RESUMO
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is important for maintenance of homeostasis during stress. Recent studies have shown a connection between the HPA axis and adipose tissue. The present study investigated the effect of acute heterotypic stress on plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), leptin, and ghrelin in adult male rats with respect to neonatal maternal social and physical stressors. Thirty rat mothers and sixty of their male progeny were used. Pups were divided into three groups: unstressed control (C), stressed by maternal social stressor (S), stressed by maternal social and physical stressors (SW). Levels of hormones were measured in adult male progeny following an acute swimming stress (10 min) or no stress. ELISA immunoassay was used to measured hormones. The ACTH and CORT levels were significantly increased in all groups of adult progeny after acute stress; however, CORT levels were significantly lower in both neonatally stressed groups compared to controls. After acute stress, plasma leptin levels were decreased in the C and SW groups but increased in the S group. The data suggest that long-term neonatal stressors lead to lower sensitivity of ACTH receptors in the adrenal cortex, which could be a sign of stress adaptation in adulthood. Acute stress in adult male rats changes plasma levels of leptin differently relative to social or physical neonatal stressors.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Corticosterona/sangue , Grelina/sangue , Leptina/sangue , Exposição Materna/efeitos adversos , Estresse Psicológico/sangue , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Temperatura Baixa/efeitos adversos , Feminino , Masculino , Ratos , Ratos Wistar , Estresse Fisiológico/fisiologia , Estresse Psicológico/etiologiaRESUMO
Patients with obesity and type 2 diabetes often display high levels of the anti-diabetic factor fibroblast growth factor-21 (FGF21), suggesting that the overproduction of FGF21 may result from increased adiposity in an attempt by white adipose tissue (WAT) to counteract insulin resistance. However, the production of FGF21 diabetes in the absence of WAT has not been examined. In this study, we investigated the effects of lipodystrophy in A-ZIP F-1 mice on FGF21 production in relation to diabetes. A-ZIP F-1 mice displayed high FGF21 plasma levels resulting from enhanced FGF21 mRNA expression in the liver. Concomitant enhancement of FGF21 receptor (FGFR1) and glucose transporter 1 (GLUT-1) mRNA expression was observed in the muscles of A-ZIP F-1 mice. Furthermore, the activation of hypothalamic NPY and AgRP mRNA expression positively correlated with plasma levels of FGF21 but not active ghrelin. Our study demonstrates that an increased FGF21 plasma level in lipodystrophic A-ZIP F-1 mice results mainly from up-regulated liver production but does not suffice to overcome the lipodystrophy-induced severe type 2-diabetes and insulin resistance in the liver linked to the augmented liver fat deposition.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Resistência à Insulina , Lipodistrofia/metabolismo , Fígado/metabolismo , RNA Mensageiro/biossíntese , Tecido Adiposo Marrom/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/biossíntese , Fatores de Crescimento de Fibroblastos/sangue , Hipotálamo/metabolismo , Camundongos , Neuropeptídeos/metabolismo , Pâncreas/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Baço/metabolismoRESUMO
The only peripherally released orexigenic hormone, ghrelin, plays a key role in food intake and body weight regulation. Antagonizing the ghrelin receptor, GHS-R1a, represents a promising approach for anti-obesity therapy. In our study, two novel GHS-R1a antagonists JMV4208 and JMV3002, which are trisubstituted 1,2,4-triazoles, decreased food intake in fasted lean mice in a dose-dependent manner, with ED50 values of 5.25 and 2.05 mg/kg, respectively. Both compounds were stable in mouse blood, with half-lives of 90 min (JMV4208) and 60 min (JMV3002), and disappeared from the blood 8h after administration. Fourteen days of treatment with the ghrelin antagonists (20 mg/kg twice a day) decreased food intake, body weight and adipose tissue mass in mice with diet-induced obesity (DIO). These results are likely attributable to an impact on food intake reduction and an attenuated expression of the lipogenesis-promoting enzymes (acetyl-CoA carboxylase 1 in subcutaneous fat and fatty acid synthase in subcutaneous and intraperitoneal fat). The decrease in fat mass negatively impacted circulating leptin levels. These data suggest that JMV4208 and JMV3002 could be useful therapeutic agents for the treatment of obesity.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Picolínicos/farmacologia , Receptores de Grelina/antagonistas & inibidores , Triazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Picolínicos/química , Triazóis/químicaRESUMO
Glucose is transported across the cell membrane by specific saturable transport system, which includes two types of glucose transporters: 1) sodium dependent glucose transporters (SGLTs) which transport glucose against its concentration gradient and 2) sodium independent glucose transporters (GLUTs), which transport glucose by facilitative diffusion in its concentration gradient. In the brain, both types of transporters are present with different function, affinity, capacity, and tissue distribution. GLUT1 occurs in brain in two isoforms. The more glycosylated GLUT1 is produced in brain microvasculature and ensures glucose transport across the blood brain barrier (BBB). The less glycosylated form is localized in astrocytic end-feet and cell bodies and is not present in axons, neuronal synapses or microglia. Glucose transported to astrocytes by GLUT1 is metabolized to lactate serving to neurons as energy source. Proinflammatory cytokine interleukin (IL)-1ß upregulates GLUT1 in endothelial cells and astrocytes, whereas it induces neuronal death in neuronal cell culture. GLUT2 is present in hypothalamic neurons and serves as a glucose sensor in regulation of food intake. In neurons of the hippocampus, GLUT2 is supposed to regulate synaptic activity and neurotransmitter release. GLUT3 is the most abundant glucose transporter in the brain having five times higher transport capacity than GLUT1. It is present in neuropil, mostly in axons and dendrites. Its density and distribution correlate well with the local cerebral glucose demands. GLUT5 is predominantly fructose transporter. In brain, GLUT5 is the only hexose transporter in microglia, whose regulation is not yet clear. It is not present in neurons. GLUT4 and GLUT8 are insulin-regulated glucose transporters in neuronal cell bodies in the cortex and cerebellum, but mainly in the hippocampus and amygdala, where they maintain hippocampus-dependent cognitive functions. Insulin translocates GLUT4 from cytosol to plasma membrane to transport glucose into cells, and GLUT8 from cytosol to rough endoplasmic reticulum to recover redundant glucose to cytosol after protein glycosylation. In autoimmune diseases, the enhanced glucose uptake was found in inflamed peripheral tissue, mainly due to proliferating fibroblasts and activated macrophages. In our experimental model of rheumatoid arthritis (adjuvant arthritis), enhanced 2-deoxy-2[F-18]fluoro-D-glucose was found in the hippocampus and amygdala two days after the induction of the disease which, similarly as in the peripheral joints, can be ascribed to the activated macrophages. The knowledge on the glucose transport and the role of glucose transporters in the brain during systemic autoimmune inflammation is still incomplete and needs further investigations.
Assuntos
Encéfalo/imunologia , Encéfalo/metabolismo , Encefalite/imunologia , Encefalite/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose/metabolismo , Animais , Humanos , Transdução de Sinais/imunologiaRESUMO
Ghrelin and agonists of its receptor GHS-R1a are potential substances for the treatment of cachexia. In the present study, we investigated the acute and long term effects of the GHS R1a agonist JMV 1843 (H Aib-DTrp-D-gTrp-CHO) on food intake, body weight and metabolic parameters in lean C57BL/6 male mice. Additionally, we examined stability of JMV 1843 in mouse blood serum. A single subcutaneous injection of JMV 1843 (0.01-10 mg/kg) increased food intake in fed mice in a dose-dependent manner, up to 5-times relative to the saline-treated group (ED(50)=1.94 mg/kg at 250 min). JMV 1843 was stable in mouse serum in vitro for 24 h, but was mostly eliminated from mouse blood after 2 h in vivo. Ten days of treatment with JMV 1843 (subcutaneous administration, 10 or 20 mg/kg/day) significantly increased food intake, body weight and mRNA expression of the orexigenic neuropeptide Y and agouti-related peptide in the medial basal hypothalamus and decreased the expression of uncoupling protein 1 in brown adipose tissue. Our data suggest that JMV 1843 could have possible future uses in the treatment of cachexia.
Assuntos
Proteína Relacionada com Agouti/metabolismo , Estimulantes do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Grelina/agonistas , Hipotálamo/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Oligopeptídeos/farmacologia , Aumento de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Estimulantes do Apetite/administração & dosagem , Estimulantes do Apetite/farmacocinética , Relação Dose-Resposta a Droga , Grelina/metabolismo , Hipotálamo/metabolismo , Indóis , Injeções Subcutâneas , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Neuropeptídeo Y/genética , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , RNA Mensageiro/metabolismo , Receptores de Grelina/agonistas , Receptores de Grelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triptofano/análogos & derivados , Proteína Desacopladora 1 , Regulação para CimaRESUMO
Drug delivery to the central nervous system (CNS) represents one of the most priority challenges in research and development of pharmaceutical nanotechnology products. Among the various non-invasive approaches for CNS delivery, nanoparticle carriers and particularly polymeric nanoparticles (PNs) seem to be one of the most interesting. This review deals with PNs as CNS drug delivery systems and their potential endocrine disrupting properties. Possible interference with the development of neuroendocrine-reproductive system is considered. Special regard is being paid to potential mechanisms of PNs toxicity. Necessity to investigate the toxicity of nanomaterials and their impact on human health are discussed.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/efeitos adversos , Sistemas Neurossecretores/efeitos dos fármacos , Polímeros/efeitos adversos , Barreira Hematoencefálica/efeitos dos fármacos , Humanos , Nanopartículas/administração & dosagem , Polímeros/administração & dosagemRESUMO
The purpose of this study was to evaluate the effect of ß-(1,3/1,6)-D: -glucan isolated from Pleurotus ostreatus (ß-glucan-PO) on prophylactic treatment of adjuvant arthritis (AA) with methotrexate (MTX) in rats. Groups of rats with AA were treated with methotrexate (1 mg/kg/week), ß-glucan-PO (1 mg/kg every second day) or their combination for the period of 28 days from adjuvant application. Body mass, hind paw swelling, arthrogram scores and a level of serum albumin were measured as markers of inflammation and arthritis. Treatment with low dose of MTX significantly inhibited the markers of both inflammation and arthritis. MTX and its combination with ß-glucan-PO significantly increased body mass of arthritic rats. ß-glucan-PO administered alone significantly decreased both the hind paw swelling and arthritic score. In combination with MTX, ß-glucan-PO markedly potentiated the beneficial effects of MTX, which resulted in a more significant reduction of hind paw swelling and arthritic scores. The concentration of albumin in the serum of arthritic controls was significantly lower than in healthy controls. Both MTX alone and the combination treatment with MTX + ß-glucan-PO significantly inhibited the decrease in serum albumin. ß-Glucan-PO increased the treatment efficacy of basal treatment of AA with MTX.
Assuntos
Artrite Experimental/tratamento farmacológico , Metotrexato/uso terapêutico , Pleurotus/química , beta-Glucanas/uso terapêutico , Animais , Peso Corporal , Masculino , Ratos , Ratos Endogâmicos Lew , Albumina Sérica/análiseRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) is associated with enhanced pro-inflammatory cytokine levels, pain, anorexia, and cognitive changes. The enhanced production of cytokines appears before the full manifestation of the disease. So far, any experimental data on behavioral effects of early arthritis are lacking. In the present series we describe anorexia early changes in, pain hyper-sensitivity and altered cognitive behavior during the first four days of adjuvant arthritis in rats (AA), when no clinical signs are yet apparent. METHODS: AA was induced to male Lewis rats by a single injection of complete Freund's adjuvant (cFA) at the base of the tail. Plasma leptin and ghrelin were measured using specific RIA methods. Gene expressions for food-regulatory peptides, neuropeptide-Y (NPY) and interleukin-1ß (IL-1ß) in the hypothalamic arcuate nuclei (nARC), were quantitated by TaqMan real-time PCR. Pain sensation was measured on all four limbs and tail by the plantar test. Cognitive functions were tested in the Morris water maze (MWM). RESULTS: Levels of orexigenic ghrelin as well as mRNA expression of orexigenic NPY in nucleus arcuatus (nRC)re significantly enhanced on day 2 of AA only. Reduced body weight and food intake persisted by day 4 with the most profound reduction on day 2. The mRNA for anorexigenic IL-1ß in the nARC was significantly enhanced on days 2 and 4. Enhanced pain sensitivity was observed on day 2, as was the cognitive impairment given by longer time to find the hidden platform, longer time spent in thigmotaxis zone, and longer trajectory. The less effective strategy used to find the hidden platform was observed up to the day 4 of AA. CONCLUSIONS: Early stage of AA brings about reduced body weight, food intake, and activation of central orexigenic pathways. The observed anorexia could be ascribed to the over-expression of anorexigenic IL-1ß which dominates over the NPY orexigenic effects. On day 2 of AA higher pain sensitivity and cognitive impairment appear. All the observed change tend to recover by day 4 of the disease.
Assuntos
Anorexia/etiologia , Artrite Experimental/complicações , Transtornos Cognitivos/etiologia , Hiperalgesia/etiologia , Animais , Núcleo Arqueado do Hipotálamo/química , Artrite Experimental/metabolismo , Expressão Gênica , Grelina/sangue , Interleucina-1beta/genética , Leptina/sangue , Masculino , Neuropeptídeo Y/genética , RNA Mensageiro/análise , Ratos , Fatores de TempoRESUMO
A certain relationship was observed between the gastrointestinal system, arthritis and immune system. Patients with rheumatoid arthritis have an altered microflora composition and disturbed intestinal defensive barrier. Effect of probiotic bacteria (Colinfant; COL) with known favorable effect on intestinal microflora was determined on the methotrexate (MTX) treatment of adjuvant arthritis. Rats with adjuvant arthritis were administered methotrexate 0.5 mg/kg body mass 2-times weekly per os, COL 1 mL/kg body mass every second day per os, and a combination of MTX+COL for a period of 28 d from the immunization. Levels of serum albumin, body mass, changes in hind paw swelling, and arthrogram score were estimated in rats as variables of inflammation and destructive arthritis-associated changes. Treatment with MTX, as well as with the combination treatment with MTX+COL significantly inhibited both inflammation and destructive arthritis-associated changes. The combination treatment inhibited both the hind paw swelling and arthrogram score more remarkably than MTX alone; on the other hand, the difference between combination treatment and MTX alone was not significant. Treatment with COL alone had no effect on adjuvant arthritis in rats. Colinfant can increase the preventive effect of MTX treatment in rat adjuvant arthritis by improving its antiarthritic effects.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/terapia , Escherichia coli , Metotrexato/administração & dosagem , Probióticos/administração & dosagem , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Terapia Combinada , Modelos Animais de Doenças , Escherichia coli/fisiologia , Humanos , Masculino , Ratos , Ratos Endogâmicos LewRESUMO
OBJECTIVE: Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity. METHODS: Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs . RESULTS: During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6. CONCLUSION: Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats.
Assuntos
Proteína Relacionada com Agouti/genética , Núcleo Arqueado do Hipotálamo/metabolismo , Interleucina-6/genética , Neuropeptídeo Y/genética , Obesidade/genética , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptor Tipo 4 de Melanocortina/genética , Adipócitos Brancos , Adiponectina/sangue , Tecido Adiposo Branco/citologia , Adiposidade , Envelhecimento , Proteína Relacionada com Agouti/metabolismo , Análise de Variância , Animais , Regulação do Apetite/fisiologia , Área Sob a Curva , Peso Corporal , Tamanho Celular , Gorduras na Dieta/administração & dosagem , Ingestão de Energia , Comportamento Alimentar , Expressão Gênica , Grelina/sangue , Intolerância à Glucose , Insulina/sangue , Interleucina-6/metabolismo , Leptina/sangue , Tamanho da Ninhada de Vivíparos , Masculino , Neuropeptídeo Y/metabolismo , Nicotinamida Fosforribosiltransferase/sangue , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Receptor Tipo 4 de Melanocortina/metabolismoRESUMO
The purpose of the present study was (i) to compare secretory responses of prolactin and corticosterone to the acute stress of immobilization in male rats of the Lewis and Long Evans strains and (ii) to compare secretion of the two hormones in rats with fully developed adjuvant arthritis (AA) and their relationship with the intensity of the inflammatory reaction. A short immobilization of 5 min induced equal elevations of both hormones in both strains, but 20-min immobilization produced significantly stronger responses in Long Evans rats than in Lewis rats. AA inhibited prolactin secretion equally in both strains (from 11.6 +/- 1.3 ng/ml to 4.2 +/- 0.6 ng/ml in Lewis rats, p < 0.01, and from 3.7 +/- 0.6 to 2.12 +/- 0.1 ng/ml in Long Evans rats, p < 0.05), but caused a conspiciously larger elevation of corticosterone in the Long Evans than in the Lewis animals (11.5 +/- 1.2 microg/dl in Long Evans rats versus 5.1 +/- 0.5 microg/dl in Lewis rats, p < 0.01) while basal levels were similar. The larger corticosterone response in the Long Evans rats was associated with a stronger inflammatory reaction assessed by hind paw swelling (2.3 +/- 0.1 ml for Long Evans rats versus 1.8 +/- 0.08 ml for Lewis rats, p < 0.01) and plasma levels of nitric oxide (47.5 +/- 5.7 microM for Long Evans rats versus 28.7 +/- 2.5 microM for Lewis rats, p < 0.01) than in the Lewis males with lower corticosterone levels. In conclusion, there are significant, obviously genetically based, differences in the corticosterone responses to both immobilization and AA between the two strains, with the Long Evans rats reacting more strongly than the Lewis rats. The lack of the expected inverse relationship between corticosterone levels and the intensity of the inflammation indicates that the activity of corticosterone is not its primary determinant and that other important factors are involved.
Assuntos
Artrite Experimental/sangue , Corticosterona/metabolismo , Hormônios/metabolismo , Inflamação/complicações , Prolactina/metabolismo , Animais , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Corticosterona/sangue , Hormônios/sangue , Inflamação/patologia , Masculino , Prolactina/sangue , Ratos , Ratos Endogâmicos Lew , Ratos Long-Evans , Especificidade da EspécieRESUMO
The aim of the present experiments was to study the effect of stress of chronic food restriction (FR) and of repeated psychological challenge (PS) on the development of adjuvant arthritis in the Long Evans male rats. In the FR series, four groups of animals were compared: non-treated control (C) and arthritic (AA) rats, both with free access to food and water, and two analogous groups with a 40% food restriction-FR and AA-FR. All animals were killed 22 days after injection of cFA. In the PS series, stress was induced by random daily exposures of the rats to isolation, over-crowding, food/water deprivation, foot shock, tilting, fear for 14 days before cFA injection and 12 days thereafter (groups: C, AA, PS, and AA-PS). Arthritis causes swelling of the hindpaw, which was prevented in the AA-FR group. PS causes more severe disease symptoms: AA-PS rats had more severe hindpaw swelling than AA rats. Forty percent food restriction associated with elevated CORT levels mitigated inflammatory parameters activated during AA. PS worsened the disease. These results suggested that activated CORT is not the only cause of disease suppression, but some metabolic changes during FR play a role.
Assuntos
Artrite Experimental/etiologia , Privação de Alimentos/fisiologia , Estresse Fisiológico/fisiopatologia , Animais , Corticosterona/metabolismo , Aglomeração/fisiopatologia , Aglomeração/psicologia , Desidratação/complicações , Suscetibilidade a Doenças , Eletrochoque/efeitos adversos , Medo , Adjuvante de Freund/toxicidade , Imobilização/efeitos adversos , Masculino , Aprendizagem em Labirinto , Ratos , Estresse Fisiológico/etiologia , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologiaRESUMO
Glucose tolerance, serum insulin, insulin receptors in epididymal fat tissue, and GLUT 4 content in muscle, as well as serum prolactin, were studied in obese and lean spontaneously hypertensive rats (SHRs) of both sexes. Obese animals displayed insulin resistance and decreased capacity of high-affinity binding sites of insulin receptors in fat tissue plasma membranes. GLUT 4 content in musculus quadriceps was diminished only in obese females. Terguride treatment lowered prolactin serum levels, which was concomitant with ameliorated insulin sensitivity in obese animals of both sexes. Similarly, only in obese females, terguride significantly increased the affinity of high-affinity insulin-binding sites and normalized GLUT 4 content. Our results document downregulation of insulin receptors and GLUT 4 in obesity and suggest a role for prolactin in obesity-induced insulin resistance, particularly in female rats.
Assuntos
Lisurida/análogos & derivados , Lisurida/farmacologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Obesidade/metabolismo , Prolactina/metabolismo , Receptor de Insulina/metabolismo , Fatores Sexuais , Animais , Feminino , Transportador de Glucose Tipo 4 , Insulina/metabolismo , Masculino , Ligação Proteica , Ratos , Ratos Endogâmicos SHRRESUMO
Glucose tolerance, serum insulin, insulin receptors in epididymal fat tissue, circulating total cholesterol and triglyceride concentrations as well as serum prolactin were studied in obese and lean spontaneously hypertensive rats (SHR) of both sexes. Obese animals displayed insulin resistance and elevated insulin and triglyceride concentrations. Moreover, in obese rats the increased mass of epididymal fat tissue was accompanied with decreased capacity of high affinity binding sites of insulin receptors in the tissue plasma membranes. Terguride treatment lowered prolactin serum levels which was accompanied by ameliorated insulin sensitivity in obese animals of both sexes. In addition, terguride treatment decreased serum insulin and triglyceride concentrations in obese females and at the same time enhanced the affinity of high affinity insulin binding sites. Our results show that obesity in SHR is associated with a decreased capacity of insulin receptors and that prolactin may play a role in obesity-induced insulin resistance, particularly in female rats.
Assuntos
Agonistas de Dopamina/farmacologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Lisurida/análogos & derivados , Lisurida/farmacologia , Obesidade/tratamento farmacológico , Prolactina/sangue , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Feminino , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Obesidade/metabolismo , Ratos , Ratos Endogâmicos SHRRESUMO
OBJECTIVE: To study the effect of the stress of chronic food restriction on the development of adjuvant arthritis in Long Evans male rats. METHODS: Four groups of animals were compared: non-treated control (C) and arthritic (AA) rats, both with free access to food and water and two analogous groups with a 40% food restriction, i.e. non-treated (FR) and arthritic (AA-FR) animals. All rats were killed 22 days following the injection of complete Freund's adjuvant. The parameters measured were: serum levels of albumin (ALB), nitrate, glucose, insulin, corticosterone (CORT), prolactin (PRL) and PRL mRNA in the adenopituitaries. In addition the activity of gamma-glutamyl transpeptidase (GGTP) was measured in the spleen. The pain threshold was determined by the tailflick method. The body weight of the animals was recorded on day 0, 3, 7, 11, 15 and 18 of the disease. RESULTS: Arthritis caused swelling of the hind paw (2.37 +/- 0.15 ml vs 1.1 +/- 0.05ml in controls, p < 0.01) which was prevented in the AA-FR group (1.44 +/- 0.13 ml, not significant against controls). Arthritis increased serum NO and reduced ALB levels; both changes were significantly restored in the FR-AA group. Food restriction did not alter the activation of GGTP, or the decrease of PRL mRNA observed in the AA group. Serum CORT was elevated in rats with food restriction (15.49 +/- 2.1 vs. 3.7 +/- 0.87 microg/dL) and remained enhanced to the same extent in AA and FR-AA groups. The tailflick latency prolonged in the AA group was reduced by food restriction. CONCLUSION: These results show that 40% food restriction associated with elevated CORT levels mitigated the inflammatory parameters activated during AA.
Assuntos
Artrite Experimental/prevenção & controle , Privação de Alimentos , Estresse Psicológico , Animais , Artrite Experimental/sangue , Artrite Experimental/psicologia , Glicemia , Peso Corporal/fisiologia , Corticosterona/sangue , Feminino , Membro Posterior/patologia , Insulina/sangue , Masculino , Nitratos/sangue , Medição da Dor , Limiar da Dor/psicologia , Adeno-Hipófise/metabolismo , Prolactina/sangue , Prolactina/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Albumina Sérica/análise , Fatores Sexuais , Baço/enzimologia , gama-Glutamiltransferase/metabolismoRESUMO
1. The aim of this study was to compare the effects of acute amphetamine (AMPH) treatment and restraint stress on plasma level of prolactin (PRL) and PRL mRNA expression in the adenohypophysis in Sprague-Dawley and Lewis male rats, the latter known to have a deficient hypothalamo-pituitary-adrenal (HPA) axis. 2. Both restraint stress and AMPH treatment (i.p. in a dose of 8 mg/kg of b.w.) were applied 15 or 30 min before termination of the experiment. Plasma PRL and corticosterone (CORT) were determined by radioimmunoassay. PRL mRNA expression was estimated by a dot-blot hybridization. 3. Restraint stress and AMPH treatment induced a significant increase in the CORT plasma level, as an indicator of stress response. Compared to Sprague-Dawley rats, the magnitude of CORT increase after both stimuli was significantly lower in Lewis rats. 4. Although restraint stress significantly increased the PRL plasma levels in both rat strains, AMPH treatment reduced the PRL levels in both rat strains. However, the changes of PRL plasma levels had another pattern in Lewis rats than in Sprague-Dawley rats. Control plasma PRL levels were significantly higher in Lewis rats, and in this rat strain AMPH treatment for 30 min increased the PRL levels as compared to the values obtained after AMPH treatment for 15 min. 5. Expression of PRL mRNA in adenohypophysis by restraint stress and AMPH treatment had a similar pattern. After a 15-min lasting restraint stress, the expression of PRL mRNA was decreased insignificantly in both rat strains. AMPH treatment induced in Sprague-Dawley rats a significant decrease of PRL mRNA after a 15-min interval while after 30 min there was a significant increase. However, in Lewis rats AMPH failed to significantly change PRL mRNA. 6. The results from the present study indicate that the mechanisms mediating the effects of acute restraint stress and acute AMPH treatment differ in PRL response in Sprague-Dawley and Lewis male rat strains. Differences in the observed responses in Lewis rats could be related to the deficient activity of HPA axis in this rat strain.
Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Prolactina/sangue , Prolactina/genética , Estresse Fisiológico/fisiopatologia , Doença Aguda , Animais , Corticosterona/sangue , Expressão Gênica/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Restrição Física , Especificidade da Espécie , Estresse Fisiológico/sangueRESUMO
OBJECTIVE: The effect of the immunosuppressive fraction of boar seminal vesicle fluid (ISF) was tested on the manifestation of adjuvant arthritis (AA) in rats. METHODS: The inhibitory effect of ISF on mitogen-stimulated proliferation of rat lymphocytes was evaluated by immunoassay using bromodeoxyuridine incorporation. Adjuvant arthritis was induced in male Long Evans rats with Mycobacterium butyricum in adjuvant. ISF was administered at the time of the induction of arthritis. At the time of maximal manifestation of the disease, the hind paw swelling and thymus weight were estimated. IgM and IgG in the rat blood sera were quantified by sandwich ELISA. Serum corticosterone was analyzed by radioimmunoassay. Serum NO2-/NO3-were estimated by diazotation. Serum albumin was measured spectrophotometrically. The expression of IL-6 mRNA in peritoneal macrophages was estimated by dot-blot hybridization. RESULTS: Treatment of arthritic rats with ISF attenuated hind paw edema. The production of IgG subclasses dropped in ISF-treated AA rats. The thymus mass and serum albumin concentration were partially restored due to the ISF treatment. Serum corticosterone as well as NO2-/NO3- concentrations were reduced by the ISF effect. The expression of IL-6 in peritoneal macrophages was inhibited in AA rats after ISF treatment. CONCLUSION: ISF attenuated the manifestation of AA in rats and mitigated the inflammation. Immunoglobulin production was most probably inhibited by the decreased proliferation of B lymphocytes.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Imunossupressores/farmacologia , Proteínas/farmacologia , Animais , Corticosterona/sangue , Expressão Gênica/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Imunossupressores/imunologia , Injeções Intraperitoneais , Interleucina-6/genética , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Nitratos/sangue , Nitritos/sangue , Proteínas/imunologia , RNA Mensageiro/análise , Ratos , Ratos Long-Evans , Ratos Wistar , Sêmen/química , Sêmen/imunologia , Proteínas de Plasma Seminal , Albumina Sérica , SuínosRESUMO
We studied the effect of prolactin (PRL) inhibition by bromocriptine (BRC) in the first phase of adjuvant induced arthritis (AA), up to day 11(BRCl-AA), and in the whole time course of AA, up to day 23 (BRC-AA), on the development of the disease in male Lewis rats. On day 24, arthritic rats showed inhibition of PRL secretion, but not PRL mRNA expression in adenopituitaries. BRC treatment suppressed PRL serum levels and PRL mRNA expression in adenopituitaries. In BRC/-AA group PRL levels and PRLmRNA were at the level of rats with AA. Serum corticosterone (CORT) was stimulated by AA from 16.9+/-5.8 to 59.1+/-8.7 ngml(-1), p<0.05, to the same level in BRC-control (BRC-C) and BRC-AA group and further potentiated in BRCI-AA group (148.2+/-33.1 ngml(-1), p<0.05 vs. group with AA). Hind paw swelling was reduced but not completely inhibited in BRC1-AA group and totally prevented in BRC-AA rats as was the core temperature (36.5+/-0.1 degrees C vs. 37.4+/-.0.1 degrees C in AA rats on day 23, p<0.01). Serum concentration of NO-ZNO-3 rose in rats with AA to 28.7+/-2.5 &mgr;mo1L-1 against. 13.9+/-1.9 &mgr;molL(-1) in controls (p<0.01), remained elevated in BRC-AA group and was potentiated in BRC1-AA group (48.2+/-3.5 &mgr;mol(-1), p<0.01 vs. AA or BRC1-AA group) Thiobarbituric acid reactive substances (TBARS) and antioxidant capacity in the spleen were enhanced in rats with AA and to the same extent in BRC-AA or BRC1-AA groups. These results show a discrepancy between the suppression of clinical symptoms and persisting oxidative stress in AA rats after the BRC induced PRL inhibition. The potentiation of nintric oxide (NO-) production after the sudden cessation of PRL inhibition during the disease may promote further joint damage.
RESUMO
The expression of platelet-derived growth factor-A (PDGF-A) mRNA was examined in the cotyledons of normal human placentae and those from patients with pre-eclampsia. These patients exhibited pre-delivery blood pressure of 154+/-4/99+/-4 mmHg (mean+/-SEM) and met the criteria established for pre-eclampsia. During labour they received MgSO4 infusion for various time intervals (4-25 h). The PDGF-A message was quantitated to beta-actin by the solution hybridization nuclease protection assay. Since the two groups differed in two parameters (pre-eclampsia and MgSO4 treatment), the direct comparison was not feasible. An analysis of covariance revealed a significant difference in the message between the pre-eclamptic and control groups (P<0.01); the gestational age was not a significant covariate for either group but the time on MgSO4 in pre-eclampsia group was significant (P<0.002). A linear regression analysis of PDGF-A mRNA values for the pre-eclamptic group showed a time-dependent downregulation of the message by MgSO4 (P<0.01, r=- 0.796). These results show a uniform expression of PDGF-A mRNA in cotyledons of normal human placenta between 35 and 40 weeks of gestation. Furthermore, MgSO4 has an inhibitory effect on the expression of this message which may have aside from its anticonvulsive action beneficial effect on the function of pre-eclamptic placenta.
Assuntos
Sulfato de Magnésio/administração & dosagem , Placenta/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Pré-Eclâmpsia/metabolismo , RNA Mensageiro/metabolismo , Actinas/genética , Actinas/metabolismo , Adulto , Feminino , Humanos , Recém-Nascido , Infusões Intravenosas , Magnésio/sangue , Fator de Crescimento Derivado de Plaquetas/genética , GravidezRESUMO
OBJECTIVE: To evaluate the impact of repeated neonatal mother deprivation (RMD) of male rats on the behavioral parameters and response of prolactin to mild stress stimuli in the adulthood. METHODS: Afer birth, the pups of Wistar Porton Olac rats were crossfostered and their number was adjusted to 8 per litter (4 males and 4 females). They were removed from the dam for 6 hours daily on postnatal day 6, 7, 8 and for 12 hours daily on postnatal day 12, 13, 15, 16 and placed to another cage lined with cotton wool at controlled temperature 37 øC. Body weight was estimated repeatedly from postnatal day 9 to 97. At 14 weeks of life the behavioral activity was measured in an open field on 2 occasions, 2 days apart. One week later the rats were exposed to 15 min novelty stress or to 3 min handling and decapitated 15 min after the initiation of both. Trunk blood was collected and plasma prolactin (PRL) was measured by radioimmunoassay. RESULTS: On postnatal day 15 the eye opening was found in 75 % of control pups and 73 % of pups with RMD. In the rats after RMD the body weight gain was significantly decreased from day 21 until the day 97. Vertical behavioral activity (rearing) was enhanced in RMD rats when measured on the first occasion. Horizontal behavioral activity did not significantly differ from the control group. Stress of novel environment elicited the activation of PRL secretion in untreated animals (19.3 1+4.6 ng/ml vs. 7.17+1.03 ng/ml, P<0.05), while no change was found in the rats after RMD (8.15+2.0 ng/ml vs. 4.35+0.48 ng/ml). CONCLUSIONS: In the rats exposed to neonatal mother deprivation the lower emotionality was found. Significantly decreased body weight gain in these animals was probably due to the nutritional deprivation during the postnatal separation from the mother. The nonresponsiveness of lactotrophs to mild stressor in adult rats after RMD may have a negative impact on defense mechanisms to immune challenges.