Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Alcohol Clin Exp Res ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589333

RESUMO

BACKGROUND: Adolescence is a critical period for neural development and alcohol exposure during adolescence can lead to an elevated risk for health consequences as well as alcohol use disorders. Clinical and experimental data suggest that chronic alcohol exposure may produce immunomodulatory effects that can lead to the activation of proinflammatory cytokine pathways as well as microglial markers. The present study evaluated, in brain and blood, the effects of adolescent alcohol exposure and withdrawal on microglia and on the most representative pro and anti-inflammatory cytokines and major chemokines that can contribute to the establishing of a neuroinflammatory environment. METHODS: Wistar rats (males, n=96) were exposed to ethanol vapors, or air control, for 5 weeks over adolescence (PD 22-58). Brains and blood samples were collected at three time points: 1) after 35 days of vapor/air exposure (PD58); 2) after 1 day of withdrawal (PD59), and 3) 28 days after withdrawal (PD86). The ionized calcium binding adapter molecule 1 (Iba-1) was used to index microglia activation, and cytokine/chemokine responses were analyzed using Magnetic Bead Panels. RESULTS: After 35 days of adolescent vapor exposure, a significant increase in Iba-1 immunoreactivity was seen in: amygdala, frontal cortex, hippocampus and substantia nigra. However, Iba-1 density returned to control levels at both 1 day and 28 days of withdrawal except in the hippocampus where Iba-1 density was significantly lower than controls. In serum, adolescent ethanol exposure induced a reduction of IL-13 and an increase in fractalkine at day 35. After 1 day of withdrawal IL-18 was reduced, and IP-10 was elevated, whereas both IP-10 and IL-10 were elevated at 28 days following withdrawal. In the frontal cortex adolescent ethanol exposure induced an increase of IL-1ß at day 35, and 28 days of withdrawal, and IL-10 was increased after 28 days of withdrawal. CONCLUSION: These data demonstrate that ethanol exposure during adolescence produces significant microglial activation, however, inflammatory markers seen in the blood appear to differ from those observed in the brain.

2.
Alcohol ; 76: 37-45, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30554034

RESUMO

Alcohol produces complex effects on the immune system. Moderate alcohol use (1-2 drinks per day) has been shown to produce anti-inflammatory responses in human blood monocytes, whereas, the post mortem brains of severe alcoholics show increased immune gene expression and activated microglial markers. The present study was conducted to evaluate the time course of alcohol effects during exposure and after withdrawal, and to determine the relationship between microglial and cytokine responses in brain and blood. Forty-eight adult, male Wistar rats were exposed to chronic ethanol vapors, or air control, for 5 weeks. Following ethanol/air exposure blood and brains were collected at three time points: 1) while intoxicated, following 35 days of air/vapor exposure; 2) following 24 h of withdrawal from exposure, and 3) 28 days after withdrawal. One hemisphere of the brain was flash-frozen for cytokine analysis, and the other was fixed for immunohistochemical analysis. The ionized calcium-binding adapter molecule 1 (Iba-1) was used to evaluate microglia activation at the three time points, and rat cytokine/chemokine Magnetic Bead Panels (Millipore) were used to analyze frontal cortex tissue lysate and serum. Ethanol induced a significant increase in Iba-1 that peaked at day 35, remained significant after 1 day of withdrawal, and was elevated at day 28 in frontal cortex, amygdala, and substantia nigra. Ethanol exposure was associated with a transient reduction of the serum level of the major pro- and anti-inflammatory cytokines and chemokines and a transient increase of effectors of sterile inflammation. Little or no changes in these molecules were seen in the frontal cortex except for HMG1 and fractalkine that were reduced and elevated, respectively, at day 28 following withdrawal. These data show that ethanol exposure produces robust microglial activation; however, measures of inflammation in the blood differ from those in the brain over a protracted time course.

3.
Proc Natl Acad Sci U S A ; 114(36): 9731-9736, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28827363

RESUMO

When food resources are scarce, endothermic animals can lower core body temperature (Tb). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrus-specific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent Tb regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.


Assuntos
Restrição Calórica/efeitos adversos , Hipotermia/fisiopatologia , Receptor IGF Tipo 1/fisiologia , Envelhecimento/fisiologia , Animais , Metabolismo Energético/fisiologia , Feminino , Dosagem de Genes , Homeostase/fisiologia , Hipotermia/etiologia , Hipotermia/prevenção & controle , Longevidade/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Caracteres Sexuais , Transdução de Sinais/fisiologia
4.
J Neuroinflammation ; 14(1): 88, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28427412

RESUMO

BACKGROUND: The majority of Parkinson's disease (PD) cases are sporadic and idiopathic suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Stress and neuroinflammation are among the factors being investigated for their possible contributions to PD. Experiments in rodents showed that severe chronic stress can reduce the number of dopaminergic neurons in the substantia nigra pars compacta (SNc); the same cells that are lost in PD. These actions are at least in part mediated by increased oxidative stress. Here, we tested the hypothesis that the interleukin-13 receptor alpha 1 (IL-13Rα1), a cytokine receptor whose activation increases the vulnerability of dopaminergic neurons to oxidative damage, participates in the stress-dependent damage of these neurons. METHODS: Mice were subject to daily sessions of 8 h (acute) stress for 16 weeks (5 days a week), a procedure previously showed to induce loss of dopaminergic neurons in the SNc. The source and the kinetics of interleukin-13 (IL-13), the endogenous ligand of IL-13Rα1, were evaluated 0, 1, 3, 6, and 8 h and at 16 weeks of stress. Identification of IL-13 producing cell-type was performed by immunofluorescent and by in situ hybridization experiments. Markers of oxidative stress, microglia activation, and the number of dopaminergic neurons in IL-13Rα1 knock-out animals (Il13ra1 Y/ - ) and their wild-type littermates (Il13ra1 Y/+ ) were evaluated at 16 weeks of stress and at 20 weeks, following a 4 week non-stressed period and compared to non-stressed mice. RESULTS: IL-13 was expressed in microglial cells within the SN and in a fraction of the tyrosine hydroxylase-positive neurons in the SNc. IL-13 levels were elevated during daily stress and peaked at 6 h. 16 weeks of chronic restraint stress significantly reduced the number of SNc dopaminergic neurons in Il13ra1 Y/+ mice. Neuronal loss at 16 weeks was significantly lower in Il13ra1 Y/- mice. However, the loss of dopaminergic neurons measured at 20 weeks, after 4 weeks of non-stress following the 16 weeks of stress, was similar in Il13ra1 Y/+ and Il13ra1 Y/- mice. CONCLUSIONS: IL-13, a cytokine previously demonstrated to increase the susceptibility of SNc dopaminergic neurons to oxidative stress, is elevated in the SN by restraint stress. Lack of IL-13Rα1 did not prevent nor halted but delayed neuronal loss in the mouse model of chronic restraint stress. IL-13/IL-13Rα1 may represent a target to reduce the rate of DA neuronal loss that can occur during severe chronic restraint stress.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/deficiência , Estresse Oxidativo/fisiologia , Estresse Psicológico/metabolismo , Animais , Contagem de Células/métodos , Neurônios Dopaminérgicos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Psicológico/patologia , Substância Negra/metabolismo , Substância Negra/patologia
5.
Brain Sci ; 6(2)2016 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-27304970

RESUMO

The cytokines interleukin 13 and 4 share a common heterodimeric receptor and are important modulators of peripheral allergic reactions. Produced primarily by T-helper type 2 lymphocytes, they are typically considered as anti-inflammatory cytokines because they can downregulate the synthesis of T-helper type 1 pro-inflammatory cytokines. Their presence and role in the brain is only beginning to be investigated and the data collected so far shows that these molecules can be produced by microglial cells and possibly by neurons. Attention has so far been given to the possible role of these molecules in neurodegeneration. Both neuroprotective or neurotoxic effects have been proposed based on evidence that interleukin 13 and 4 can reduce inflammation by promoting the M2 microglia phenotype and contributing to the death of microglia M1 phenotype, or by potentiating the effects of oxidative stress on neurons during neuro-inflammation. Remarkably, the heterodimeric subunit IL-13Rα1 of their common receptor was recently demonstrated in dopaminergic neurons of the ventral tegmental area and the substantia nigra pars compacta, suggesting the possibility that both cytokines may affect the activity of these neurons regulating reward, mood, and motor coordination. In mice and man, the gene encoding for IL-13Rα1 is expressed on the X chromosome within the PARK12 region of susceptibility to Parkinson's disease (PD). This, together with finding that IL-13Rα1 contributes to loss of dopaminergic neurons during inflammation, indicates the possibility that these cytokines may contribute to the etiology or the progression of PD.

6.
J Neurosci ; 36(18): 5170-80, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27147667

RESUMO

UNLABELLED: The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons. SIGNIFICANCE STATEMENT: Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.


Assuntos
Comportamento Alimentar/fisiologia , Interleucina-18/fisiologia , Núcleos Septais/fisiologia , Animais , Fenômenos Eletrofisiológicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Interleucina-18/biossíntese , Interleucina-18/genética , Subunidade alfa de Receptor de Interleucina-18/genética , Subunidade alfa de Receptor de Interleucina-18/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Proteínas Recombinantes/farmacologia , Sinapses/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia
7.
Elife ; 5: e12345, 2016 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-26779719

RESUMO

Metabolic specialization among major brain cell types is central to nervous system function and determined in large part by the cellular distribution of enzymes. Serine hydrolases are a diverse enzyme class that plays fundamental roles in CNS metabolism and signaling. Here, we perform an activity-based proteomic analysis of primary mouse neurons, astrocytes, and microglia to furnish a global portrait of the cellular anatomy of serine hydrolases in the brain. We uncover compelling evidence for the cellular compartmentalization of key chemical transmission pathways, including the functional segregation of endocannabinoid (eCB) biosynthetic enzymes diacylglycerol lipase-alpha (DAGLα) and -beta (DAGLß) to neurons and microglia, respectively. Disruption of DAGLß perturbed eCB-eicosanoid crosstalk specifically in microglia and suppressed neuroinflammatory events in vivo independently of broader effects on eCB content. Mapping the cellular distribution of metabolic enzymes thus identifies pathways for regulating specialized inflammatory responses in the brain while avoiding global alterations in CNS function.


Assuntos
Encéfalo/enzimologia , Proteômica , Serina Endopeptidases/análise , Animais , Astrócitos/química , Lipase Lipoproteica/análise , Camundongos , Microglia/química , Neurônios/química
8.
Proc Natl Acad Sci U S A ; 113(1): 26-33, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26668358

RESUMO

Diacylglycerol lipases (DAGLα and DAGLß) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.


Assuntos
Ácidos Araquidônicos/metabolismo , Encéfalo/efeitos dos fármacos , Diglicerídeos/metabolismo , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Glicerídeos/metabolismo , Lipase Lipoproteica/antagonistas & inibidores , Plasticidade Neuronal/efeitos dos fármacos , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Inibidores Enzimáticos/química , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Canabinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
PLoS One ; 10(8): e0134437, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26287872

RESUMO

Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1ß-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Febre/tratamento farmacológico , Febre/enzimologia , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Animais , Temperatura Corporal , Moduladores de Receptores de Canabinoides/uso terapêutico , Febre/genética , Febre/metabolismo , Deleção de Genes , Masculino , Camundongos , Monoacilglicerol Lipases/genética , Receptor CB1 de Canabinoide/antagonistas & inibidores
10.
Clin Exp Rheumatol ; 31(2 Suppl 76): 3-7, 2013 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23910606

RESUMO

Systemic sclerosis or scleroderma (SSc) is a clinically heterogeneous disease of the connective tissue characterised by vascular, immune/inflammatory and fibrotic manifestations. Despite extensive investigations, the key pathogenic links between these disease hallmarks remain obscure, as well as the etiology underlying the beginning of this complex disorder. As for other diseases characterised by prominent autoimmune phenomena, the search for infectious agents responsible for immune tolerance breaks or molecular mimicry events has been a long-pursued issue. In this review, we summarise the current knowledge regarding the association of different viral infections with SSc, focusing mainly on those reports describing a mechanistic interplay between the viral agents and the pathogenesis of SSc. Moreover, we speculate on how viral infections may trigger additional pathogenic mechanisms recently proposed to contributing to SSc phenotype.


Assuntos
Infecções por Citomegalovirus/complicações , Infecções por Parvoviridae/complicações , Parvovirus B19 Humano , Escleroderma Sistêmico/virologia , Autoimunidade/imunologia , Infecções por Citomegalovirus/imunologia , Humanos , Infecções por Parvoviridae/imunologia , Escleroderma Sistêmico/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA