Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.241
Filtrar
1.
J Photochem Photobiol B ; 200: 111635, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31671372

RESUMO

Parkinson disease is one of the most common neurological movement disorders affecting geriatric population. Biosynthesized gold nanoparticles are the ideal alternatives spotlighted by many researchers to treat various diseases. In the present study we synthesized gold nanoparticles using the root extract of Paeonia mountan, woody trees which are used in traditional Chinese medicine to be prescribed for diverse diseases. The synthesis of gold nanoparticles was confirmed with UV-Vis spectroscopic analysis and characterized using FTIR, HR-TEM, EDAX and XRD analysis. The cytotoxicity property of synthesized gold nanoparticles was assessed using MTT assay in the murine microglial BV2 cells. The neuroprotective effect of synthesized gold nanoparticles in inflammatory agent lipopolysaccharides triggered murine microglial BV2 cells was evaluated using nitric oxide, prostaglandin E2 and inflammatory cytokines assays such as IL-6&IL-1ß. Further to confirm in vivo effect of synthesized nanoparticles, the nanoparticles were treated to Parkinson induced C57BL/6 mice. Behavioral, biochemical and molecular analysis were performed to estimate the potency of synthesized gold nanoparticles against the Parkinson induction in mice model. Our characterization results prove the gold nanoparticles synthesized using Paeonia mountan fulfills the requirement of ideal nanodrug and it potentially inhibited the inflammation in in vitro murine microglial BV2. The results of in vivo experiments authentically confirm gold nanoparticles synthesized using Paeonia mountan alleviates the neuroinflammation and improves the motor coordination in Parkinson induced mice.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Fármacos Neuroprotetores/química , Paeonia/química , Extratos Vegetais/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Química Verde , Lipopolissacarídeos/farmacologia , Masculino , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico/metabolismo , Paeonia/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Doença de Parkinson/veterinária , Raízes de Plantas/química , Raízes de Plantas/metabolismo
2.
Life Sci ; 237: 116915, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610207

RESUMO

AIMS: The objective of the study was to determine whether ß-caryophyllene (BCP) exerts a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury by inhibiting microglial activation and modulating their polarization via the TLR4 pathway. MAIN METHODS: Wild-type (WT) and TLR4 knockout (KO) C57BL/6J mice were subjected to cerebral I/R injury and neurologic dysfunction, cerebral infarct volume, brain edema, microglia activation and polarization, and TLR4 expression were determined. In vitro, primary microglia were stimulated with LPS and IFN-γ or IL-4 to induce polarization of microglia toward M1 or M2 phenotypes. KEY FINDINGS: BCP reduced cerebral infarct volume, brain edema, and neurologic deficits in WT mice after I/R. The optimal dose of BCP, 72 mg/kg body weight, inhibited microglial activation and reduced the secretion of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 by microglia of WT mice. BCP inhibited the level of TLR4 in WT mice, and partially reduced neurologic deficits, infarct volume, and brain edema in TLR4 KO mice. Importantly, BCP reduced the number of activated M1-type microglia and increased the number of M2-type microglia in the ipsilateral cortex of both WT and TLR4 KO mice. In vitro, BCP decreased the secretion of proinflammatory cytokines induced by LPS plus IFN-γ, downregulated the level of TLR4 protein, and polarized microglia towards the M2 phenotype. SIGNIFICANCES: The decrease in TLR4 activity mediated, at least in part, the anti-inflammatory effects of BCP and its ability to shift microglia polarization from the M1 to M2 phenotype.


Assuntos
Isquemia Encefálica/prevenção & controle , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Receptor 4 Toll-Like/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
3.
Br J Anaesth ; 123(6): 827-838, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31623841

RESUMO

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Inflamação/tratamento farmacológico , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Microglia/efeitos dos fármacos , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
4.
Phytochemistry ; 167: 112085, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437665

RESUMO

Six undescribed phenolic derivatives along with thirty two known compounds were isolated from the twigs of Betula schmidtii. The chemical structures were characterized through extensive spectroscopic analysis and chemical methods. All known compounds were first isolated in this plant. The anti-inflammatory effect of the isolates was tested by measuring nitric oxide production in lipopolysaccharide-activated BV-2 cells. Isotachioside, 4-allyl-2-hydrophenyl 1-O-ß-D-apiosyl-(1 → 6)-ß-D-glucopyranoside, genistein 5-O-ß-D-glucoside, and prunetinoside showed a slight potency to lower the NO production against LPS-activated microglia with IC50 values of 23.9, 25.3, 28.8, and 34.0 µM, respectively.


Assuntos
Betula/química , Fenóis/química , Linhagem Celular , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/biossíntese , Fenóis/isolamento & purificação , Fenóis/farmacologia , República da Coreia
5.
Adv Exp Med Biol ; 1155: 857-867, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468452

RESUMO

We want to find the anti-neuroinflammatory action of the taurine derivative Glucose-Taurine Reduced (G-T-R). The anti-neuroinflammatory action by G-T-R were investigated in lipopolysaccharide (LPS)-induced BV2 microglia. G-T-R inhibited the production of nitric oxide and prostaglandin E2, and down-regulated the protein expression of inducible NO synthase and cyclooxygenase-2. In addition, G-T-R reduced the cytokines secretion such as tumor necrosis factor (TNF-α), interleukin (IL) -1ß and IL-6, in BV2 microglia treated with LPS. In addition, G-T-R dose-dependently decreased the activation of nuclear factor-kappa B. These findings confirmed the anti-neuroinflammatory activity of G-T-R, which may exert protective effects against neuroinflammatory-related diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Taurina/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Glucose , Lipopolissacarídeos , Camundongos , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/metabolismo
6.
J Agric Food Chem ; 67(35): 9796-9804, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393712

RESUMO

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of Lycoris chejuensis (CJ) and its active compound, 7-deoxy-trans-dihydronarciclasine (named E144), attenuated expressions of pro-inflammatory factors, including nitric oxide, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and interleukin 6, secreted by lipopolysaccharide-activated BV-2 microglial cells, as measured by an enzyme-linked immunosorbent assay or western blotting. In contrast, CJ extract and E144 promoted the secretion of the anti-inflammatory cytokine, interleukin 10. Moreover, we found that E144 attenuated the expression of TNF-α and COX-2 in the cerebral cortex of lipopolysaccharide-treated mice and/or T2576 transgenic mice as well as reduced the reactive immune cells visualized by ionized calcium-binding adaptor molecule 1. Our results suggest the possibility of E144 to serve as a potential anti-neuroinflammatory agent by preventing excess production of pro-inflammatory factors.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Isoquinolinas/administração & dosagem , Lycoris/química , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Isoquinolinas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
J Agric Food Chem ; 67(36): 10079-10088, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31461286

RESUMO

Geraniin has been reported to possess potent anti-inflammatory properties and to modulate the macrophage polarization. This study sought to evaluate the protective effects and underlying mechanisms of geraniin on lipopolysaccharide (LPS)-induced neuroinflammation and neurobiological alternations as well as cognitive impairment. Daily intragastrical administration with geraniin (20 mg kg-1 day-1) for 14 days significantly prolonged the duration in the target quadrant (26.53 ± 2.03 versus 37.09 ± 3.27%; p < 0.05) and increased crossing-target number (1.93 ± 0.22 versus 3.08 ± 0.17; p < 0.01) in the probe test of LPS-treated mice. Geraniin also ameliorated LPS-elicited neural/synaptic impairments and decreased levels of LPS-induced Aß generation (p < 0.05), amyloid precursor protein (APP) (p < 0.05) and ß-site amyloid precursor protein cleavage enzyme 1 (BACE1) (p < 0.05). Furthermore, geraniin suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) (9.85 ± 0.58 versus 5.20 ± 0.52 pg/mg of protein; p < 0.01), interleukin (IL)-1ß (16.31 ± 0.67 versus 8.62 ± 0.46 pg/mg of protein; p < 0.01), and IL-6 (12.12 ± 0.45 versus 7.43 ± 0.32 pg/mg of protein; p < 0.05), and inhibited glial cell activation. Moreover, geraniin effectively polarized the microglia toward an anti-inflammatory M2 phenotype. Further study revealed that geraniin targeted toll-like receptor 4 (TLR4)-mediated signaling and decreased the production of pro-inflammatory cytokines in BV-2 microglial cells. These results indicate that geraniin mitigates LPS-elicited neural/synaptic neurodegeneration, amyloidogenesis, neuroinflammation, and cognitive impairment and suggest geraniin as a therapeutic option for neuroinflammation-associated neurological disorders, such as Alzheimer's disease.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Glucosídeos/administração & dosagem , Taninos Hidrolisáveis/administração & dosagem , Receptor 4 Toll-Like/imunologia , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/imunologia , Animais , Ácido Aspártico Endopeptidases , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/genética , Disfunção Cognitiva/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
8.
Chem Pharm Bull (Tokyo) ; 67(7): 640-647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257319

RESUMO

Neuroinflammation manifested by over-activation of microglial cells plays an essential role in neurodegenerative diseases. Short-term activation of microglia can be beneficial, but chronically activated microglia can aggravate neuronal dysfunction possibly by secreting potentially cytotoxic substances such as tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO), which can result in dysfunction and death of neurons. Therefore inhibiting over-activation of microglia and the production of cytotoxic intermediates may become an effective therapeutic approach for neuroinflammation. In this paper, we review our continuous research on natural inhibitors of over-activated microglia from traditional herbals, including flavonoids, lignans, sesquiterpene coumarins, and stilbenes.


Assuntos
Produtos Biológicos/química , Microglia/metabolismo , Animais , Produtos Biológicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Lignanas/química , Lignanas/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico/biossíntese , Estilbenos/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
9.
J Toxicol Sci ; 44(7): 471-479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270303

RESUMO

M1-microglia (neurotoxic microglia) regulate neuronal development and cell death and are involved in many pathologies in the brain. Although organotypic brain slice cultures are widely used to study the crosstalk between neurons and microglia, little is known about the properties of microglia in the mouse cerebral cortex slices. Here, we aimed to optimize the mouse cerebral slice cultures that reflect microglial functions and evaluate the effects of neurotoxic metals on M1-microglial activation. Most microglia in the cerebral slices prepared from postnatal day (P) 7 mice were similar to mature microglia in adult mice brains, but those in the slices prepared from P2 mice were immature, which is a conventional preparation condition. The degree of expression of M1-microglial markers (CD16 and CD32) and inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) by lipopolysaccharide, a representative microglia activator, in the cerebral slices of P7 mice were higher than that in the slices of P2 mice. These results indicate that M1-microglial activation can be evaluated more accurately in the cerebral slices of P7 mice than in those of P2 mice. Therefore, we next examined the effects of various neurotoxic metals on M1-microglial activation using the cerebral slices of P7 mice and found that methylmercury stimulated the activation to M1-microglia, but arsenite, lead, and tributyltin did not induce such activation. Altogether, the optimized mouse cerebral slice cultures used in this study can be a helpful tool to study the influence of various chemicals on the central nervous system in the presence of functionally mature microglia.


Assuntos
Córtex Cerebral/citologia , Metais/toxicidade , Microglia/efeitos dos fármacos , Microglia/fisiologia , Animais , Animais Recém-Nascidos , Arsenitos/toxicidade , Células Cultivadas , Córtex Cerebral/metabolismo , Citocinas/metabolismo , Expressão Gênica , Mediadores da Inflamação/metabolismo , Chumbo/toxicidade , Compostos de Metilmercúrio/toxicidade , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurônios/fisiologia , Receptores de IgG/genética , Receptores de IgG/metabolismo , Compostos de Trialquitina/toxicidade
10.
Chem Biol Interact ; 311: 108762, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348917

RESUMO

Neurotoxicity caused by particulate matter (PM) has been highlighted as being a potential risk factor for neurodegenerative diseases. However, the effects of brain inflammation in response to traffic-related PM remain unclear. The objective of this study was to investigate the effects of traffic-related PM on microglial responses. We determined the cytotoxicity, oxidative stress, lipid peroxidation, inflammation, activation, autophagy, and apoptosis due to exposure to carbon black (CB) and diesel exhaust particles (DEPs) in Bv2 microglial cells. Additionally, cells were pretreated with corticosteroid to determine alterations in microglial activation and inflammation. For in vivo confirmation, Sprague Dawley (SD) rats were whole-body exposed to traffic-related PM1 (PM with an aerodynamic diameter of <1 µm) for 3 and 6 months. We observed that a decrease in cell viability and increases in dichlorodihydrofluorescein (DCFH), lactate dehydrogenase (LDH), and thiobarbituric acid-reactive substances (TBARSs) occurred due to CB and DEP. Production of interleukin (IL)-6 and soluble tumor necrosis factor (TNF)-α was significantly stimulated by CB and DEP, whereas production of cellular TNF-α was significantly stimulated by CB. Iba1 and prostaglandin E2 (PGE2) significantly increased due to CB and DEP. Consistently, we observed significant increases in Iba1 in the hippocampus of rats after 3 and 6 months of exposure to traffic-related PM1. We found that the light chain 3II (LC3II)/LC3I ratio and caspase-3 activity increased due to CB and DEP exposure. Subsequently, LDH, TBARS, LC3II/I, and caspase-3 activities did not clearly respond to corticosteroid pretreatment followed by DEP exposure in BV2 cells. Results of the present study suggested that traffic-related PM induced cytotoxicity, lipid peroxidation, microglial activation, and inflammation as well as autophagy and caspase-3 regulation in microglia. We demonstrated that microglial activation and inflammation may play important roles in the response of the brain to traffic-related PM.


Assuntos
Inflamação/etiologia , Microglia/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Autofagia/efeitos dos fármacos , Encéfalo/patologia , Proteínas de Ligação ao Cálcio/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/análise , Interleucina-6/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Proteínas dos Microfilamentos/análise , Microglia/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Emissões de Veículos/toxicidade
11.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261895

RESUMO

Preventive approaches for age-related memory decline and dementia have become a high priority in the aging society because of the lack of therapeutic approaches. Recent epidemiological studies have reported that fermented dairy products can help prevent dementia. Previously, we identified tryptophan-tyrosine (WY) and tryptophan-methionine (WM) peptides as the suppressants of activation of the primary microglia and showed that WY peptide consumption suppresses inflammation in the brains of Alzheimer's disease model mice. However, the effects of the WM peptide on inflammation in the brain and Alzheimer's pathology have not been investigated. Here, we evaluated the effect of WM peptide consumption on Alzheimer's disease model (5×FAD) mice. In 5×FAD mice, intake of WM peptide suppressed the production of inflammatory cytokines, activation of microglia, and infiltration of activated microglia around ß amyloid (Aß) depositions. WM peptide intake reduced Aß deposition in the cortex and hippocampus and then improved the object recognition memory. Taken together with previous reports, the current findings indicate that ingestion of tryptophan-related peptides or food material rich in tryptophan-related peptides, thereby regulating microglial activity, represents a potential preventive approach for cognitive decline and dementia related to inflammation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Dipeptídeos/farmacologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Suplementos Nutricionais , Dipeptídeos/administração & dosagem , Dipeptídeos/química , Dipeptídeos/uso terapêutico , Feminino , Metionina/química , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas do Leite/química , Triptofano/química
12.
Sci Total Environ ; 689: 662-678, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279213

RESUMO

Microcystin-leucine-arginine (MC-LR), which produced by toxic cyanobacteria and widely present in eutrophic waters, has been shown to have potent acute hepatotoxicity. MC-LR has been revealed to inflict damage to brain, while the neurotoxicity of chronic exposure to MC-LR and mechanisms underlying it are still confusing. Here, the mice were exposed to MC-LR dissolved in drinking water at dose of 1, 7.5, 15, and 30 µg/L for consecutive 180 days. MC-LR accumulated in mouse brains and impaired the blood-brain barrier by inducing the expression of matrix metalloproteinase-8 (MMP-8), which was regulated by NF-κB, c-Fos and c-Jun. Furthermore, MC-LR exposure induced microglial and astrocyte activation and resultant neuroinflammatory response. This study highlights the risks to human health of the current microcystin exposure.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Inflamação/fisiopatologia , Microcistinas/toxicidade , Junções Íntimas/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/fisiologia , Junções Íntimas/metabolismo
13.
Life Sci ; 232: 116647, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301416

RESUMO

AIM: Brain injury after sepsis leads to high mortality and long-term brain dysfunction in patients. Previous studies revealed that borneol has a protective effect on the brain, but its function on sepsis associated encephalopathy (SAE) remains unknown. Herein, we investigated the protective effect of borneol against sepsis-related brain injury. MAIN METHODS: Lipopolysaccharide (LPS)-induced sepsis mice and cells were treated with borneol at the dose of 100 mg/kg by gavage or 10 µg/ml in culture, respectively. The protective effect of borneol on neurons and the microglia were assessed in vivo and in vitro. KEY FINDINGS: We observed that borneol attenuated brain neuronal and microglial inflammation in LPS-induced sepsis mice with a suppression of p-p65 and p38 signaling that were initially activated by LPS in the brain. In vitro examination confirmed that the protective effect of borneol on both neurons and microglia, and its suppressive effect on p-p65 and p38 pathways were, at least in part, direct. SIGNIFICANCE: An early protection of neurons and microglia from bacterial endotoxin during sepsis is beneficial, and borneol has the potential to protect these cells.


Assuntos
Bornanos/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Endotoxinas/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Sepse/complicações , Animais , Bornanos/administração & dosagem , Bornanos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia
14.
Life Sci ; 232: 116621, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269415

RESUMO

Kainate (KA) mouse model induced by intraperitoneal injection has been widely used for epilepsy and neurodegeneration studies. KA elicits sustained epileptic activity in mouse brain revealed by recurrent behavioral seizures, deteriorative neurodegeneration and various neurological deficits. However, to date, the vast majority of the studies used male mice only, and few studies on the comparison of brain injury between male and female mice in this model were reported. Epidemiological studies indicate that sex may affect the susceptibility to seizure response and neurodegeneration process. Therefore, this study focused on the effect of sex difference on KA-induced recurrent seizures and mortality, locomotor activity and cognitive impairment, and hippocampal neurodegeneration and reactive gliosis in mice. Our results showed that, compared to females, adult male mice exhibited worse performance in mortality rate, severity of epileptic seizures, and cognitive impairment indicated by novel object recognition task. Unexpectedly, post-KA male and female mice underwent similar decline and recovery of locomotor activity. KA-induced neurodegeneration in the whole hippocampus, particularly in CA1 and CA3 subregions, along with the deteriorative reactive gliosis in astrocytes and microglia, was more severe in males than that in females. These data provided the direct in vivo evidence that indicates the key role of sex difference in studies with KA mouse model, and this could be beneficial for optimizing the design of future studies.


Assuntos
Ácido Caínico/efeitos adversos , Ácido Caínico/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Feminino , Gliose/induzido quimicamente , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores Sexuais
15.
Chem Biol Interact ; 310: 108743, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299241

RESUMO

Paraquat (PQ) is a widely characterized neurotoxicant able to induce a series of nervous system disorders, including neurobehavioral defects and neurodegenerative diseases. Despite the direct evidence that PQ could induce inflammatory responses in central nervous system and largely contribute to neurotoxicity, the putative adverse effects of PQ on the neuroimmune interactions have rarely been investigated. Therefore, the present study investigated underlying mechanisms of PQ-induced inflammatory response in BV-2 microglia cells. Proliferation, migration and phagocytosis of BV-2 cells upon PQ exposure were first investigated to demonstrate that PQ did stimulate BV-2 microglia into an active phenotype. Increased microglia M1 markers expression and decreased microglia M2 markers expression confirmed that PQ induces BV-2 cells towards M1 activation. The levels of pro-inflammatory cytokines were determined using ELISA and western blotting assays, showing that paraquat significantly promote the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). The up-regulation of TLR4/MyD88 protein expressions and enhanced translocation of NF-κB p65 protein upon PQ exposure were further demonstrated. Taken together, our results suggested that PQ induces M1 microglia polarization by increased production of pro-inflammatory molecules, which could be explained by the activation of the TLR4-mediated NF-κB signaling pathway.


Assuntos
Inflamação/induzido quimicamente , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Paraquat/farmacologia , Animais , Citocinas/metabolismo , Camundongos , Microglia/patologia , NF-kappa B/efeitos dos fármacos , Paraquat/efeitos adversos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
16.
Toxicol Lett ; 314: 106-116, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306743

RESUMO

Chronic low-level lead exposure alters cognitive function in young children however the mechanisms mediating these deficits in the brain are not known. Previous studies in our laboratory showed that early lead exposure reduced the number of microglial cells in hippocampus/dentate gyrus of C57BL/6 J mice. In the current study, C-C chemokine receptor 7 (CCR7) and major histocompatibility complex II (MHC II) were examined to investigate whether these neuroimmune factors which are known to trigger cell migration and antigen presentation, were altered by early chronic lead exposure. Thirty-six C57BL/6 J male mice were exposed to 0 ppm (controls, n = 12), 30 ppm (low-dose, n = 12), or 430 ppm (higher-dose, n = 12) of lead acetate via dams' milk from postnatal day (PND) 0 to 28. Flow cytometry was used to quantify cell types and cell surface expression of MHC II and CCR7 in hippocampal and whole brain microglia. Non-parametric independent samples median tests were used to test for statistically significant differences between groups. As compared to controls, CCR7 in hippocampal microglia was decreased in the low-dose group, measured as geometric mean fluorescence intensity (GMFI); in the higher-dose group CCR7+MHC II- hippocampal microglia were decreased. Further analyses revealed that the higher-dose group had decreased percentage of CCR7+MHC II- hippocampal macrophages as compared to controls but increased MHC II levels in CCR7+MHC II+ hippocampal macrophages as compared to controls. It was also noted that lead exposure disrupted the balance of MHC II and/or CCR7 in lead exposed animals. Reduced CCR7 in hippocampal microglia might alter the neuroimmune environment in hippocampi of lead exposed animals. Additional studies are needed to test this possibility.


Assuntos
Hipocampo/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo na Infância/etiologia , Microglia/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Receptores CCR7/metabolismo , Animais , Animais Recém-Nascidos , Regulação para Baixo , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Lactação , Intoxicação do Sistema Nervoso por Chumbo na Infância/metabolismo , Intoxicação do Sistema Nervoso por Chumbo na Infância/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Fatores de Tempo
17.
Spine (Phila Pa 1976) ; 44(12): E707-E714, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150368

RESUMO

STUDY DESIGN: The effect of triptolide on spinal cord injury (SCI) and inflammatory response was observed by establishing SCI rat model. And in vitro experiments were conducted to determine the underlying mechanism of triptolide-mediated in murine microglial cell line BV2. OBJECTIVE: To determine the underlying mechanism of triptolide in suppressing the microglia activation to improve SCI. SUMMARY OF BACKGROUND DATA: Triptolide, as a major active ingredient of Chinese herb Tripterygium wilfordii, can promote spinal cord repair through inhibiting microglia activation, but the underlying mechanism is not clear. METHODS: Locomotion recovery was accessed by Basso, Beattie, and Bresnahan score, the number of footfalls, stride length, and angle of rotation analysis. Expressions of microRNA 96 (miR-96), microglia activation marker Iba-1, and IκB kinase (IKKß)/nuclear factor (NF)-κB-related proteins were detected by qRT-PCR or western blot. Inflammatory cytokines tumor necrosis factor-α and interleukin -1ß were measured by enzyme-linked immuno sorbent assay. The regulation of miR-96 on IKKß was confirmed by dual luciferase reporter assay. RESULTS: Triptolide promoted locomotion recovery of SCI rats, upregulated the expression of miR-96, decreased microglia activation marker Iba-1 and IKKß/NF-κB-related proteins, and inhibited inflammatory cytokines tumor necrosis factor-α and interleukin-1ß levels in spinal cord tissues and lipopolysaccharide -induced microglia. Triptolide suppressed the microglia activation and inflammatory cytokines secretion in BV2 cells through up-regulating miR-96. We confirmed the interaction between miR-96 and IKKß, and IKKß expression was negatively regulated by miR-96. Finally, we determined that triptolide suppressed the microglia activation and inflammatory cytokines secretion through miR-96/IKKß pathway. CONCLUSION: Triptolide suppressed microglia activation after SCI through miR-96/IKKß/NF-κB pathway. LEVEL OF EVIDENCE: N/A.


Assuntos
Diterpenos/uso terapêutico , Quinase I-kappa B/biossíntese , MicroRNAs/biossíntese , Microglia/metabolismo , NF-kappa B/biossíntese , Fenantrenos/uso terapêutico , Traumatismos da Medula Espinal/metabolismo , Animais , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fenantrenos/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico
18.
Carbohydr Polym ; 219: 219-228, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151520

RESUMO

Coreopsis tinctoria is being widely cultivated in Xinjiang of China, whose consumption is known to prevent diabetes and neurodegenerative diseases. To elucidate the bioactive ingredients responsible for these benefits, the alkaline soluble crude polysaccharide (CTB) was isolated from C. tinctoria. In vitro experiments showed that the inhibition of α-amylase and α-glucosidase by CTB was 13407-fold and 906-fold higher than that by positive control, respectively. Then, a novel arabinogalactan, CTBP-1, was isolated and purified from CTB. Structural analysis showed that CTBP-1 possessed a 1,6-linked ß-d-Galp and 1,5-linked α-l-Araf backbone with branches substituted at the C-3 position of the 1,6-linked ß-d-Galp, and the side chains included 1,5-linked α-l-Araf, T-linked ß-d-Galp and T-linked α-l-Araf. The inhibitory effects of CTBP-1 on α-amylase and α-glucosidase were 2.7 and 17.9 times that of acarbose, respectively. CTBP-1 could avoid indigestion and similar side effects. In addition, CTBP-1 remarkably inhibited the release of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. In summary, CTBP-1 is a novel arabinogalactan with great potential as a treatment for type 2 diabetes and Alzheimer's disease.


Assuntos
Coreopsis/metabolismo , Galactanos , Inibidores de Glicosídeo Hidrolases/farmacologia , Microglia , Extratos Vegetais/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Células Cultivadas , China , Galactanos/química , Galactanos/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Life Sci ; 232: 116501, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163175

RESUMO

AIMS: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The disease mechanisms driving progressive MS remain unresolved. Without this information, current therapeutic strategies are unsatisfactory in preventing disease progression. Our previous work revealed that DL-3-n-butylphthalide (NBP) treatment reduced demyelination in an ethidium bromide mouse model of demyelination. Here, we examine the effect of NBP in the cuprizone model of demyelination by evaluating the pathologic, functional, and behavioral consequences of treatment with NBP. MATERIALS AND METHODS: Forty mice were divided randomly into 4 groups: a normal diet group, a cuprizone diet group, and two NBP groups (10 and 20 mg/kg). CNS infiltration by microglia, axon health and myelination were assessed using immunohistochemistry and electron microscopy, and the levels of cytoplasmic complexes were assessed by Western blotting. KEY FINDINGS: The results showed the neuroprotective effects of the NBP included suppressing the microglia activation through inhibition of nuclear factor-κB (NF-κB) expression, thus decreasing activation of the NF-κB signaling pathway. In particular, myelin density was increased due to an increased mean number of mature oligodendrocytes (OLs) in the high-dose NBP (20 mg/kg) subgroup through reduced oligodendrocyte apoptosis. Meanwhile, increased expression of myelin sheath proteins, including proteolipid protein (PLP) and myelin basic protein (MBP), was observed in the same subgroup. SIGNIFICANCE: These data suggest that NBP may not only have anti-inflammatory properties but also promote the survival of OLs in a mouse cuprizone model of demyelination. NBP may have a potential role in the treatment of MS.


Assuntos
Benzofuranos/farmacologia , Doenças Desmielinizantes/tratamento farmacológico , Esclerose Múltipla/metabolismo , Animais , Astrócitos/metabolismo , Axônios/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/fisiologia , Cuprizona/farmacologia , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , NF-kappa B/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
Life Sci ; 232: 116600, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251998

RESUMO

Neuroinflammation is one of the significant neuropathological conditions in Parkinson's disease (PD) which is due to microglial and astrocytes activation leads to progressive dopaminergic neuronal loss. To date, Current PD drugs offers only symptomatic relief with adverse effects and lack of ability to prevent the progression of neurodegeneration. Therefore, a better approach to develop a multi potent drug of natural origin would be beneficial in managing the disease. Therefore, the present study aimed to investigate the neuroprotective and anti-inflammatory effects of PHL by exploring its neuroprotective mechanism in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP) induced PD in mice. MPTP intoxication in mice cause motor abnormalities, decreased dopamine (DA) levels, reduced tyrosine hydroxylase (TH) enzyme protein expression and inflammation which were effectively restored by PHL. Moreover gliotic specific inflammatory markers like glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1 (Iba-1), iNOS and COX-2 were found to be expressed more in MPTP intoxicated mice, Further the levels of proinflammatory cytokines like IL-ß, IL-6, and TNF-α were significantly upregulated in MPTP intoxicated mice, these deleterious responses were diminished to extend neuroprotection by PHL treatment. Our findings strongly suggest PHL as a potent therapeutic agent in treating PD.


Assuntos
Transtornos Parkinsonianos/tratamento farmacológico , Floretina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA