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1.
Adv Exp Med Biol ; 1191: 103-120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002925

RESUMO

Oxytocin, a neuropeptide synthesized by the hypothalamus, plays a central role in human social behavior, social cognition, anxiety, mood, stress modulation, and fear learning and extinction. The relationships between oxytocin and psychiatric disorders including depression, anxiety, schizophrenia, and autism spectrum disorder have been extensively studied. In this chapter, we focus on the current knowledge about oxytocin and anxiety disorder. We discuss the anxiolytic effects of oxytocin in preclinical and clinical findings, possible related neurobehavioral mechanisms (social cognition, fear learning, and extinction), related neurotransmitter and neuroendocrine systems (hypothalamus-pituitary-adrenal axis, serotoninergic, and GABAergic systems), and studies regarding plasma levels of oxytocin, genetic and epigenetic findings, and effects of intranasal oxytocin in DSM-5 anxiety disorder (primarily social anxiety disorder and separation anxiety disorder) patients.


Assuntos
Transtornos de Ansiedade/metabolismo , Ocitocina/metabolismo , Ansiedade/metabolismo , Medo , Humanos , Comportamento Social
2.
Adv Exp Med Biol ; 1191: 121-140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002926

RESUMO

Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets: serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes. Close translational collaboration between fundamental academic and discovery research will lead to badly needed breakthroughs in the search for new anxiolytics.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/fisiopatologia , Ansiedade/fisiopatologia , Descoberta de Drogas , Neurotransmissores/metabolismo , Pesquisa Médica Translacional , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Humanos
3.
Adv Exp Med Biol ; 1191: 523-541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002944

RESUMO

Exposure therapy, a key treatment for anxiety disorders, can be modelled in the laboratory using Pavlovian fear extinction. Understanding the hormonal and neurobiological mechanisms underlying fear extinction in females, who are twice more likely than males to present with anxiety disorders, may aid in optimising exposure therapy outcomes in this population. This chapter will begin by discussing the role of the sex hormones, estradiol and progesterone, in fear extinction in females. We will also propose potential mechanisms by which these hormones may modulate fear extinction. The second half of this chapter will discuss the long-term hormonal, neurological and behavioural changes that arise from pregnancy and motherhood and how these changes may alter the features of fear extinction in females. Finally, we will discuss implications of this research for the treatment of anxiety disorders in women with and without prior reproductive experience.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/terapia , Ansiedade/metabolismo , Ansiedade/terapia , Estradiol/metabolismo , Progesterona/metabolismo , Reprodução , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Extinção Psicológica , Medo , Feminino , Humanos , Gravidez
4.
Ann Hematol ; 98(12): 2683-2691, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31745600

RESUMO

In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values.


Assuntos
Arginina/administração & dosagem , Família , Heme/administração & dosagem , Hospitalização , Porfiria Aguda Intermitente , Qualidade de Vida , Inquéritos e Questionários , Adulto , Ansiedade/tratamento farmacológico , Ansiedade/genética , Ansiedade/metabolismo , Ansiedade/psicologia , Depressão/tratamento farmacológico , Depressão/genética , Depressão/metabolismo , Depressão/psicologia , Feminino , Alemanha , Humanos , Masculino , Porfiria Aguda Intermitente/tratamento farmacológico , Porfiria Aguda Intermitente/genética , Porfiria Aguda Intermitente/metabolismo , Porfiria Aguda Intermitente/psicologia , Estudos Prospectivos
5.
Med Sci Monit ; 25: 7889-7897, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31634896

RESUMO

BACKGROUND Empathy between doctor and patient has an important bearing on patient health. The purpose of this study was to assess whether anxiety, sleep quality, and self-efficacy of patients have mediating effects in the relationship of patient-reported physician empathy and inflammatory factor in ulcerative colitis (UC) patients. MATERIAL AND METHODS This study included 242 patients attended by 45 doctors. Self-reported doctors' empathy ability was measured at patient admission (T1), and patient-reported physician empathy was measured 3 months later (T2). Patient anxiety, general self-efficacy, sleep, and inflammatory factor (IL-6) were measured on T1 and T2. Pearson correlation analysis was used to assess the relationships between self-reported doctor empathy ability and patient indices on T1 and T2. The relationships between anxiety, sleep quality, self-efficacy, IL-6, and patient-reported physician empathy were measured by Pearson correlation analysis and structural equation modeling. RESULTS On T1, no significant correlation was reported between self-reported doctors' empathy ability and indices of the patients (P>0.05). On T2, self-reported doctors' empathy ability was significantly positively correlated with patient sleep and self-efficacy (P<0.01), and significantly negatively correlated with patient anxiety and IL-6 (P<0.01). Moreover, on T2, patient-reported physician empathy was negatively correlated with anxiety and IL-6 and was positively correlated with self-efficacy and sleep quality. The effect of patient-reported physician empathy on IL-6 was mediated by anxiety, sleep quality, and self-efficacy. CONCLUSIONS The anxiety, self-efficacy, and sleep quality of UC patients had mediating effects in the relationship between patient-reported physician empathy and IL-6.


Assuntos
Colite Ulcerativa/psicologia , Pacientes/psicologia , Relações Médico-Paciente , Adulto , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , China , Empatia , Feminino , Humanos , Inflamação , Interleucina-6/análise , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Médicos , Autoeficácia , Sono/fisiologia , Inquéritos e Questionários
6.
Nat Chem Biol ; 15(12): 1214-1222, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31591566

RESUMO

Iron is essential for a broad range of biochemical processes in the brain, but the mechanisms of iron metabolism in the brain remain elusive. Here we show that iron functionally translocates among brain regions along specific axonal projections. We identified two pathways for iron transport in the brain: a pathway from ventral hippocampus (vHip) to medial prefrontal cortex (mPFC) to substantia nigra; and a pathway from thalamus (Tha) to amygdala (AMG) to mPFC. While vHip-mPFC transport modulates anxiety-related behaviors, impairment of Tha-AMG-mPFC transport did not. Moreover, vHip-mPFC iron transport is necessary for the behavioral effects of diazepam, a well-known anxiolytic drug. By contrast, genetic or pharmacological promotion of vHip-mPFC transport produced anxiolytic-like effects and restored anxiety-like behaviors induced by repeated restraint stress. Taken together, these findings provide key insights into iron metabolism in the brain and identify the mechanisms underlying iron transport in the brain as a potential target for development of novel anxiety treatments.


Assuntos
Ansiedade/metabolismo , Axônios/metabolismo , Encéfalo/metabolismo , Ferro/metabolismo , Animais , Transporte Biológico , Masculino , Camundongos
7.
Medicine (Baltimore) ; 98(37): e17186, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517876

RESUMO

BACKGROUND: Ashwagandha (Withania somnifera (L.) Dunal) is a herb traditionally used to reduce stress and enhance wellbeing. The aim of this study was to investigate its anxiolytic effects on adults with self-reported high stress and to examine potential mechanisms associated with its therapeutic effects. METHODS: In this 60-day, randomized, double-blind, placebo-controlled study the stress-relieving and pharmacological activity of an ashwagandha extract was investigated in stressed, healthy adults. Sixty adults were randomly allocated to take either a placebo or 240 mg of a standardized ashwagandha extract (Shoden) once daily. Outcomes were measured using the Hamilton Anxiety Rating Scale (HAM-A), Depression, Anxiety, and Stress Scale -21 (DASS-21), and hormonal changes in cortisol, dehydroepiandrosterone-sulphate (DHEA-S), and testosterone. RESULTS: All participants completed the trial with no adverse events reported. In comparison with the placebo, ashwagandha supplementation was associated with a statistically significant reduction in the HAM-A (P = .040) and a near-significant reduction in the DASS-21 (P = .096). Ashwagandha intake was also associated with greater reductions in morning cortisol (P < .001), and DHEA-S (P = .004) compared with the placebo. Testosterone levels increased in males (P = .038) but not females (P = .989) over time, although this change was not statistically significant compared with the placebo (P = .158). CONCLUSIONS: These findings suggest that ashwagandha's stress-relieving effects may occur via its moderating effect on the hypothalamus-pituitary-adrenal axis. However, further investigation utilizing larger sample sizes, diverse clinical and cultural populations, and varying treatment dosages are needed to substantiate these findings. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI registration number: CTRI/2017/08/009449; date of registration 22/08/2017).


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Adulto , Ansiolíticos/efeitos adversos , Ansiedade/metabolismo , Sulfato de Desidroepiandrosterona/metabolismo , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Fitoterapia , Extratos Vegetais/efeitos adversos , Estresse Psicológico/metabolismo , Testosterona/metabolismo , Resultado do Tratamento
8.
PLoS Genet ; 15(9): e1008358, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557158

RESUMO

Stressful life events are major environmental risk factors for anxiety disorders, although not all individuals exposed to stress develop clinical anxiety. The molecular mechanisms underlying the influence of environmental effects on anxiety are largely unknown. To identify biological pathways mediating stress-related anxiety and resilience to it, we used the chronic social defeat stress (CSDS) paradigm in male mice of two inbred strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), that differ in their susceptibility to stress. Using a multi-omics approach, we identified differential mRNA, miRNA and protein expression changes in the bed nucleus of the stria terminalis (BNST) and blood cells after chronic stress. Integrative gene set enrichment analysis revealed enrichment of mitochondrial-related genes in the BNST and blood of stressed mice. To translate these results to human anxiety, we investigated blood gene expression changes associated with exposure-induced panic attacks. Remarkably, we found reduced expression of mitochondrial-related genes in D2 stress-susceptible mice and in exposure-induced panic attacks in humans, but increased expression of these genes in B6 stress-susceptible mice. Moreover, stress-susceptible vs. stress-resilient B6 mice displayed more mitochondrial cross-sections in the post-synaptic compartment after CSDS. Our findings demonstrate mitochondrial-related alterations in gene expression as an evolutionarily conserved response in stress-related behaviors and validate the use of cross-species approaches in investigating the biological mechanisms underlying anxiety disorders.


Assuntos
Ansiedade/genética , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Genômica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , MicroRNAs/genética , Mitocôndrias , Proteômica , RNA Mensageiro/genética , Núcleos Septais/metabolismo , Estresse Psicológico/fisiopatologia , Transcriptoma/genética
9.
PLoS One ; 14(8): e0220112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31390349

RESUMO

Short stress management interventions such as relaxation therapy have demonstrated preliminary effectiveness in reducing stress-related problems. A promising tool to strengthen the effectiveness of relaxation-based interventions is the use of verbal suggestions, as previous research provided evidence that verbal suggestions can induce positive outcome expectancies, facilitate adaptive responses to stress and improve health outcomes. The present experimental proof-of-concept study aimed to investigate the effects of a brief relaxation intervention and specifically the role of verbal suggestions on stress-related outcomes assessed by self-report questionnaires and psychophysiological data. 120 participants (mean age = 22.1 years) were randomized to one of four intervention conditions: a brief relaxation intervention plus verbal suggestions condition, a brief relaxation intervention only condition, a verbal suggestions only condition, and a control condition. Afterwards, participants were subjected to a psychosocial stress challenge to assess reactivity to a stressful event. Immediately after both relaxation interventions (with and without verbal suggestions), lower self-reported state anxiety was found compared to the control condition, but no differences were observed in response to the stressor. The verbal suggestions only condition did not impact state anxiety. No significant effects were found for verbal suggestion interventions on cortisol, alpha amylase, heart rate and skin conductance. This is the first study investigating the role of verbal suggestions in the effectiveness of a brief relaxation intervention. Although this experimental proof-of-concept study provides support for the effectiveness of a brief relaxation intervention in lowering state anxiety directly after the intervention, the effects did not impact the response to a subsequent stressor and we did not observe any evidence for the add-on effectiveness of verbal suggestions. The effectiveness of brief relaxation interventions on stress responses should be investigated further in future research by incorporating interventions that are tailored to the specific stress challenge and various types of verbal suggestions.


Assuntos
Terapia de Relaxamento/métodos , Sugestão , Adolescente , Adulto , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Ansiedade/psicologia , Ansiedade/terapia , Feminino , Resposta Galvânica da Pele , Frequência Cardíaca , Humanos , Hidrocortisona/metabolismo , Masculino , Saliva/metabolismo , Autorrelato , Resultado do Tratamento , Adulto Jovem , alfa-Amilases/metabolismo
10.
Psychopharmacology (Berl) ; 236(8): 2389-2403, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31375849

RESUMO

RATIONALE: According to psychological theories, cognitive distortions play a pivotal role in the aetiology and recurrence of mood disorders. Although clinical evidence for the coexistence of depression and altered sensitivity to performance feedback is relatively coherent, we still do not know whether increased or decreased sensitivity to positive or negative feedback is associated with 'pro-depressive' profile in healthy subjects. OBJECTIVE: Our research has been designed to answer this question, and here, we present the first steps in that direction. METHODS: Using a rat version of the probabilistic reversal-learning (PRL) paradigm, we evaluated how sensitivity to negative and positive feedback influences other cognitive processes associated with mood disorders, such as motivation in the progressive ratio schedule of reinforcement (PRSR) paradigm, hedonic status in the sucrose preference (SP) test, locomotor and exploratory activity in the open field (OF) test, and anxiety in the light/dark box (LDB) test. RESULTS: The results of our study demonstrated for the first time that in rodents, sensitivity to negative and positive feedback could be considered a stable and enduring behavioural trait. Importantly, we also showed that these traits are independent of each other and that trait sensitivity to positive feedback is associated with cognitive flexibility in the PRL test. The computational modelling results also revealed that in animals classified as sensitive to positive feedback, the α learning rates for both positive and negative reward prediction errors were higher than those in animals classified as insensitive. We observed no statistically significant interactions between sensitivity to negative or positive feedback and the parameters measured in the PRSR, SP, OF or LDB tests. CONCLUSIONS: Further studies using animal models of depression based on chronic stress should reveal whether sensitivity to feedback is a latent trait that when interacts with stressful life events, could produce correlates of depressive symptoms in rats.


Assuntos
Retroalimentação Fisiológica/fisiologia , Locomoção/fisiologia , Motivação/fisiologia , Esquema de Reforço , Reversão de Aprendizagem/fisiologia , Recompensa , Animais , Ansiedade/metabolismo , Ansiedade/psicologia , Simulação por Computador , Depressão/metabolismo , Depressão/psicologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
11.
BMC Mol Cell Biol ; 20(1): 41, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464580

RESUMO

BACKGROUND: Microtubule proteins are able to produce electromagnetic fields and have an important role in memory formation, and learning. Therefore, microtubules have the potential to be affected by exogenous electromagnetic fields. This study aimed to examine the comparison of microtubule polymerization and its structural behavior in brain and sperm affected by 50 Hz extremely low-frequency electromagnetic field (ELEF). RESULTS: Twenties adult male rats were randomly and equally divided into control and experimental groups, to evaluate the effect of 50 Hz ELEF on the sperm and brain functions. Plus-maze, serum testosterone and corticosterone, and sperm evaluation were performed. Next, the semen and brain samples were obtained, and they were divided into four experimental groups for investigation of microtubule polymerization. There was no significant difference in testosterone and, corticosterone levels, anxiety behaviors, and sperm morphology between control and ELEF-exposure groups. The sperm viability, total and progressive motility were significantly higher in the ELEF-exposed group than that of the control group. The microtubule polymerization in sperm ELEF was significantly higher than in other groups. The secondary and tertiary structures of tubulins were significantly affected in the brain, and sperm ELEF groups. CONCLUSION: It seems that the polymerization of microtubules and conformational changes of tubulin dimers are improved by ELEF application.


Assuntos
Encéfalo/metabolismo , Campos Eletromagnéticos , Microtúbulos/química , Polimerização , Espermatozoides/metabolismo , Animais , Ansiedade/metabolismo , Comportamento Animal , Peso Corporal , Forma Celular , Sobrevivência Celular , Corticosterona/sangue , Fluorescência , Masculino , Microtúbulos/metabolismo , Multimerização Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos Wistar , Espermatozoides/citologia , Testosterona/sangue , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
12.
Biol Pharm Bull ; 42(9): 1575-1580, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257273

RESUMO

Cedrol has been reported to be effective in reducing anxiety of male mice. The limited application of females in animal models of anxiety makes it difficult to systematically investigate new drug substitutes with potential anxiolytic activity. In the present study, we investigated the behavioral response of female ICR mice to cedrol after intraperitoneal (i.p.) administration using the elevated plus maze (EPM) and the light-dark box (LDB) test, followed by determination of neurochemical changes in brain. The data suggested that cedrol at dose of 1200-1600 mg·kg-1 exhibited anxiolytic activity on the female mice, as reflected by greater percentage of entries into the open arms and time spent in the open arms in the EPM, and greater transitions between chambers and percentage of time spent in the light chamber in the LDB. Cedrol increased the level of 5-hydroxytryptamine (5-HT), decreased the level of dopamine (DA), reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and increased the ratio of 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, compared with the control group, indicative of an anxiolytic-like effect on female mice via the 5-HTnergic or DAnergic pathways.


Assuntos
Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Neurotransmissores/metabolismo , /uso terapêutico , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Feminino , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos
13.
Mediators Inflamm ; 2019: 7651383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281228

RESUMO

Many patients experience excellent physical recoveries after surgery; however, there are some of them who from suffer mood fluctuation, even depression. Postoperative depression may be resulted from cognitive dysfunction, pain, and a compromised immune system during the surgery. But there is a higher possibility that general anaesthesia may be responsible for the development of depression. Here, we employed one of the most used anaesthetics, propofol, in a mouse model to investigate whether this intravenous anaesthetic compound could cause depressive-like behavioural performance in mice. We found a single dose of propofol caused significant abnormal behavioural performance in tail suspension, forced swimming, and open field tests. We also examined the brain section of these mice and revealed that there was significant reduced expression of the CD11b protein, which demonstrated an inhibition of propofol on microglial function. We investigated the effect of propofol on synaptic protein, SYP, and found there was no notable influence on the protein expression. These above results suggested that propofol treatment might promote the depressive-like behaviours in mice via influencing the microglial cell function. Furthermore, we found the level of the IL-6 cytokine was significantly increased in the brain tissue, which might subsequently cause the activation of the transcriptional factor, STAT3. Our finding may provide a new perspective of further understanding the mechanism of anaesthetic drugs and deciphering the underlying mechanism of postoperative depression.


Assuntos
Depressão/induzido quimicamente , Microglia/efeitos dos fármacos , Microglia/fisiologia , Propofol/efeitos adversos , Anestesia Intravenosa , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Antígeno CD11b/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Sinaptofisina/metabolismo
14.
Chin Med J (Engl) ; 132(14): 1689-1699, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31268909

RESUMO

BACKGROUND: Depression affects approximately 5% of elderly people and its etiology might be related to chronic stress exposure during neurodevelopmental periods. In this study, we examined the effects of adolescent chronic social stress in aged mice on depressive behaviors and the excitatory-inhibitory (E/I) balance in stress-sensitive regions of the brain. METHODS: Sixty-four adolescent, male C57BL/6 mice were randomly assigned to either the 7-week (from post-natal days 29 to 77) social instability stress (stress group, n = 32) or normal housing conditions (control group, n = 32). At 15 months of age, 16 mice were randomly selected from each group for a series of behavioral tests, including two depression-related tasks (the sucrose preference test and the tail suspension test). Three days following the last behavioral test, eight mice were randomly selected from each group for immunohistochemical analyses to measure the cell density of parvalbumin (PV)- and calretinin (CR)-positive gamma-aminobutyric-acid (GABA)ergic inhibitory inter-neurons, and the expression levels of vesicular transporters of glutamate-1 (VGluT1) and vesicular GABA transporter (VGAT) in three stress-sensitive regions of the brain (the medial pre-frontal cortex [mPFC], hippocampus, and amygdala). RESULTS: Behaviorally, compared with the control group, adolescent chronic stress increased depression-like behaviors as shown in decreased sucrose preference (54.96 ±â€Š1.97% vs. 43.11 ±â€Š2.85%, t(22) = 3.417, P = 0.003) and reduced latency to immobility in the tail suspension test (92.77 ±â€Š25.08 s vs. 33.14 ±â€Š5.95 s, t(25) = 2.394, P = 0.025), but did not affect anxiety-like behaviors and pre-pulse inhibition. At the neurobiologic level, adolescent stress down-regulated PV, not CR, inter-neuron density in the mPFC (F(1, 39) = 19.30, P < 0.001), and hippocampus (F(1, 42) = 5.823, P = 0.020) and altered the CR, not PV, inter-neuron density in the amygdala (F(1, 28) = 23.16, P < 0.001). The VGluT1/VGAT ratio was decreased in all three regions (all F > 10.09, all P < 0.004), which suggests stress-induced hypoexcitability in these regions. CONCLUSIONS: Chronic stress during adolescence increased depression-like behaviors in aged mice, which may be associated with the E/I imbalance in stress-sensitive brain regions.


Assuntos
Envelhecimento/fisiologia , Depressão/metabolismo , Depressão/fisiopatologia , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Ácido gama-Aminobutírico/metabolismo
15.
Vopr Pitan ; 88(3): 53-62, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31265775

RESUMO

Numerous experimental and clinical studies have shown high efficiency of plant polyphenolic compounds in restoring age-related memory and learning disorders. In the present study a functional food ingredient (FFI) was obtained by sorption of an aqueous solution of bilberry leaves extract on buckwheat flour, which allowed to concentrate polyphenols and increase their storage stability. The aim of this study was to evaluate the impact of a developed FFI, enriched with bilberry leaves` polyphenols, on the anxiety level, locomotor activity, memory and spatial learning of db/db mice with genetical type 2 diabetes. Material and methods. The experiment was conducted using 10 heterozygote male db/db mice and 10 homozygote male db/+ mice as the comparison control group (7 weeks of age). According to body weight, blood glucose level, the results of insulin resistance test and elevated plus-maze (EPM) test, animals were randomized into three groups: control group C1 - db/+ animals, control group C2 and experimental group G3 - obese db/db mice. Buckwheat flour was included into the diet of C2 group in a dose 22.5 g/100 g; FFI was included into the diet of G3 group in a dose 2.5 g/100 g (that was equal to 59.2± 1.4 mg-eq gallic acid per 100 g of the diet). The anxiety level and general locomotor activity were evaluated in the EPM test. The evaluation of behavior, memory and spatial learning was performed using passive avoidance test (PAT). Glycated hemoglobin level was determined in blood, insulin and leptin levels were determined in blood plasma, general antioxidant activity was determined in liver cytosolic fraction. Results and discussion. The obtained data on biochemical parameters and insulin resistance tests showed the absence of normalizing effects of developed FFI. However, the inclusion of polyphenol-containing FFI into the diet led to beneficial changes in physiological parameters. Animals of G3 group, provided with FFI, were significantly less anxious compared to both control groups. During PAT testing of short-term memory, no animals in G3 group entered to the dark compartment (0%), what demonstrated increased learning ability and well-established memory of these animals in comparison with C1 (50%) and C2 groups (80%). Conclusion. The results prove the effectiveness of bilberry leaves` polyphenols, sorbed on the brown buckwheat flour, in the correction of central nervous system disorders in db/ db mice with genetically altered type 2 diabetes, what points at possible prospect of FFI inclusion in therapeutic products for patients with type 2 diabetes mellitus.


Assuntos
Ansiedade/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Aprendizagem em Labirinto , Memória/efeitos dos fármacos , Folhas de Planta/química , Polifenóis/farmacologia , Vaccinium myrtillus/química , Animais , Ansiedade/metabolismo , Ansiedade/patologia , Ansiedade/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Masculino , Camundongos , Polifenóis/química
16.
Neurosci Lett ; 708: 134359, 2019 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-31265872

RESUMO

The aim of this study was to evaluate salivary cortisol and plasma brain-derived neurotrophic factor (BDNF) in people with PD, to compare them with healthy controls and to associate them with levels of anxiety and depression. For this, 18 people with PD and 17 controls were recruited. The stage of the disease was determined by Hoehn and Yahr Disability Scale (H&Y), biomarkers levels were determined by enzyme-linked immunosorbent assay (ELISA) and anxiety and depression levels were assessed by the Hamilton Anxiety Assessment Scale (HAM-A) and Hamilton Depression Scale (HAM-D). The results show that in the PD group the median age was 68 years, the diagnosis time was 4.5 years and according to H&Y, 61.2% were in stage 2. The median values of cortisol were 972.5 pg/ml and BDNF, 215.7 pg/ml. The median HAM-A was 17 points and in HAM-D, 10. The control group had a median age of 62 years, cortisol values of 425 pg/ml and BDNF, 340.1 pg/ml. In HAM-A and HAM-D, the median was 2 points. There were no significant differences between levels of BDNF, but higher levels of cortisol were demonstrated in PD. Moreover, anxiety and depression were associated with biomarkers levels. These findings may suggest an involvement of neuroendocrine changes in the pathophysiology of the PD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Hidrocortisona/sangue , Doença de Parkinson/metabolismo , Saliva/química , Idoso , Ansiedade/metabolismo , Biomarcadores/análise , Estudos de Casos e Controles , Estudos Transversais , Depressão/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/psicologia
17.
Horm Behav ; 114: 104541, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31220462

RESUMO

For basic research, rodents are often housed in individual cages prior to behavioral testing. However, aspects of the experimental design, such as duration of isolation and timing of animal manipulation, may unintentionally introduce variance into collected data. Thus, we examined temporal correlates of acclimation of C57Bl/6J mice to single housing in a novel environment following two commonly used experimental time periods (7 or 14 days, SH7 or SH14). We measured circulating stress hormones (adrenocorticotropic hormone and corticosterone), basally or after injection stress, hippocampal gene expression of transcripts implicated in stress and affect regulation: the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), including the MR/GR ratio, and fibroblast growth factor 2 (FGF2). We also measured signaling in the mammalian target of rapamycin (mTOR) pathway. The basal elevation of stress hormones in the SH14 group is accompanied by a blunting in the circadian rhythms of GR and FGF2 hippocampal gene expression, and the MR/GR ratio, that is observed in SH7 mice. Following mild stress, the endocrine response and hippocampal mTOR pathway signaling are decreased in the SH14 mice. These neural and endocrine changes at 14 days of single housing likely underlie increased anxiety-like behavior measured in an elevated plus maze test. We conclude that multiple measures of stress responsiveness change dynamically between one and two weeks of single housing. The ramifications of these alterations should be considered when designing animal experiments since such hidden sources of variance might cause lack of replicability and misinterpretation of data.


Assuntos
Aclimatação/fisiologia , Ansiedade , Encéfalo/metabolismo , Hormônios/metabolismo , Abrigo para Animais , Hormônio Adrenocorticotrópico/metabolismo , Animais , Ansiedade/genética , Ansiedade/metabolismo , Corticosterona/metabolismo , Expressão Gênica , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais/genética
18.
BMC Complement Altern Med ; 19(1): 147, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234859

RESUMO

BACKGROUND: Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways. METHODS: Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays. RESULTS: MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS. CONCLUSIONS: These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.


Assuntos
Ansiolíticos/administração & dosagem , Ansiedade/tratamento farmacológico , Núcleo Central da Amígdala/efeitos dos fármacos , Etanol/efeitos adversos , Neuropeptídeos/metabolismo , Síndrome de Abstinência a Substâncias/complicações , Ziziphus/química , Animais , Ansiedade/etiologia , Ansiedade/genética , Ansiedade/metabolismo , Núcleo Central da Amígdala/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sementes/química
19.
Biofactors ; 45(5): 666-689, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185140

RESUMO

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Curcumina/farmacologia , Demência/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/metabolismo , Transtorno Autístico/fisiopatologia , Disponibilidade Biológica , Curcuma/química , Curcumina/isolamento & purificação , Demência/metabolismo , Demência/fisiopatologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/fisiopatologia , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/fisiopatologia , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatologia , Fármacos Neuroprotetores/isolamento & purificação , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Patentes como Assunto , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/metabolismo , Doenças Priônicas/fisiopatologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia
20.
Neural Plast ; 2019: 7492306, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191638

RESUMO

Hippocampal atrophy is one of the key changes in the brain implicated in the biology of depression. However, the precise molecular mechanism remains poorly understood due to a lack of biomarkers. In this research, we used behavioral experiments to evaluate anxiety and anhedonia levels in depressed rats using chronic unpredictable mild stress (CUMS) modeling. We also used isobaric tag for relative and absolute quantitation (iTRAQ) to identify the differentially expressed hippocampal proteins between depressed and normal rats. Bioinformatics analyses were also performed for a better understanding. The results showed that CUMS rats had higher anxiety and anhedonia levels than control rats, along with hippocampal lesions. Through iTRAQ and bioinformatics analyses, we found that ribosome proteins were significantly downregulated and Ras proteins exhibited a mixed change in the hippocampus of depressed rats. These findings suggest that the expression of hippocampal ribosome lesions and Ras proteins is significantly different in depressed rats than in control rats, providing new insights into the neurobiology of depression.


Assuntos
Depressão/metabolismo , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Ribossomos/metabolismo , Proteínas ras/metabolismo , Animais , Ansiedade/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Masculino , Análise Serial de Proteínas , Ratos , Ratos Wistar , Estresse Psicológico/metabolismo
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