RESUMO
BACKGROUND: Inulin-type fructo-oligosaccharides (FOSs) purified from Morinda officinalis How., an effective oral antidepressant for mild to moderate depression, have a largely unknown efficacy and poor bioavailability. PURPOSE: Therefore, the microbiota-gut-brain axis was used to investigate the antidepressive properties of FOSs at the interface of the gut microbiota (GM). STUDY DESIGN AND METHODS: FOSs was introduced via intragastric gavage to rats exposed to chronic unpredictable mild stress (CUMS), and the antidepressive effects were investigated through behavioral tests, intestinal morphology and corticosterone levels. Bacterial genomic DNA was extracted from feces, and the GM was profiled for using enterobacterial repetitive intergenic consensus (ERIC)-PCR analysis, partial least squares-discriminant analysis (PLS-DA) and 16S rRNA gene pyrosequencing. RESULTS: It was observed that FOSs alleviated depression-like behaviors and repaired intestinal epithelia damages. FOSs treatment lowered corticosterone levels in the plasma and urine of the model rats. Moreover, the GM compositions of normal and model rats were distantly clustered and were mainly related to the disappearance of beneficial bacteria (e.g., Acinetobacter, Barnesiella, Coprococcus, Dialister, Lactobacillus, and Paenibacillus) and appearance of depression-associated bacteria (e.g., Anaerostipes, Oscillibacter, Proteobacteria, and Streptococcus) in depressive rats. Interestingly, the dysbiosis in depressive rats' gut was reinstated with FOSs treatments. Notably, FOSs promoted the abundance of the bacterial phylum Cyanobacteria, a group of bacteria known for the secretion of pharmacologically important metabolites, such as H2S, that exhibit antidepressant-like properties. Apparently, FOSs-induced modulation of GM was more antidepressive compared to a component of FOSs, degrees of polymerization (DP) 5, and fluoxetine, the standard antidepressant drug. CONCLUSION: In conclusion, this study implied that antidepressant efficacy of FOSs was inseparable from and strongly associated with the modulation of the host' s GM.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Morinda/química , Oligossacarídeos/farmacologia , Animais , Corticosterona/sangue , Corticosterona/urina , Depressão/etiologia , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Masculino , RNA Ribossômico 16S , Ratos Sprague-Dawley , Estresse Psicológico/tratamento farmacológicoRESUMO
While several methods have been used to restrict the sleep of experimental animals, it is often unclear whether these different forms of sleep restriction have comparable effects on sleep-wake architecture or functional capacity. The present study compared four models of sleep restriction, using enforced wakefulness by rotation of cylindrical home cages over 11 h in male Wistar rats. These included an electroencephalographic-driven 'Biofeedback' method and three non-invasive methods where rotation was triggered according to a 'Constant', 'Decreasing' or random protocol based upon the 'Weibull' distribution fit to an archival Biofeedback dataset. Sleep-wake architecture was determined using polysomnography, and functional capacity was assessed immediately post-restriction with a simple response latency task, as a potential homologue of the human psychomotor vigilance task. All sleep restriction protocols resulted in sleep loss, behavioural task disengagement and rebound sleep, although no model was as effective as real-time electroencephalographic-Biofeedback. Decreasing and Weibull protocols produced greater recovery sleep than the Constant protocol, mirrored by comparably poorer simple response latency task performance. Increases in urinary corticosterone levels following Constant and Decreasing protocols suggested that stress levels may differ between protocols. Overall, these results provide insight into the value of choosing a specific sleep restriction protocol, not only from the perspective of animal welfare and the use of less invasive procedures, but also translational validity. A more considered choice of the physiological and functional effects of sleep-restriction protocols in rodents may improve correspondence with specific types of excessive daytime sleepiness in humans.
Assuntos
Atenção/fisiologia , Privação do Sono/fisiopatologia , Sono/fisiologia , Vigília/fisiologia , Animais , Biorretroalimentação Psicológica , Corticosterona/urina , Eletroencefalografia , Masculino , Polissonografia , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Rotação , Privação do Sono/urina , Análise e Desempenho de Tarefas , Fatores de TempoRESUMO
Hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia, and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key phosphatase induced by inflammation that is responsible for the central insulin and leptin resistance. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IRß and IRS-1) and leptin (JAK2) signaling, increased the tyrosine phosphorylation of these molecules, and restored the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an interleukin-6 (IL-6)-dependent manner because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response.
Assuntos
Hipotálamo/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Animais , Western Blotting , Corticosterona/urina , Hipotálamo/enzimologia , Imuno-Histoquímica , Inflamação/enzimologia , Insulina/sangue , Interleucina-6/sangue , Interleucina-6/metabolismo , Leptina/sangue , Masculino , Camundongos , Camundongos Obesos , Obesidade/enzimologia , Distribuição Aleatória , Ratos , Ratos Wistar , Transdução de Sinais , Organismos Livres de Patógenos EspecíficosRESUMO
Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus-dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated. Rats were deprived of sleep for 6 h throughout the first resting phase after predator scent stress exposure. Behaviors in the elevated plus-maze and acoustic startle response tests were assessed 7 days later, and served for classification into behavioral response groups. Freezing response to a trauma reminder was assessed on day 8. Urine samples were collected daily for corticosterone levels, and heart rate (HR) was also measured. Finally, the impact of manipulating the hypothalamus-pituitary-adrenal axis and adrenergic activity before SD was assessed. Mifepristone (MIFE) and epinephrine (EPI) were administered systemically 10-min post-stress exposure and behavioral responses and response to trauma reminder were measured on days 7-8. Hippocampal expression of glucocorticoid receptors (GRs) and morphological assessment of arborization and dendritic spines were subsequently evaluated. Post-exposure SD effectively ameliorated long-term, stress-induced, PTSD-like behavioral disruptions, reduced trauma reminder freezing responses, and decreased hippocampal expression of GR compared with exposed-untreated controls. Although urine corticosterone levels were significantly elevated 1 h after SD and the HR was attenuated, antagonizing GRs with MIFE or stimulation of adrenergic activity with EPI effectively abolished the effect of SD. MIFE- and EPI-treated animals clearly demonstrated significantly lower total dendritic length, fewer branches and lower spine density along dentate gyrus dendrites with increased levels of GR expression 8 days after exposure, as compared with exposed-SD animals. Intentional prevention of sleep in the early aftermath of stress exposure may well be beneficial in attenuating traumatic stress-related sequelae. Post-exposure SD may disrupt the consolidation of aversive or fearful memories by facilitating correctly timed interactions between glucocorticoid and adrenergic systems.
Assuntos
Agonistas Adrenérgicos/uso terapêutico , Epinefrina/uso terapêutico , Antagonistas de Hormônios/uso terapêutico , Mifepristona/uso terapêutico , Privação do Sono/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Estimulação Acústica/efeitos adversos , Agonistas Adrenérgicos/farmacologia , Análise de Variância , Animais , Corticosterona/urina , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Dendritos/ultraestrutura , Modelos Animais de Doenças , Eletrocardiografia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Antagonistas de Hormônios/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Mifepristona/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Coloração pela Prata , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Telemetria , Fatores de TempoRESUMO
Evidence is presented for the potentiating role of corticosterone on axonal degeneration of serotonergic neurones during ageing. Aged rats, 24 months old, were implanted subcutaneously with 2 x 100 mg pellets of corticosterone. Serotonergic and cholinergic (ChAT- and NADPHd-positive) fibre degenerations in the anteroventral thalamic nucleus (AVT) were measured 2 months after corticosterone implantation. Numbers of immunoreactive serotonergic raphe and mesolimbic cholinergic neurones were also quantified. Basal plasma corticosterone and adrenocorticotropin (ACTH) concentrations were assayed at 2, 4, 6, and 8 weeks after implantation in the plasma and at 1, 2, 4 and 6 weeks in urine. The degree of serotonergic fibre aberrations in the AVT increased significantly after corticosterone exposure, while that of ChAT-positive and NADPHd-stained axon aberrations showed a modest but nonsignificant increase. A positive correlation between the magnitudes of serotonergic and cholinergic fibre aberrations appeared in the AVT, but only in the corticosterone-treated rats. The number of serotonin immunopositive neurones in the raphe nuclei after corticosterone decreased marginally, while that of mesopontine ChAT-positive neurones was not influenced. Measurements of basal plasma corticosterone and ACTH, as well as urine corticosterone, revealed that the steroid implantation increased the plasma corticosterone level for at least 4 weeks and decreased ACTH level for at least 6 weeks. By the week 8, the pituitary-adrenal function was apparently restored. However, at sacrifice, both the weight of adrenal glands and that of thymus remained reduced, indicating the long-lasting effects of corticosterone on target tissues. It is concluded that the raphe serotonergic neurones and their projecting fibres are sensitive to corticosterone excess in aged rats and become more vulnerable to degeneration processes than under normal ageing conditions. Cholinergic neurones of brainstem origin, which also express massive NADPHd activity, are more resistant against corticosterone, but their axon degeneration correlates to serotonergic fibre degeneration.
Assuntos
Envelhecimento , Corticosterona/administração & dosagem , Degeneração Neural , Fibras Nervosas/efeitos dos fármacos , Serotonina/fisiologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/fisiologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/urina , Animais , Axônios/química , Axônios/efeitos dos fármacos , Colina O-Acetiltransferase/análise , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/fisiologia , Corticosterona/sangue , Corticosterona/urina , Implantes de Medicamento , Cinética , Masculino , NADPH Desidrogenase/análise , Fibras Nervosas/química , Fibras Nervosas/fisiologia , Neurônios/ultraestrutura , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , Núcleos da Rafe/ultraestrutura , Ratos , Ratos Wistar , Serotonina/análise , Tálamo/ultraestruturaRESUMO
Licorice-derivatives such as glycyrrhizic acid (GA) competitively inhibit 11 beta-hydroxysteroid dehydrogenase(11 beta-HSD) type 2 (11-HSD2) enzymatic activity, and chronic clinical use often results in pseudoaldosteronism. Since the effect of GA on 11-HSD2 expression remains unknown, we undertook in vivo and in vitro studies. Male Wistar rats were given 30, 60 or 120 mg/kg of GA twice a day for 2 weeks. Plasma corticosterone was decreased in those given the 120 mg dose, while urinary corticosterone excretion was increased in those given the 30 and 60 mg doses but decreased in those given 120 mg GA. NAD(+)-dependent dehydrogenase activity in kidney microsomal fraction was decreased in animals receiving doses of 60 and 120 mg GA. The 11-HSD2 protein and mRNA levels were decreased in those given 120 mg GA. In contrast, in vitro studies using mouse kidney M1 cells revealed that 24h treatment with glycyrrhetinic acid did not affect the 11-HSD2 mRNA expression levels. Thus, in addition to its role as a competitive inhibitor of 11-HSD2, the chronic high dose of GA suppresses mRNA and protein expression of 11-HSD2 possibly via indirect mechanisms. These effects may explain the prolonged symptoms after cessation of GA administration in some pseudoaldosteronism patients.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ácido Glicirrízico/farmacologia , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Hidroxiesteroide Desidrogenases/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases , Animais , Western Blotting , Corticosterona/sangue , Corticosterona/urina , Relação Dose-Resposta a Droga , Rim/metabolismo , Masculino , Microssomos/metabolismo , NAD/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
In order to elucidate the mechanisms of the antinephritic action of TJ-8014, the effect of this drug on corticosterone release from the adrenal cortex was investigated by using normal rats and rats with original-type anti-GBM nephritis. When the serum corticosterone level was determined 5 hr after test drugs were given p.o. to normal rats, TJ-8014 at 0.5 and 2.0 g/kg significantly elevated the hormone level by 48% and 74%, respectively. Of the crude drugs that constitute TJ-8014, Bupleuri radix (SAIKO) and Glycyrrhizae radix (KANZOU) at 1.0 g/kg also significantly elevated the serum level. When TJ-8014 was given p.o. daily from the next day of anti-GBM serum injection to the 15th day, 2.0 g/kg/day of the drug inhibited the urinary protein excretion. In addition, TJ-8014 (2.0 g/kg/day) inhibited the decrease in the serum and adrenal corticosterone levels induced by nephritis. When corticosterone at 10 mg/kg was given s.c. daily from the next day of the anti-serum injection to the 10th day, it not only reduced proteinuria, but also inhibited glomerular histopathological changes. In contrast, metyrapone, a corticosterone synthetase inhibitor, at 100 mg/kg x 2/day, p.o., aggravated the nephritis. These results suggest that the antinephritic action of TJ-8014 may be partly due to the enhancement of the synthesis or release of corticosterone from the adrenal cortex.
Assuntos
Glândulas Suprarrenais/metabolismo , Corticosterona/metabolismo , Medicamentos de Ervas Chinesas , Nefrite/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Plantas Medicinais/análise , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Membrana Basal/imunologia , Corticosterona/sangue , Corticosterona/urina , Técnicas In Vitro , Rim/patologia , Rim/fisiopatologia , Glomérulos Renais/imunologia , Masculino , Metirapona/farmacologia , Nefrite/patologia , Nefrite/fisiopatologia , Preparações Farmacêuticas , Extratos Vegetais/farmacologia , Proteinúria/urina , Ratos , Ratos EndogâmicosRESUMO
Measurements have been made of protein turnover, RNA and DNA in thymus and skeletal muscle from rats fed on a zinc-deficient diet (ZD) for 10 and 17 d, in pair-fed controls (CI) and in muscle from rats fed on the ZD diet for 24 d and then fed on restricted amounts of the deficient diet with (RIZS) or without (RIZD) Zn supplementation, for 8 d. In thymus the ZD diet induced a loss of DNA and protein which was not observed with the CI rats. Accumulation of RNA was less affected but protein synthesis was reduced. In muscle the accumulation of DNA and protein was slowed by the ZD diet, particularly in glycolytic muscles compared with oxidative muscles, and Zn supplementation increased DNA and protein. Protein synthesis and RNA concentrations were reduced in the ZD rats compared with the CI rats, but Zn supplementation at constant restricted food intake did not increase protein synthesis. Muscle protein synthesis per unit RNA varied markedly in the ZD rats after 10 d when the characteristic cycling of the food intakes and body-weight was most pronounced, the highest values being observed in the anabolic phase of the cycle although these were less than values for well-fed controls. The variability was inversely correlated with the plasma Zn levels. The extent of the variability was much less after 17 d and was not apparent in the food-restricted ZD animals. Protein degradation in muscle, assessed as the difference between overall and net protein synthesis, was faster in the ZD rats compared with the CI rats and fluctuated considerably, partly accounting for the cyclic changes in muscle after 10 d, and was entirely responsible after 17 d. The concentration of muscle-free 3-methylhistidine and its urinary excretion rate indicated inconsistent results which could not be satisfactorily interpreted. Plasma insulin was reduced in the ZD rats compared with the CI rats and was insensitive to food intake in contrast to urinary corticosterone excretion which was inversely correlated with the cyclic changes in body-weight and food intake. Furthermore, adrenalectomized rats exhibited increased mortality and reduced cycling of body-weight and food intake. Thus Zn deficiency impairs growth by a combination of reduced food intake, a reduced anabolic response to food due to a reduced capacity for protein synthesis and reduced activation of protein synthesis, possibly reflecting impaired insulin secretion, and an increased catabolic response to the reduced intake in which corticosterone may play a role.