metabolismo , Interleucina-17/metabolismo , Microglia/metabolismo , Ozônio/efeitos adversos , Ratos , Ratos Wistar
4.
Int J Mol Sci ; 22(19)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34639091

RESUMO

Inter-alpha Inhibitor Proteins (IAIPs) are key immunomodulatory molecules. Endogenous IAIPs are present in human, rodent, and sheep brains, and are variably localized to the cytoplasm and nuclei at multiple developmental stages. We have previously reported that ischemia-reperfusion (I/R) reduces IAIP concentrations in the fetal sheep brain. In this study, we examined the effect of I/R on total, cytoplasmic, and nuclear expression of IAIPs in neurons (NeuN+), microglia (Iba1+), oligodendrocytes (Olig2+) and proliferating cells (Ki67+), and their co-localization with histones and the endoplasmic reticulum in fetal brain cells. At 128 days of gestation, fetal sheep were exposed to Sham (n = 6) or I/R induced by cerebral ischemia for 30 min with reperfusion for 7 days (n = 5). Although I/R did not change the total number of IAIP+ cells in the cerebral cortex or white matter, cells with IAIP+ cytoplasm decreased, whereas cells with IAIP+ nuclei increased in the cortex. I/R reduced total neuronal number but did not change the IAIP+ neuronal number. The proportion of cytoplasmic IAIP+ neurons was reduced, but there was no change in the number of nuclear IAIP+ neurons. I/R increased the number of microglia and decreased the total numbers of IAIP+ microglia and nuclear IAIP+ microglia, but not the number of cytoplasmic IAIP+ microglia. I/R was associated with reduced numbers of oligodendrocytes and increased proliferating cells, without changes in the subcellular IAIP localization. IAIPs co-localized with the endoplasmic reticulum and histones. In conclusion, I/R alters the subcellular localization of IAIPs in cortical neurons and microglia but not in oligodendrocytes or proliferating cells. Taken together with the known neuroprotective effects of exogenous IAIPs, we speculate that endogenous IAIPs may play a role during recovery from I/R.


Assuntos
alfa-Globulinas/metabolismo , Feto/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Feto/patologia , Hipóxia-Isquemia Encefálica/patologia , Masculino , Microglia/patologia , Neurônios/patologia , Fármacos Neuroprotetores , Oligodendroglia/patologia , Ovinos , Frações Subcelulares/metabolismo
5.
Alzheimers Res Ther ; 13(1): 177, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670619

RESUMO

BACKGROUND: Interactions between the gut microbiota, microglia, and aging may modulate Alzheimer's disease (AD) pathogenesis but the precise nature of such interactions is not known. METHODS: We developed an integrated multi-dimensional, knowledge-driven, systems approach to identify interactions among microbial metabolites, microglia, and AD. Publicly available datasets were repurposed to create a multi-dimensional knowledge-driven pipeline consisting of an integrated network of microbial metabolite-gene-pathway-phenotype (MGPPN) consisting of 34,509 nodes (216 microbial metabolites, 22,982 genes, 1329 pathways, 9982 mouse phenotypes) and 1,032,942 edges. RESULTS: We evaluated the network-based ranking algorithm by showing that abnormal microglia function and physiology are significantly associated with AD pathology at both genetic and phenotypic levels: AD risk genes were ranked at the top 6.4% among 22,982 genes, P < 0.001. AD phenotypes were ranked at the top 11.5% among 9982 phenotypes, P < 0.001. A total of 8094 microglia-microbial metabolite-gene-pathway-phenotype-AD interactions were identified for top-ranked AD-associated microbial metabolites. Short-chain fatty acids (SCFAs) were ranked at the top among prioritized AD-associated microbial metabolites. Through data-driven analyses, we provided evidence that SCFAs are involved in microglia-mediated gut-microbiota-brain interactions in AD at both genetic, functional, and phenotypic levels. CONCLUSION: Our analysis produces a novel framework to offer insights into the mechanistic links between gut microbial metabolites, microglia, and AD, with the overall goal to facilitate disease mechanism understanding, therapeutic target identification, and designing confirmatory experimental studies.


Assuntos
Doença de Alzheimer , Microbioma Gastrointestinal , Doença de Alzheimer/genética , Animais , Encéfalo , Camundongos , Microglia , Fenótipo
6.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638882

RESUMO

Persistent inflammatory reactions in microglial cells are strongly associated with neurodegenerative pathogenesis. Additionally, geranylgeraniol (GGOH), a plant-derived isoprenoid, has been found to improve inflammatory conditions in several animal models. It has also been observed that its chemical structure is similar to that of the side chain of menaquinone-4, which is a vitamin K2 sub-type that suppresses inflammation in mouse-derived microglial cells. In this study, we investigated whether GGOH has a similar anti-inflammatory effect in activated microglial cells. Particularly, mouse-derived MG6 cells pre-treated with GGOH were exposed to lipopolysaccharide (LPS). Thereafter, the mRNA levels of pro-inflammatory cytokines were determined via qRT-PCR, while protein expression levels, especially the expression of NF-κB signaling cascade-related proteins, were determined via Western blot analysis. The distribution of NF-κB p65 protein was also analyzed via fluorescence microscopy. Thus, it was observed that GGOH dose-dependently suppressed the LPS-induced increase in the mRNA levels of Il-1ß, Tnf-α, Il-6, and Cox-2. Furthermore, GGOH inhibited the phosphorylation of TAK1, IKKα/ß, and NF-κB p65 proteins as well as NF-κB nuclear translocation induced by LPS while maintaining IκBα expression. We showed that GGOH, similar to menaquinone-4, could alleviate LPS-induced microglial inflammation by targeting the NF-kB signaling pathway.


Assuntos
Diterpenos/farmacologia , Inflamação/prevenção & controle , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos , Microglia/citologia , Microglia/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição RelA/metabolismo
8.
Nat Commun ; 12(1): 5916, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625548

RESUMO

Microglia are brain resident macrophages that play vital roles in central nervous system (CNS) development, homeostasis, and pathology. Microglia both remodel synapses and engulf apoptotic cell corpses during development, but whether unique molecular programs regulate these distinct phagocytic functions is unknown. Here we identify a molecularly distinct microglial subset in the synapse rich regions of the zebrafish (Danio rerio) brain. We found that ramified microglia increased in synaptic regions of the midbrain and hindbrain between 7 and 28 days post fertilization. In contrast, microglia in the optic tectum were ameboid and clustered around neurogenic zones. Using single-cell mRNA sequencing combined with metadata from regional bulk sequencing, we identified synaptic-region associated microglia (SAMs) that were highly enriched in the hindbrain and expressed multiple candidate synapse modulating genes, including genes in the complement pathway. In contrast, neurogenic associated microglia (NAMs) were enriched in the optic tectum, had active cathepsin activity, and preferentially engulfed neuronal corpses. These data reveal that molecularly distinct phagocytic programs mediate synaptic remodeling and cell engulfment, and establish the zebrafish hindbrain as a model for investigating microglial-synapse interactions.


Assuntos
Mesencéfalo/citologia , Microglia/citologia , Neurogênese/genética , Rombencéfalo/citologia , Colículos Superiores/citologia , Transcriptoma , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/imunologia , Catepsina B/genética , Catepsina B/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/imunologia , Microglia/imunologia , Neurogênese/imunologia , Neurônios/citologia , Neurônios/imunologia , Fagocitose , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/imunologia , Análise de Célula Única , Colículos Superiores/crescimento & desenvolvimento , Colículos Superiores/imunologia , Sinapses/imunologia , Sinapses/metabolismo , Sinapses/ultraestrutura , Peixe-Zebra , Proteínas de Peixe-Zebra/imunologia
9.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638890

RESUMO

Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells. Among them, astrocytes are the most abundant glial cells in the mammalian brain and play a wide range of roles, from structural maintenance of the brain to regulation of neurotransmission. Furthermore, since astrocytes can take up EVs, it is possible that EVs originating from inside and outside the brain affect astrocyte function, which in turn affects brain function. However, it has not been fully clarified whether the specific targeting mechanism of EVs to astrocytes as recipient cells exists. In recent years, EVs have attracted attention as a cell-targeted therapeutic approach in various organs, and elucidation of the targeting mechanism of EVs to astrocytes may pave the way for new therapies for brain diseases. In this review, we focus on EVs in the brain that affect astrocyte function and discuss the targeting mechanism of EVs to astrocytes.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Vesículas Extracelulares/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Animais , Astrócitos/citologia , Encéfalo/citologia , Vesículas Extracelulares/genética , Humanos , MicroRNAs/genética , Microglia/citologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/citologia , RNA Mensageiro/genética
10.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638900

RESUMO

We assessed the effect of antioxidant therapy using the Food and Drug Administration-approved respiratory drug N-acetylcysteine (NAC) or sulforaphane (SFN) as monotherapies or duotherapy in vitro in neuron-BV2 microglial co-cultures and validated the results in a lateral fluid-percussion model of TBI in rats. As in vitro measures, we assessed neuronal viability by microtubule-associated-protein 2 immunostaining, neuroinflammation by monitoring tumor necrosis factor (TNF) levels, and neurotoxicity by measuring nitrite levels. In vitro, duotherapy with NAC and SFN reduced nitrite levels to 40% (p < 0.001) and neuroinflammation to -29% (p < 0.001) compared with untreated culture. The treatment also improved neuronal viability up to 72% of that in a positive control (p < 0.001). The effect of NAC was negligible, however, compared with SFN. In vivo, antioxidant duotherapy slightly improved performance in the beam walking test. Interestingly, duotherapy treatment decreased the plasma interleukin-6 and TNF levels in sham-operated controls (p < 0.05). After TBI, no treatment effect on HMGB1 or plasma cytokine levels was detected. Also, no treatment effects on the composite neuroscore or cortical lesion area were detected. The robust favorable effect of duotherapy on neuroprotection, neuroinflammation, and oxidative stress in neuron-BV2 microglial co-cultures translated to modest favorable in vivo effects in a severe TBI model.


Assuntos
Acetilcisteína/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Isotiocianatos/farmacologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sulfóxidos/farmacologia , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Ratos Sprague-Dawley
12.
Neuron ; 109(20): 3228-3230, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34672979

RESUMO

The trafficking of protein aggregates through neural circuitries causes adverse outcomes, including propagation of pathology and toxicity in neurodegenerative diseases. In a recent issue of Cell, Scheiblich et al. (2021) describe an advantageous aggregate-sharing strategy in microglial networks that nurtures α-synuclein-loaded members back to health.


Assuntos
Microglia , Doenças Neurodegenerativas , Humanos , Agregados Proteicos , alfa-Sinucleína
13.
J Vis Exp ; (175)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34633366

RESUMO

The ability to generate microglia from human induced pluripotent stem cells (iPSCs) provides new tools and avenues for investigating the role of microglia in health and disease. Furthermore, iPSC-derived microglia can be maintained in co-culture with iPSC-derived cortical neurons, which enable investigations of microglia-neuron interactions that are hypothesized to be dysregulated in a number of neuropsychiatric disorders. Human iPSCs were differentiated to generate microglia using an adapted version of a protocol developed by the Fossati group, and the iPSC-derived microglia were validated with marker analysis and real-time PCR. Human microglia generated using this protocol were positive for the markers CD11C, IBA1, P2RY12, and TMEM119, and expressed the microglial-related genes AIF1, CX3CR1, ITGAM, ITGAX, P2RY12, and TMEM119. Human iPSC-derived cortical neurons that had been differentiated for 30 days were plated with microglia and maintained in co-culture until day 60, when experiments were undertaken. The density of dendritic spines in cortical neurons in co-culture with microglia was quantified under baseline conditions and in the presence of pro-inflammatory cytokines. In order to examine how microglia modulate neuronal function, calcium imaging experiments of the cortical neurons were undertaken using the calcium indicator Fluo-4 AM. Live calcium activity of cortical neurons was obtained using a confocal microscope, and fluorescence intensity was quantified using ImageJ. This report describes how co-culturing human iPSC-derived microglia and cortical neurons provide new approaches to interrogate the effects of microglia on cortical neurons.


Assuntos
Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Técnicas de Cocultura , Humanos , Microglia , Neurônios
14.
Ecotoxicol Environ Saf ; 226: 112862, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624533

RESUMO

OBJECTIVE: To investigate the mechanisms of ATR-induced dopaminergic toxicity by microglia activation and the response of the Keap1/ Nrf2- ARE signaling pathway. METHODS: Wistar rats were treated with 50, 100 and 200 mg/kg ATR and BV-2 microglia cells were treated with 50, 100 µM ATR or 100 ng/mL LPS, respectively. Rats behavioral responses and histopathological changes were monitored. Immunohistochemical and immunofluorescence analysis detected Iba-1 and TH+ cells in rats. Keap1/Nrf2-ARE signaling-related proteins and inflammatory factors from BV-2 cells and rats were detected using ELISA, Western blot and Real-time PCR. RESULTS: After ATR treatment, the grip strength of Wistar rats was significantly decreased, and anxiety were clearly observed. TH+ neurons were reduced, however, the number of microglia cells and Iba-1 levels were increased clearly in SN. The release of ROS, TNF-α and IL-Iß were increased, and levels of SOD and GSH-Px were significantly decreased. Keap1 mRNA expression and protein levels were decreased, while nuclear Nrf2 mRNA expression and protein levels were both increased in vivo and in vitro. CONCLUSION: ATR could significantly activate microglia and exacerbate neurotoxicity and neuroinflammation, leading to accelerate dopaminergic neuron cell death by inhibiting Keap1/Nrf2-ARE signaling pathway.


Assuntos
Atrazina , Fator 2 Relacionado a NF-E2 , Animais , Neurônios Dopaminérgicos/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Microglia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
15.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638697

RESUMO

BACKGROUND: The prevention of age-related neurodegenerative disorders is an important issue in an aging society. Microglia-mediated neuroinflammation resulting in dopaminergic neuron loss may lead to the pathogenesis of Parkinson's disease (PD). Lipopolysaccharide (LPS), an endotoxin, induces neuroinflammatory microglial activation, contributing to dopaminergic neuron damage. Diosgenin is a phytosteroid sapogenin with a wide spectrum of pharmacological activities, e.g., anti-inflammatory activity. However, the preventive effect of diosgenin on neuroinflammation is not clear. Thus, in this study, we further investigated the neuroprotective effect of diosgenin on LPS-induced neural damage in vitro and in vivo. METHODS: For in vitro experiments, primary mesencephalic neuron-glia cultures and primary microglia cultures isolated from Sprague-Dawley rats were used. Cells were pretreated with diosgenin and then stimulated with LPS. The expression of proinflammatory cytokines or tyrosine hydroxylase (TH) in the cells was analyzed. In vivo, rats were fed a diet containing 0.1% (w/w) diosgenin for 4 weeks before being administered a unilateral substantia nigra (SN) injection of LPS. Four weeks after the LPS injection, the rats were assessed for lesion severity using the amphetamine-induced rotation test and TH immunohistochemistry. RESULTS: Diosgenin pretreatment prevented LPS-induced neurite shortening in TH-positive neurons in mesencephalic neuron-glia cultures. In addition, pretreatment of primary microglia with diosgenin significantly reduced tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression. Moreover, diosgenin pretreatment significantly suppressed LPS-induced extracellular signal-regulated kinase (ERK) activation. In vivo, the intranigral injection of LPS in rats fed a diosgenin-containing diet significantly improved motor dysfunction and reduced TH expression in SN. CONCLUSION: These results support the effectiveness of diosgenin in protecting dopaminergic neurons from LPS-induced neuroinflammation.


Assuntos
Diosgenina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Doenças Neurodegenerativas , Fármacos Neuroprotetores/farmacologia , Animais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neuritos/metabolismo , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Ratos , Ratos Sprague-Dawley
16.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34639071

RESUMO

The search for methods of cognitive impairment treatment and prevention in neurological and neurodegenerative diseases is an urgent task of modern neurobiology. It is now known that various diseases, accompanied by dementia, exhibit a pronounced neuroinflammation. Considering the significant docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids' therapeutic potential, we decided to investigate and compare anti-inflammatory activity of their N-acylethanolamine derivatives. As a result, we found that both N-docosahexaenoylethanolamine (synaptamide) and N-eicosapentaenoylethanolamine (EPEA) prevents an LPS-mediated increase in the proinflammatory cytokines TNF-α and IL-6 production in the SIM-A9 microglia culture. In an in vivo experiment, synaptamide reversed an increase in LPS-mediated hippocampal TNF-α and IL-1ß, but EPEA did not. However, both compounds contributed to the microglia polarization towards the M2-phenotype. Synaptamide, rather than EPEA, inhibited the Iba-1-positive microglia staining area increase. However, both synaptamide and EPEA prevented the LPS-mediated astrogliosis. A study of BDNF immunoreactivity showed that synaptamide, but not EPEA, reversed an LPS-mediated decrease in BDNF production. Despite the more pronounced anti-inflammatory activity of synaptamide, both compounds were effective in maintaining a normal level of hippocampal long-term potentiation in neuroinflammation. The results indicate a high therapeutic potential for both compounds. However, some tests have shown higher activity of synaptamide compared to EPEA.


Assuntos
Anti-Inflamatórios/farmacologia , Etanolaminas/farmacologia , Inflamação/etiologia , Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Camundongos , Microglia/metabolismo , Resultado do Tratamento
17.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638595

RESUMO

Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Transtornos Mentais/terapia , Neuroglia/citologia , Animais , Astrócitos/citologia , Sistema Nervoso Central/citologia , Desenvolvimento de Medicamentos/métodos , Humanos , Inflamação/patologia , Microglia/citologia , Neurônios/citologia , Qualidade de Vida
18.
J Vis Exp ; (176)2021 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-34661566

RESUMO

In Parkinson's disease, progressive dysfunction and degeneration of dopamine neurons in the ventral midbrain cause life-changing symptoms. Neuronal degeneration has diverse causes in Parkinson's, including non-cell autonomous mechanisms mediated by astrocytes. Throughout the CNS, astrocytes are essential for neuronal survival and function, as they maintain metabolic homeostasis in the neural environment. Astrocytes interact with the immune cells of the CNS, microglia, to modulate neuroinflammation, which is observed from the earliest stages of Parkinson's, and has a direct impact on the progression of its pathology. In diseases with a chronic neuroinflammatory element, including Parkinson's, astrocytes acquire a neurotoxic phenotype, and thus enhance neurodegeneration. Consequently, astrocytes are a potential therapeutic target to slow or halt disease, but this will require a deeper understanding of their properties and roles in Parkinson's. Accurate models of human ventral midbrain astrocytes for in vitro study are therefore urgently required. We have developed a protocol to generate high purity cultures of ventral midbrain-specific astrocytes (vmAstros) from hiPSCs that can be used for Parkinson's research. vmAstros can be routinely produced from multiple hiPSC lines, and express specific astrocytic and ventral midbrain markers. This protocol is scalable, and thus suitable for high-throughput applications, including for drug screening. Crucially, the hiPSC derived-vmAstros demonstrate immunomodulatory characteristics typical of their in vivo counterparts, enabling mechanistic studies of neuroinflammatory signaling in Parkinson's.


Assuntos
Células-Tronco Pluripotentes Induzidas , Astrócitos , Neurônios Dopaminérgicos , Humanos , Mesencéfalo , Microglia
19.
Front Cell Infect Microbiol ; 11: 741370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692564

RESUMO

Cerebral malaria (CM) is a severe neurological complication of malaria caused by the Plasmodium falciparum parasite. It is one of the leading causes of death in children under 5 years of age in Sub-Saharan Africa. CM is associated with blood-brain barrier disruption and long-term neurological sequelae in survivors of CM. Despite the vast amount of research on cerebral malaria, the cause of neurological sequelae observed in CM patients is poorly understood. In this article, the potential roles of glial cells, astrocytes, and microglia, in cerebral malaria pathogenesis are reviewed. The possible mechanisms by which glial cells contribute to neurological damage in CM patients are also examined.


Assuntos
Malária Cerebral , Doenças do Sistema Nervoso , Astrócitos , Pré-Escolar , Humanos , Microglia , Plasmodium falciparum
20.
Front Immunol ; 12: 689453, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616393

RESUMO

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.


Assuntos
Alcoolismo/metabolismo , Sistema Límbico/metabolismo , Microglia/metabolismo , Neuroimunomodulação , Dor/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores Opioides mu/metabolismo , Abstinência de Álcool , Alcoolismo/imunologia , Alcoolismo/fisiopatologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Adjuvante de Freund , Mediadores da Inflamação/metabolismo , Sistema Límbico/imunologia , Sistema Límbico/fisiopatologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/imunologia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Dor/induzido quimicamente , Dor/imunologia , Dor/fisiopatologia , Fosforilação , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiopatologia , Ratos Sprague-Dawley , Recidiva , Fatores Sexuais
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