RESUMO
The issue of soil contamination by heavy metals is widely acknowledged. Some plants, including medicinal species like St. John's wort (Hypericum perforatum L.), exhibit accumulation traits, allowing them to accumulate elevated levels of metals, e.g., cadmium (Cd), within their cells. Selenium (Se) may increase the tolerance of plants to abiotic stress caused by the presence of heavy metal in the environment. Depending on its form (oxidation state, organic/inorganic), Se influences plant growth, secondary metabolite content, and biotic stress, as well as incorporates into shoots, providing economic and health benefits for consumers. So far, there are no data on the influence of organic Se(IV) on plants. Our study aimed to determine the effect of organic Se(IV) on the growth, active compound levels (anthranoids, polyphenols), and ultrastructure of St. John's wort without and under cadmium stress. The phytochemical analysis and microscopic examination was performed on shoots from different days of St. John's wort in vitro culture on a few variants of Murashige and Skoog medium with Cd (25 and 400 µM) and/or organic Se (IV). Exposure to Se(IV) did not affect hypericins but increased the polyphenol content in the shoots and the biomass. Se(IV) caused an increase in starch grain number in chloroplasts, whereas Cd exposure resulted in the degradation of the chloroplast structure, increased cell vacuolation, as well as swollen mitochondrial cristae. The addition of Se(IV) to these combinations reduced the degree of degradation and growth inhibition and a high content of Se(IV) in plants was observed. Se(IV) had no impact on Cd content at environmental Cd concentrations, but showed an effect at extremely high Cd concentrations. Thus, organic Se(IV) has a beneficial effect on St. John's wort growth, polyphenol content, and incorporation in shoots and prevents Cd toxicity. Media enriched with organic Se(IV) have both economic advantages and health benefits due to a higher plant growth rate and increased concentrations of polyphenols with strong antioxidant properties, relatively enriched with Se. However, organic Se(IV) should be used with caution in polluted areas. In perspective, speciation analysis and molecular study are crucial to understand the fate and effect of Se (IV) on plants.
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INTRODUCTION AND OBJECTIVE: Hazel, alder, birch, and poplar pollen allergens are a common cause of pollen allergies. In a temperate climate, wind-pollinated plants are characterized by a seasonal pollen release cycle associated with the seasons of the year and weather conditions. Therefore, the aim of the present study was to assess the course of pollen seasons of some allergenic plants and to determine the effect of meteorological factors on the content of pollen grains in the bioaerosol in 2021 in Kielce, Poland. MATERIAL AND METHODS: In relation to selected meteorological parameters, the length of the total and main pollen season, the sum of daily pollen grain concentrations in the season, the peak pollen concentration, and the number of days with values exceeding the species-specific threshold concentrations, were determined. RESULTS: Hazel and alder pollen were the first to appear in the air of Kielce. The longest pollen season was observed for birch, while hazel was characterized by the shortest season. The alder pollen release was intense, with the highest maximum concentration of pollen grains. The study revealed a significant influence of the maximum air temperature on the dynamics of hazel, alder and poplar pollen release. Birch pollen release was significantly correlated with the average air humidity. The concentration of alder and birch pollen grains also depended on rainfall intensity. The wind force had a significant impact on the pollen season of plants. CONCLUSIONS: There were various relationships between the meteorological factors and the content of pollen grains in the air. The wind speed and temperature had the greatest impact on plant pollen release, with birch and alder being particularly sensitive to weather conditions.
Assuntos
Alnus , Betula , Estações do Ano , Polônia , Pólen , Alérgenos , Conceitos MeteorológicosRESUMO
Many species of fungi including lichenized fungi (lichens) and algae have the ability to biosynthesize biologically active compounds. They produce, among others, polysaccharides with anticancer and immunostimulatory properties: (1) Background: This paper presents the characteristics of the most important bioactive compounds produced by fungi and algae; (2) Methods: Based on the example of the selected species of mushrooms, lichens and algae, the therapeutic properties of the secondary metabolites that they produce and the possibilities of their use are presented; (3) Results: The importance of fungi, especially large-fruited mushrooms, lichens and algae, in nature and human life is discussed, in particular, with regard to their use in the pharmaceutical industry and their nutritional value; (4) Conclusions: The natural organisms, such as fungi, lichenized fungi and algae, could be used as supplementary medicine, in the form of pharmaceutical preparations and food sources. Further advanced studies are required on the pharmacological properties and bioactive compounds of these organisms.
Assuntos
Clorófitas , Fungos , Valor Nutritivo , Compostos Fitoquímicos/administração & dosagem , Agaricales , Antioxidantes/administração & dosagem , Carotenoides/administração & dosagem , Dieta/métodos , Flavonoides/administração & dosagem , Humanos , Líquens , Polifenóis/administração & dosagem , Polissacarídeos/administração & dosagemRESUMO
BACKGROUND: Polydatin (PD) is a compound, originally isolated from the root and rhizome of the Chinese herb Polygonum cuspidatum. To date, various biological properties of this compound, such as analgesic, anti-pyretic or diuretic effects, have been shown. Recently, anti-oxidant and anti-inflammatory properties have been widely postulated, yet PD instability and low bioavailability limit its beneficial actions. Therefore, it has been suggested that an encapsulation process may be a promising strategy for overcoming these limitations and increasing the therapeutic efficacy of PD. METHODS: We examined the effects of PD in two forms, including free and in PD-loaded polymeric nanocapsules, on lipopolysaccharide (LPS)-induced changes in hippocampal organotypic cultures. RESULTS: Our results indicated that free and encapsulated PD diminished cell death processes and attenuated the secretion of pro-inflammatory cytokines induced by LPS administration. Additionally, PD in both forms strongly inhibited the production of nitric oxide and down-regulated the level of iNOS enzyme in LPS-stimulated hippocampal cultures. CONCLUSION: Taken together, our study showed that PD exerts anti-inflammatory and anti-oxidant properties in LPS-treated hippocampal organotypic cultures. Furthermore, we show that the encapsulation procedure preserved the features of the free form of this compound, and therefore, the polymeric nanocapsules containing PD may be used as a novel and promising delivery system in therapeutic strategies.
Assuntos
Anti-Inflamatórios/farmacologia , Glucosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Nanocápsulas/química , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Glucosídeos/química , Glucosídeos/toxicidade , Hipocampo/imunologia , Hipocampo/patologia , Nanocápsulas/toxicidade , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/toxicidade , Ratos Sprague-Dawley , Estilbenos/química , Estilbenos/toxicidade , Propriedades de Superfície , Técnicas de Cultura de Tecidos , Testes de ToxicidadeRESUMO
BACKGROUND: In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex - brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions. METHODS: Adult male PS rats were subjected to acute stress and/or received orally glucose. Levels of hormones and their receptors were assayed with ELISA method. In vitro studies were performed on mHypoA-2/12 hypothalamic cell line, stably transfected with CRH promoter coupled with luciferase. RESULTS: PS has reduced GLP-1 and GLP-1R levels, attenuated glucose-induced increase in insulin concentration and increased the amount of phosphorylated IR in the hypothalamus of animals subjected to additional stress stimuli, and also decreased the GLP-1R level in the hippocampus. In vitro studies demonstrated that insulin is capable of increasing CRH promoter activity in the condition of stimulation of the cAMP/PKA pathway in the applied cellular model. CONCLUSION: Prenatal stress may act as a preconditioning factor, affecting the concentrations of hormones such as insulin and GLP-1 in the hypothalamus in response to adverse stimuli. The decreased GLP-1R level in the hippocampus could be linked with the disturbances in neuronal plasticity.
Assuntos
Depressão/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Animais , Linhagem Celular , Hormônio Liberador da Corticotropina/genética , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Exenatida/metabolismo , Feminino , Glucose/metabolismo , Masculino , Camundongos , Plasticidade Neuronal/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Regiões Promotoras Genéticas/genética , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/fisiopatologiaRESUMO
An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia's viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1ß, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-ß, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark.
Assuntos
Antidepressivos Tricíclicos/farmacologia , Inflamassomos/metabolismo , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tiazepinas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Benzophenones used as UV filters, in addition to the effects on the skin, can be absorbed into the blood and affect the function of certain organs. So far, their effects on the sex hormone receptors and gonadal function have been studied, but not much is known about their potential action on other systems. The aim of the present study was to determine the effect of benzophenone-2 (BP-2) on immune system activity, hypothalamic-pituitary-thyroid (HPT) axis activity and hematological parameters. BP-2 was administered dermally, twice daily at a dose of 100â¯mg/kg for 4-weeks to male Wistar rats. Immunological and hematological parameters and HPT axis activity were assayed 24â¯h after the last administration. It was found that BP-2 did not change relative weights of the thymus and spleen and did not exert toxic effect on tymocytes and splenocytes. However, this compound increased proliferative activity of splenocytes, enhanced metabolic activity of splenocytes and thymocytes and nitric oxide production of these cells. In animals exposed to BP-2, the HPT axis activity was increased, as evidenced by reduction in the thyroid stimulating hormone (TRH) level and increase in free fraction of triiodothyronine (fT3) and thyroxin (fT4) in blood. BP-2 had no effect on leukocyte, erythrocyte and platelet counts or on morphology and hemoglobin content in erythrocytes. The conducted research showed that dermal, sub-chronic BP-2 administration evoked hyperthyroidism, increased activity or function of the immune cells but did not affect hematological parameters. We suggest that topical administration of BP-2 leading to a prolonged elevated BP-2 level in blood causes hyperthyroidism, which in turn may be responsible for the increased immune cell activity or function. However, only future research can explain the mechanism and functional importance of the changes in thyroid hormones and immunological parameters observed after exposure to BP-2.
Assuntos
Benzofenonas/toxicidade , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/imunologia , Hormônios Tireóideos/imunologia , Administração Cutânea , Animais , Benzofenonas/administração & dosagem , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Masculino , Ratos , Ratos Wistar , Hormônios Tireóideos/metabolismoRESUMO
BACKGROUND: Alteration in the brain mitochondrial functions have been suggested to participate, as a relevant factor, in the development of mental disorders. Therefore, the brain mitochondria may be a crucial therapeutic target in the course of depression. METHODS: Our goal was to find out the impact of two antidepressant drugs with various mechanisms of action - imipramine and fluoxetine, on the frontal cortex mitochondria-enriched fraction in an animal model of depression based on the prenatal stress procedure. RESULTS: Our results confirmed that the prenatal stress caused depressive-like disturbances in the adult offspring rats, which were normalized by the chronic imipramine and fluoxetine administration. For the first time, using 2D-LC-MS/MS, we demonstrated nine differentially expressed proteins after the imipramine administration. Of these proteins, the up-regulation of the 2',3'-cyclic-nucleotide 3'-phosphodiesterase enzyme and down-regulation of the Hypoxanthine-guanine phosphoribosyltransferase (HPRT), Ras-related proteins (Rap-1A and Rap-1B) and Transgelin-3 (NP25) were the most striking. In contrast, after the chronic fluoxetine treatment, we observed differential expression in five proteins, including the enhanced expression of component of pyruvate dehydrogenase complex and diminished of Glutathione S-transferase P (Gstp-1), as well as Maleylacetoacetate isomerase. CONCLUSIONS: These results overcome the interesting data that brain mitochondria in the frontal cortex may constitute the target for pharmacotherapy. The multifaceted profile of both antidepressant drugs action makes difficult to elucidate the exact mechanism of imipramine and fluoxetine action in the brain mitochondria. Further study of mitochondrial dysfunction in psychiatric disorders will be base to know the possible biological consequences of our observations.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Lobo Frontal/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Proteoma/metabolismo , Animais , Depressão/metabolismo , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Lobo Frontal/metabolismo , Imipramina/farmacologia , Masculino , Mitocôndrias/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteômica/métodos , Ratos , Ratos Sprague-DawleyRESUMO
The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8+ and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats.
Assuntos
Adenocarcinoma/complicações , Adenocarcinoma/secundário , Desipramina/farmacologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/secundário , Estresse Psicológico/complicações , Animais , Antidepressivos/farmacologia , Linhagem Celular Tumoral , Subpopulações de Linfócitos/efeitos dos fármacos , Masculino , Ratos , Ratos EndogâmicosRESUMO
Formyl peptide receptor2 (FPR2) is a G-protein coupled receptor that plays critical roles in inflammatory reactions. FPR2-specific interaction can be possibly used to facilitate the resolution of pathological inflammatory responses by enhancing endogenous anti-inflammation systems. Starting from our lead agonist 5, we designed new ureidopropanamides derivatives able to activate FPR2 in transfected cells and human neutrophils. The new FPR2 agonists showed good stability towards oxidative metabolism in vitro. Moreover, selected compounds showed anti-inflammatory properties in LPS-stimulated rat primary microglial cells. (S)-3-(4-Cyanophenyl)-N-[[1-(3-chloro-4-fluorophenyl)cyclopropyl]methyl]-2-[3-(4-fluorophenyl)ureido]propanamide ((S)-17) emerged as prospective pharmacological tool to study the effects of FPR2 activation in the central nervous system (CNS) being able to reduce IL-1ß and TNF-α levels in LPS-stimulated microglial cells and showing good permeation rate in hCMEC/D3 cells, an in vitro model of blood brain barrier. These results are very promising and can open new therapeutic perspectives in the treatment of CNS disorders characterized by neuroinflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Receptores de Lipoxinas/agonistas , Uridina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Barreira Hematoencefálica/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doenças do Sistema Nervoso Central/metabolismo , Relação Dose-Resposta a Droga , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Ratos , Ratos Sprague-Dawley , Receptores de Lipoxinas/metabolismo , Relação Estrutura-Atividade , Uridina/síntese química , Uridina/químicaRESUMO
An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-ß, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-ß signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.
RESUMO
CXCL12/SDF-1α and CX3CL1/fractalkine are constitutively expressed in the brain, which indicates their significant functions. Emerging evidence highlights the role of astrocytes and the immune system in the pathophysiology of stress-related disorders. The aim of this study was to assess whether prenatal stress affects chemokine signaling, cell viability/activation, and the iNOS pathway in astroglial cultures. Our results showed that prenatal stress lowered astrocyte viability and simultaneously increased GFAP expression. Furthermore, CX3CL1 production and the CXCL12/CXCR4-7 axis were also altered by prenatal stress. Taken together, malfunctions caused by prenatal stress may adversely influence brain development, leading to long-term effects on adult brain function and behavior.
Assuntos
Astrócitos/metabolismo , Quimiocinas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais/fisiologia , Estresse Psicológico/patologia , Animais , Animais Recém-Nascidos , Astrócitos/imunologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Córtex Cerebral/patologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocinas/genética , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , L-Lactato Desidrogenase/metabolismo , Óxido Nítrico/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Regulação para Cima/fisiologiaRESUMO
Several lines of evidence indicate that adverse experience in early life may be a triggering factor for disturbances in the brain mitochondrial proteins and lead to the development of depression in adulthood. On the other hand, little is known about the impact of chronic administration of various antidepressant drugs on the brain mitochondria, as a target for the pharmacotherapy of depression. The purpose of our study was to compare the impact of chronic treatment with two antidepressant drugs with different mechanisms of action, a tricyclic antidepressant (TCA), imipramine, and an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, fluoxetine, on the mitochondria-enriched subproteome profile in the hippocampus of 3-month-old male rats following a prenatal stress procedure (an animal model of depression). We clearly confirmed that chronic imipramine and fluoxetine administration not only normalized depression-like disturbances evoked by the prenatal stress procedure but also modulated the mitochondria-enriched subproteome profile in the hippocampus of adult offspring rats. In line with this, two-dimensional electrophoresis coupled with mass spectrometry showed a statistically significant down-regulation of 14-3-3 and cytochrome bc1 proteins and an up-regulation of COP9 signalosome expression after chronic imipramine treatment in the hippocampus of prenatally stressed offspring. Fluoxetine administration strongly up-regulated the expression of cathepsin D, one of the key proteins involved in the prevention of the development of neurodegenerative processes. Furthermore, this antidepressant treatment enhanced expression of proteins engaged in the improvement of learning and memory processes (STMN1, Dnm-1) as well as in mitochondrial biogenesis and defense against oxidative stress (DJ-1). These findings provide new evidence that chronic administration of antidepressants exerts a varied impact on the mitochondria-enriched subproteome in the hippocampus of adult rats following a prenatal stress procedure. In particular, the effect of fluoxetine requires additional experiments to elucidate the possible beneficial biological consequences underlying the effects mediated by this antidepressant.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Fluoxetina/farmacologia , Hipocampo/citologia , Imipramina/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Proteínas 14-3-3/metabolismo , Animais , Antidepressivos/uso terapêutico , Complexo do Signalossomo COP9/metabolismo , Catepsina D/metabolismo , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Dinaminas/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Fluoxetina/uso terapêutico , Imipramina/uso terapêutico , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Proteína Desglicase DJ-1/metabolismo , Proteômica , Ratos , Estatmina/metabolismo , Estresse PsicológicoRESUMO
Some antidepressants show a significantly lower efficacy in elderly patients, particularly in women. Previous studies have shown that antidepressants administered to young animals reduced depression-like symptoms induced by lipopolysaccharide (LPS). The aim of this study was to find out whether the antidepressant and anti-inflammatory properties of fluoxetine (FLU) can be observed also in old female C57BL/6J mice. A depression-like state was evoked by the administration of LPS (100µg/kg for 4 consecutive days) which was followed by reduction of sucrose preference (anhedonia) and enhancement of immobility-time in the forced swim test (FST). Animals, which received FLU (10mg/kg, 11days) exhibited a decreased LPS-induced expression of some inflammatory cytokines in the hippocampus and spleen but this effect was not accompanied by beneficial changes in animals' behavior. Despite the lack of antidepressant-properties of FLU in this model, our studies have proven significant profound anti-inflammatory properties of chronic FLU treatment which may suggest its suitability for fending off inflammatory processes in the elderly.
Assuntos
Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Citocinas/imunologia , Depressão/imunologia , Fluoxetina/farmacologia , Envelhecimento/imunologia , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Citocinas/genética , Depressão/tratamento farmacológico , Feminino , Fluoxetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
A growing body of evidence supports the involvement of disturbances in the brain insulin pathway in the pathogenesis of depression. On the other hand, data concerning the impact of antidepressant drug therapy on brain insulin signaling remain scare and insufficient. We determinated the influence of chronic treatment with antidepressant drugs (imipramine, fluoxetine and tianeptine) on the insulin signaling pathway of the brain of adult prenatally stressed rats. 3-month-old prenatally stressed and control rats were treated for 21 days with imipramine, fluoxetine or tianeptine (10mg/kg/day i.p.).The impact of chronic antidepressant administration was examined in forced swim test. In the frontal cortex and hippocampus, the mRNA and protein expression of insulin, insulin receptor, insulin receptor substrates (IRS-1,IRS-2) and adaptor proteins (Shc1, Grb2) before and after drugs administration were measured.Rats exposed prenatally to stressful stimuli displayed depressive-like disturbances, which were attenuated by antidepressant drug administration. We did not reveal the impact of prenatal stress or antidepressant treatment on insulin and the insulin receptor expression in the examined structures. We revealed that diminished insulin receptor phosphorylation evoked by the prenatal stress procedure was attenuated by drugs treatment. We demonstrated that the favorable effect of antidepressans on insulin receptor phosphorylation in the frontal cortex was mainly related with the normalization of serine312 and tyrosine IRS-1 phosphorylation, while in the hippocampus, it was related with the adaptor proteins Shc1/Grb2. It can be suggested that the behavioral effectiveness of antidepressant drug therapy may be related with the beneficial impact of antidepressant on insulin receptor phosphorylation pathways.
Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal , Receptor de Insulina/metabolismo , Estresse Psicológico , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Transtorno Depressivo/etiologia , Transtorno Depressivo/metabolismo , Feminino , Fluoxetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Imipramina/farmacologia , Insulina/metabolismo , Fosforilação/efeitos dos fármacos , Gravidez , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Tiazepinas/farmacologiaRESUMO
The repeated administration of microglial inhibitor (minocycline) and CCR2 antagonist (RS504393) attenuated the neuropathic pain symptoms in rats following chronic constriction injury of the sciatic nerve, which was associated with decreased spinal microglia activation and the protein level of CCL2 and CCR2. Furthermore, in microglia primary cell cultures minocycline downregulated both CCL2 and CCR2 protein levels after lipopolysaccharide-stimulation. Additionally, in astroglia primary cell cultures minocycline decreased the expression of CCL2, but not CCR2. Our results provide new evidence that modulation of CCL2/CCR2 pathway by microglial inhibitor as well as CCR2 antagonist is effective for neuropathic pain development in rats.
Assuntos
Analgésicos/uso terapêutico , Quimiocina CCL2/metabolismo , Receptores CCR2/metabolismo , Ciática/tratamento farmacológico , Animais , Animais Recém-Nascidos , Benzodiazepinas/uso terapêutico , Benzoxazinas/uso terapêutico , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/uso terapêutico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Minociclina/farmacologia , Neuroglia/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Ratos , Ratos Wistar , Receptores CCR2/genética , Ciática/complicações , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Compostos de Espiro/uso terapêuticoRESUMO
Calcitriol (1,25-dihydroxyvitamin D3), an active metabolite of vitamin D3, besides the role in calcium and phosphorus metabolism, plays a role in maintaining the functions of the brain. Active forms of vitamin D3 stimulate neurotrophic factors' expression, regulate brain immune processes, and prevent neuronal damage. Therefore, a potential utility of vitamin D3 in a therapy of neurodegenerative disorders should be taken into account. On the other hand, systemic vitamin D3 treatment carries the risk of undesirable effects, e.g., hypercalcemia. Thus, 1,25-dihydroxyvitamin D3 targeting delivery by nanoparticles would be a tremendous advancement in treatment of brain disorders. Calcitriol was enclosed in emulsion-templated nanocapsules with different polymeric shells: PLL (Poly(L-lysine hydrobromide)), PLL/PGA (/Poly(L-glutamic acid)), and PLL/PGA-g-PEG (Poly(L-glutamic acid) grafted with polyethylene glycol). The average size of all synthesized nanocapsules ranged from -80 to -100 nm. Biocompatibilities of synthesized nanocarriers were examined in hippocampal organotypic cultures in basal conditions and after treatment with lipopolysaccharide (LPS) using various biochemical tests. We demonstrated that nanocapsules coated with PLL were toxic, while PLL/PGA- and PLL/PGA-g-PEG-covered ones were nontoxic and used for further experiments. Our study demonstrated that in LPS-treated hippocampal slices, both types of loaded nanoparticles have protective ability. Our findings underlined that the neuroprotective action of vitamin D3 in both free and nanoparticle forms seems to be related to the suppression of LPS-induced nitric oxide release.
Assuntos
Calcitriol/administração & dosagem , Hipocampo/efeitos dos fármacos , Nanocápsulas , Fármacos Neuroprotetores/administração & dosagem , Polieletrólitos , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Citometria de Fluxo , Ácido Glutâmico/química , Hipocampo/metabolismo , Hipocampo/patologia , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos , Nanocápsulas/química , Nanocápsulas/toxicidade , Óxido Nítrico/metabolismo , Tamanho da Partícula , Polieletrólitos/química , Polietilenoglicóis , Polilisina/análogos & derivados , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos , Testes de ToxicidadeRESUMO
The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1ß, IL-18, IL-6, TNF-α, CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain.
Assuntos
Quimiocina CX3CL1/metabolismo , Microglia/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores de Citocinas/metabolismo , Receptores de HIV/metabolismo , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Animais , Receptor 1 de Quimiocina CX3C , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Quimiocina CX3CL1/farmacologia , Feminino , Interleucinas/metabolismo , Microglia/efeitos dos fármacos , Óxido Nítrico/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos Sprague-Dawley , Receptores de Citocinas/genética , Receptores de HIV/genética , Estresse Psicológico/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Elevated levels of glucocorticoids exert neurotoxic effects, and the hippocampus is particularly sensitive to the effects of glucocorticoids. Because some data have indicated that an increased action of glucocorticoids in the perinatal period enhances the susceptibility of brain tissue to adverse substances later in life, the main purpose of the present study was to compare necrotic/apoptotic corticosterone action in hippocampal organotypic cultures obtained from control animals with the effect of this steroid in tissue from prenatally stressed rats. Because the adverse effects of glucocorticoid action on nerve cell viability appear to result mainly from an increase in the intensity of the effects of glutamate and changes in growth factor and pro-inflammatory cytokine synthesis, the involvement of these factors in corticosterone action were also determined. In stress-like concentration (1 µM), corticosterone, when added to hippocampal cultures for 1 and 3 days, alone or jointly with glutamate, did not induce necrosis. In contrast, in 3-day cultures, corticosterone (1 µM) increased caspase-3 activity and the mRNA expression of the pro-apoptotic Bax. Moreover, corticosterone's effect on caspase-3 activity was stronger in hippocampal cultures from prenatally stressed compared to control rats. Additionally, 24 h of exposure to corticosterone and glutamate, when applied separately and together, increased Bdnf, Ngf, and Tnf-α expression. In contrast, after 72 h, a strong decrease in the expression of both growth factors was observed, while the expression of TNF-α remained high. The present study showed that in stress-like concentrations, corticosterone exerted pro-apoptotic but not necrotic effects in hippocampal organotypic cultures. Prenatal stress increased the pro-apoptotic effects of corticosterone. Increased synthesis of the pro-inflammatory cytokine TNF-α may be connected with the adverse effects of corticosterone on brain cell viability.
Assuntos
Apoptose/fisiologia , Corticosterona/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3 , Sobrevivência Celular/fisiologia , Células Cultivadas , Corticosterona/toxicidade , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Ácido Glutâmico/toxicidade , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Masculino , Necrose/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/patologia , Gravidez , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Estresse Psicológico/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Several lines of evidence indicate that adverse experience in early life may be a triggering factor for pathological inflammatory processes and lead to the development of depression. Fractalkine (CX3CL1), a chemokine, plays an important role not only in the migration, differentiation and proliferation of neuronal and glial cells but also in the regulation of neuronal-microglial signaling and the production of pro-inflammatory factors. In the present study, we examined the impact of a prenatal stress procedure on the expression of fractalkine in the hippocampus and frontal cortex of young and adult male rats. Furthermore, we measured the age-dependent effect of stress during pregnancy on the expression of pro-inflammatory factors IL-1ß, IL-18, TNF-α, IL-6, and CCL2 in both brain structures. Next, to illustrate the link between fractalkine signaling and the behavioral and biochemical changes induced by prenatal stress, adult prenatally stressed offspring were injected intracerebroventricularly (icv) with exogenous fractalkine. We reported that prenatal stress leads to long-lasting deficits in fractalkine signaling and enhanced inflammatory activation. The study demonstrates that icv administration of fractalkine attenuates the behavioural changes evoked by prenatal stress procedure in adult animals. Moreover, fractalkine administration, exhibits anti-inflammatory action, mainly in the frontal cortex of adult prenatally stressed rats. The effect of fractalkine is related to inhibition of NLRP3 inflammasome. However, its action on the other members of NOD-like receptor family (NLR) cannot be excluded. These findings provide new in vivo evidence that the behavioral and inflammatory disturbances observed in adult prenatally stressed rats may be related to long-lasting malfunctions in fractalkine signaling.