RESUMO
G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1ß and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1ß. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions.
Assuntos
Ácidos Graxos Ômega-3 , Microglia , Receptores Acoplados a Proteínas G , Adulto , Animais , Humanos , Camundongos , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Doenças Neuroinflamatórias , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.
Assuntos
Encefalopatias , Transtorno Depressivo Maior , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Transtorno Depressivo Maior/metabolismo , Depressão , Encefalopatias/patologia , Camundongos Endogâmicos BALB C , Permeabilidade Capilar/fisiologiaRESUMO
The incidence of depression and anxiety is amplified by obesity. Mounting evidence reveals that the psychiatric consequences of obesity stem from poor diet, inactivity, and visceral adipose accumulation. Resulting metabolic and vascular dysfunction, including inflammation, insulin and leptin resistance, and hypertension, have emerged as key risks to depression and anxiety development. Recent research advancements are exposing the important contribution of these different corollaries of obesity and their impact on neuroimmune status and the neural circuits controlling mood and emotional states. Along these lines, this review connects the clinical manifestations of depression and anxiety in obesity to our current understanding of the origins and biology of immunometabolic threats to central nervous system function and behavior.
Assuntos
Ansiedade , Depressão , Depressão/epidemiologia , Depressão/etiologia , Depressão/metabolismo , Humanos , Inflamação/metabolismo , Obesidade/complicações , Obesidade/epidemiologia , PrevalênciaRESUMO
Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1âRAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1âERK1/2âJNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.
Assuntos
Anti-Inflamatórios/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Trimebutina/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Quimiocinas/metabolismo , Feminino , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Receptor para Produtos Finais de Glicação Avançada/deficiência , Receptor para Produtos Finais de Glicação Avançada/genética , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , Trimebutina/uso terapêuticoRESUMO
The Hatano strains of the Sprague Dawley rats have been selectively bred to create high- (HAA) and low- (LAA) active avoidance variants. We previously reported that HAA rats display more anxiety-related behavior than LAA rats, but whether this strain difference is affected by postnatal environmental factors remains unclear. In this study, we performed in- and cross-fostering between the HAA and LAA strains and investigated the effect of postnatal maternal traits on the emotional responses in each strain of the male offspring. We evaluated the effect of the fostering treatment on the emotional responses of the male offspring using the elevated plus maze test. The male LAA offspring reared by HAA dam showed higher anxiety-related behavior than those reared by LAA dam. Next, we quantified and typed various maternal behavior under the in- and cross-fostering conditions during the lactation period using a snapshot sampling method. This method allowed us to evaluate potential maternal traits that may influence the emotional responses of the offspring observed in our first experiment. We found that HAA dams showed long-term resting without offspring and offspring arrangement compared with LAA dams. These findings suggest that postnatal environmental factors may alter anxiety-related behavior in the male LAA offspring and that less direct contact with their offspring during the lactation period may induce anxiety-related behavior in male offspring.
Assuntos
Aprendizagem da Esquiva , Lactação , Animais , Ansiedade , Feminino , Humanos , Masculino , Comportamento Materno , Fenótipo , Ratos , Ratos Sprague-DawleyRESUMO
Extreme stress is closely linked with symptoms of depression. Chronic social stress can cause structural and functional changes in the brain. These changes are associated with dysfunction of neuroprotective signalling that is necessary for cell survival, growth, and maturation. Reduced neuronal numbers and volume of brain regions have been found in depressed patients, which may be caused by decreased cell survival and increased cell death. Elucidating the mechanism underlying the degeneration of the neuroprotective system in social stress-induced depression is important for developing neuroprotective measures. The Repressor Element 1 Silencing Transcription Factor (REST) also known as Neuron-Restrictive Silencing Factor (NRSF) has been reported as a neuroprotective molecule in certain neurological disorders. Decreased expression levels of REST/NRSF in the nucleus can induce death-related gene expression, leading to neuronal death. Under physiological stress conditions, REST/NRSF over expression is known to activate neuronal survival in the brain. Alterations in REST/NRSF expression in the brain has been reported in stressed animal models and in the post-mortem brain of patients with depression. Here, we highlight the neuroprotective function of REST/NRSF and discuss dysregulation of REST/NRSF and neuronal damage during social stress and depression.
Assuntos
Depressão/metabolismo , Transtorno Depressivo/metabolismo , Proteínas Repressoras/metabolismo , Estresse Psicológico/metabolismo , Animais , Depressão/genética , Transtorno Depressivo/genética , Humanos , Neurônios/metabolismo , Proteínas Repressoras/genética , Estresse Psicológico/genéticaRESUMO
We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.
Assuntos
Proteína HMGB1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Trimebutina/farmacologia , Animais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Janus Quinases/antagonistas & inibidores , Macrófagos , Camundongos , Papaverina/química , Papaverina/farmacologia , Células RAW 264.7 , Trimebutina/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Previous studies have suggested the potential efficacy of middle chain fatty acids (MCFAs) in the treatment of mood disorders and cognitive dysfunction. MCFAs are metabolized to ketone bodies in astrocytes; however, their effects on neuronal development including neurotrophic factor level are not well-understood. In the present study, we examined the effect of MCFAs on the mRNA expression of growth factors and cytokines in primary cultures of cortical astrocytes. The effect of MCFAs on neuron-astrocyte interaction in neuronal maturation was also determined using co-culture and astrocyte-conditioned medium. Lauric acid (LA) typically increased the mRNA expression of glial-derived neurotrophic factor (Gdnf), interleukin-6 (Il6), and C-C motif chemokine 2 (Ccl2) in astrocytes. LA-induced phosphorylation of extracellular signal-regulated kinase contributed to these changes. In primary cultures of cortical neurons containing astrocytes, LA enhanced the presynaptic protein levels. Astrocyte-conditioned medium after LA treatment also enhanced the presynaptic protein levels in the cortical neuron cultures. These results suggest that LA increase the mRNA expression of GDNF and cytokines in astrocytes, and thereby, enhances the presynaptic maturation.
RESUMO
Repressor element-1 silencing transcription factor (REST) is highly expressed in the dorsal raphe where serotonin (5-hydroxytryptamine, 5-HT) neurons are located. REST works as a transcription factor for the 5-HT receptor and tryptophan hydroxylase two-gene expression. We hypothesized that REST is co-expressed in 5-HT neurons, which, if demonstrated, would be useful to understand the mechanism of 5-HT dysfunction-related disorders such as negative emotions and depression. Therefore, the present study was designed to examine the expression of the REST gene in the brain (forebrain, midbrain, and hindbrain) of adult male Nile tilapia (Oreochromis niloticus) using rt-PCR. Besides, using immunocytochemistry, co-localization of the REST gene was examined in 5-HT neurons and with neuronal-/glial-cell markers. We found a high expression of the REST gene in the midbrain region of the dorsal raphe, an area of 5-HT neurons. Double-label immunocytochemistry showed neuron-specific expression of REST co-localized in 5-HT neurons in the dorsal and ventral parts of the periventricular pretectal nucleus, paraventricular organ, and dorsal and medial raphe nucleus. Since midbrain 5-HT neurons express REST, we speculate that REST may control 5-HT neuronal activity related to negative emotions, including depression.
RESUMO
BACKGROUND: Obesity is considered to be a risk factor for neurodegenerative- and psychiatric- diseases including Alzheimer's disease, schizophrenia, and depression. A high-lard diet is widely used to induce obesity in model animal experiments, which also leads to anxiety-like and depression-like behaviors. However, the contribution of dietary fat source to these abnormal behaviors in obesity is largely unknown. METHODS: Sprague-Dawley rats were treated with different types of high-fat (lard and olive oil) diet with high sucrose for more than 8 weeks. Anxiety-like behavior (open-field and social interaction tests) and cognitive function (Y-maze test) after the treatment were analyzed. The expression of mRNA related to neurotransmitter and nutrient transporters in the prefrontal cortex were determined using real-time PCR. Serum lipid species were determined using liquid chromatography with tandem mass spectrometry. RESULTS: Both high-fat/high-sucrose diets increased body weight (BW), adipose tissue, and serum leptin level. However, the high-lard/high-sucrose (HL/HS), but not high-olive oil/HS, diet induced anxiety-like behavior in open field and social interaction tests. BW and endocrine hormones such as leptin and insulin were not correlated to anxiety-like behavior. HL/HS diet induced an increase in glutamate transporter and a decrease of glutamate receptor mRNA expressions in the prefrontal cortex. Further, serum lysophosphatidyl choline conjugated with several fatty acids was decreased by HL/HS diet. LPC conjugated with eicosapentaenoic acid (EPA) was strongly correlated with anxiety-like behavior. CONCLUSIONS: These results suggest that lipid composition, rather than obesity per se, is a major cause of anxiety-like behavior in high-fat diet-induced obesity. Decreased levels of peripheral LPC conjugated with EPA and altered glutamate system in the prefrontal cortex might be involve in the pathophysiology of the behavioral change.
Assuntos
Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Ácidos Graxos/farmacologia , Lisofosfatidilcolinas/sangue , Obesidade/fisiopatologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologiaRESUMO
Astrocytes exhibit an important role in neural lipid metabolism for the regulation of energy balance to supply fatty acids (FAs) and ketone bodies to other neural cells. Lipid droplets (LDs) consisting of neutral- and phospho-lipids increase in the brains of patients with neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. However, the role of LDs and its lipid source remains largely unexplored. Here, we found that oleic acid (OA) was a potent inducer of astrocytic LD accumulation among various FAs. Lipidomic analysis using liquid chromatography equipped with tandem mass spectrometry revealed that the cellular triacylglycerol and phospholipid compositions in astrocytes during LD accumulation reflected the condition of extracellular FAs. Furthermore, the inhibition of diacylglycerol acyltransferase blocked OA-induced LD accumulation and caused lipotoxicity-induced cell death in astrocytes. The present study demonstrated that the formation of LDs, caused due to the increased extracellular OA, facilitated survival against lipotoxic condition.
Assuntos
Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Glicerol/metabolismo , Gotículas Lipídicas/metabolismo , Ácido Oleico/metabolismo , Animais , Esterificação , Metabolismo dos Lipídeos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos Endogâmicos ICR , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that contains a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. Using mouse models for multiple sclerosis (cuprizone-induced demyelination and experimental autoimmune encephalomyelitis) and traumatic brain injury, we revealed that cPA and its metabolically stabilized cPA derivative, 2-carba-cPA (2ccPA), have potential to protect against neuroinflammation. In this study, we investigated whether 2ccPA has anti-inflammatory effect on peripheral immune function or not using inflammation-induced macrophages-like cell line, THP-1 monocytes differentiated by phorbol 12-myristate 13-acetate (PMA). Lipopolysaccharide (LPS)-stimulated THP-1â¯cells were found to have higher expression of the mRNAs of several inflammation-related cytokines and of the enzyme cyclooxygenase-2 (Cox-2); however, when THP-1â¯cells were stimulated by LPS in the presence of 2ccPA, the increase in the expression of pro-inflammatory cytokine and Cox-2 mRNA was attenuated. 2ccPA treatment also decreased the amount of prostaglandin E2 (PGE2) produced by LPS-stimulated THP-1â¯cells and decreased expression of the mRNA of prostaglandin E receptor 2 (EP2, PTGER2), a PGE2 receptor that mediates inflammation. These results indicate that 2ccPA has anti-inflammatory properties.
RESUMO
The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic ß-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7â¯cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Proteína HMGB1/antagonistas & inibidores , Inflamação/tratamento farmacológico , Papaverina/uso terapêutico , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Feminino , Proteína HMGB1/imunologia , Inflamação/complicações , Inflamação/imunologia , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos ICR , Células RAW 264.7 , Receptor para Produtos Finais de Glicação Avançada/imunologia , Sepse/complicações , Sepse/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The study was aimed to compare the satiating effect of various protein hydrolysates in rats and examine the underlying mechanism associated with the satiety hormones. Food intake and portal satiety hormone levels were measured in rats. Enteroendocrine cell-lines were employed to study the direct effect of protein hydrolysates on gut hormone secretions. The results showed that oral preload of wheat gluten hydrolysate (WGH) suppressed food intake greater and longer than other hydrolysates. The portal peptide-YY levels in WGH-treated rats at 2 h and 3 h were higher than those in control- and lactalbumin hydrolysate (LAH)-treated rats. In a distal enteroendocrine cell model, WGH more potently stimulated glucagon-like peptide-1 secretion than LAH, and the effect was largely enhanced by pepsin/pancreatin digestion of WGH. These results suggest WGH is potent in activating enteroendocrine cells to release satiety hormones leading to the prolonged suppression of food intake.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Glutens/farmacologia , Peptídeo YY/metabolismo , Triticum/química , Animais , Linhagem Celular , Células Enteroendócrinas/efeitos dos fármacos , Hormônios Gastrointestinais/sangue , Hormônios Gastrointestinais/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glutens/metabolismo , Hidrólise , Masculino , Camundongos , Pancreatina/metabolismo , Pepsina A/metabolismo , Ratos Wistar , Saciação/efeitos dos fármacosRESUMO
Cyclic phosphatidic acid (cPA) is a simple lipid containing a fatty acid attached at the sn-1 position and a cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. The pharmacological effects of cPA have been demonstrated in several diseases such as cancer and neuropathic pain; however, the composition of the molecular species of cPA in relative to other lipid species in biological samples is still unclear. Recently, hydrophilic interaction liquid chromatography (HILIC) has demonstrated the ability to perform lipidomic analyses of biological samples. In the present study, we developed the quantitative measurement of cPA and its related lipid species, such as lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), in rat serum using HILIC equipped with tandem-mass spectrometry (MS/MS). The lipid analysis using HILIC-MS/MS system demonstrated high linearity and reproducibility. The modified Bligh and Dyer method using citric acid was showed high efficiency on the extraction of cPA and LPA without contamination of artificial products. In rat serum, cPA and LPC contained more saturated fatty acids such as palmitic acid and stearic acid than unsaturated fatty acids, whereas LPA and phosphatidylcholine more contained unsaturated fatty acids than saturated fatty acids. The analytical methods for measuring cPA and its related lipid species in the present study will aid the analysis of their metabolism.
Assuntos
Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Ácidos Fosfatídicos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Ácido Cítrico/química , Ácido Clorídrico/química , Lisofosfolipídeos/sangue , Masculino , Fosfatidilcolinas/sangue , Ratos Wistar , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
Prolonged and intense stress chronically increases blood concentration of glucocorticoids, which in turn causes downregulation of glucocorticoid receptor (GR) in the central nervous system (CNS). This process has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). Here, we found that basic fibroblast growth factor (bFGF) increased the expression of GR in the rat cerebral cortex and cultured cortical neurons and restored the reduced GR expression caused by glucocorticoid exposure. Among intracellular signaling pathways stimulated by bFGF, extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway was responsible for the upregulation of GR. The bFGF-induced GR was functional as a transcription factor to enhance transcription of a target gene. Because high stress augments bFGF levels in the brain, it is likely that bFGF plays a compensating role for reduced GR expression after stress and thus should be studied as a therapeutic target for the treatment of MDD.
Assuntos
Córtex Cerebral/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neurônios/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized-peptide strategy drug design system. Papaverine significantly inhibited RAGE-dependent nuclear factor κ-B activation driven by high mobility group box-1, a RAGE ligand. Using RAGE- or dominant-negative RAGE-expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE-dependent cell proliferation and migration dose-dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.
RESUMO
Lysophosphatidic acid (LPA) and cyclic phosphatidic acid (cPA) are one of the lipid mediators regulating cell proliferation and differentiation through the activation of LPA receptors. An LPA receptor-mediated signal is important for the development of the central nervous system, while it has been demonstrated that LPA caused microglial activation and astroglial dysfunction. Previously, we have reported that cPA and carba analog of cPA, 2-O-carba-cPA (2ccPA), protected neural damage caused by transient ischemia. However, little is known about the target cell of cPA/2ccPA in the central nervous systems. Here, we examined the effect of 2ccPA on glial proliferation and differentiation using the primary astrocytes and oligodendrocyte precursor cells (OPCs) cultures. 2ccPA increased the DNA synthesis of astrocytes and OPCs, but it did not reduce the formazan production in the mitochondria. Further, 2ccPA increased the cell number and cell survival against oxidative stress. The inhibition of LPA receptors by ki16425 abolished 2ccPA-induced DNA synthesis. Extracellular signal-regulated kinase (ERK) was activated by 2ccPA, which contributed to the astroglial DNA synthesis. These results suggest that 2ccPA is a beneficial regulator of glial population through the activation of LPA receptor without reduction of mitochondrial activity.
Assuntos
Astrócitos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Ácidos Fosfatídicos/administração & dosagem , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Astrócitos/metabolismo , Células Cultivadas , Lisofosfolipídeos/administração & dosagem , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Correct perinatal oestrogen levels are critical for sexual differentiation. For example, perinatal exposure to oestrogen causes masculinization and defeminization of the brain in female rats and also induces delayed effects after maturation characterized by early onset of abnormal oestrus cycling. However, the mechanisms underlying the above effects of oestrogen remain to be fully determined. 17α-ethinyloestradiol (EE), a common synthetic oestrogen widely used in oral contraceptives, binds specifically to oestrogen receptors. In this study, we demonstrated the effects of a single neonatal injection of high- or low-dose EE on reproductive behaviours. Female rats within 24 h after birth were subcutaneously injected with sesame oil, EE (0.02, 2 mg kg-1 ) and 17ß-oestradiol (E2 ) (20 mg kg-1 ). Between 11 and 15 weeks of age, sexual behaviour was tested twice in a paced mating situation. Latency to enter, lordosis and soliciting behaviour were recorded. Both high-dose EE- and E2 -treated females showed a significantly lower lordosis quotient, decreased soliciting behaviours, increased rejection and fighting numbers. Accessibility to males was also delayed by neonatal E2 exposure, although it was shortened by high-dose EE exposure. In contrast, low-dose EE-treated females did not exhibit impaired sexual behaviour. These results suggest that single neonatal exposure to a high dose of EE or E2 disturbs the normal development of the female brain, resulting in impaired sexual behaviours in a female-paced mating situation. Besides, the differences noted between high-dose EE- and E2 -treated females might be caused by different affinities of the oestrogen receptors, metabolic rates or mechanisms of action. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Estrogênios/toxicidade , Etinilestradiol/toxicidade , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Anticoncepcionais Orais , Relação Dose-Resposta a Droga , Estrogênios/administração & dosagem , Etinilestradiol/administração & dosagem , Feminino , Injeções Subcutâneas , Masculino , Ratos WistarRESUMO
Growing evidence suggests that excess glucocorticoids (GCs) exposure during the pregnancy results in behavioral abnormality in offspring. Although research using animal models has demonstrated that systemic GCs treatment impairs development of fetal brain, direct impact of GCs on the phenotype of embryonic neural stem/progenitor cells (eNSPCs) and its mechanism has not been fully understood. Here, we investigated the effect of chronic GCs exposure on cell proliferation, differentiation, and survival of eNSPCs in vitro. Corticosterone (CORT, a murine GC) treatment did not affect the proliferation of eNSPCs. On the other hand, decreased expression of neuronal, synaptic, and astroglial marker proteins were observed when the differentiation of eNSPCs was induced in the presence of CORT. CORT also reduced the survival rate of eNSPCs after the differentiation. Moreover, CORT inhibited extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling pathways, which were activated during cell differentiation of eNSPCs. Inhibiting these signaling pathways reduced neural differentiation and eNSPCs viability, indicating their essential roles in the eNSPCs differentiation. Furthermore, IGF-I, a potent PI3K/Akt and ERK signaling stimulator, partially restored the adverse effect of CORT on eNSPCs, suggesting a possible involvement of the repression of these intracellular signaling in the GCs-caused eNSPCs impairment.