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1.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540539

RESUMO

Treatment of the unpredictable chronic mild stress (UCMS) mice with the ethanol extract of Dipterocarpus alatus leaf attenuated anhedonia (increased sucrose preference) and behavioral despair (decreased immobility time in tail suspension test (TST) and forced swimming test (FST)). The extract not only decreased the elevation of serum corticosterone level and the index of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, caused by UCMS, but also ameliorated UCMS-induced up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression and down-regulation of cyclic AMP-responsive element binding (CREB) and brain-derived neurotrophic factor (BDNF) mRNAs in frontal cortex and hippocampus. In vitro monoamine oxidase (MAO) inhibition assays showed that the extract exhibited the partial selective inhibition on MAO-A. HPLC analysis of the extract showed the presence of flavonoids (luteolin-7-O-glucoside, kaempferol-3-glucoside, rutin) and phenolic acids (gallic acid, ferulic acid, and caffeic acid) as major constituents.


Assuntos
Depressão , Dipterocarpaceae/química , Etanol/química , Extratos Vegetais , Folhas de Planta/química , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Proteínas Imediatamente Precoces/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Serina-Treonina Quinases/biossíntese , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
2.
Food Funct ; 10(8): 4533-4545, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31264676

RESUMO

Gardenia blue pigments derived from genipin reacting with amino acids have been used as natural food colorants for nearly 30 years in East Asia. However, their pharmacological effects, especially antidepressant-like effects, have not been reported so far. In this study, one of the gardenia blue pigments, was obtained from the reaction of genipin with tyrosine (genipin-tyrosine derivant (GTD)), and its antidepressant-like effects were investigated in lipopolysaccharide (LPS) or chronic unpredictable mild stress (CUMS) models. The results showed that GTD could attenuate depressive-like behaviors in both animal models. GTD reversed the LPS-induced cytokine increase of TNF-α, IL-6, and corticosterone (CORT) in mice plasma and hippocampus. In CUMS rats, GTD treatment significantly reduced hypothalamic-pituitary-adrenal (HPA) axis-related stress hormone levels in plasma including those of CORT, adrenocorticotropic hormone (ACTH), and corticotropin-releasing hormone (CRH). Besides, GTD increased plasma testosterone and hippocampal brain-derived neurotrophic factor (BDNF) levels in CUMS rats. GTD increased serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in rat hippocampus and corpus striatum. Consistently, hippocampal metabolomic analysis demonstrated that GTD restored monoamine neurotransmitter metabolism, mitochondrial oxidative function, and membrane structural integrity. Our data suggested that GTD produced antidepressant-like activity through the restoration of the HPA axis hormone balance and the regulation of neurotransmitter release.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Gardenia/química , Iridoides/química , Pigmentos Biológicos/administração & dosagem , Extratos Vegetais/administração & dosagem , Tirosina/química , Animais , Antidepressivos/química , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/metabolismo , Depressão/genética , Depressão/metabolismo , Depressão/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pigmentos Biológicos/química , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
3.
Gerontology ; 65(5): 465-473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31212285

RESUMO

Anxiety disorders are common, yet clinically underrecognized in late life, with estimated prevalence rates ranging from 1.2 to 15%. They are highly comorbid with depression, sleep disorders, and substance use disorders, may accelerate cognitive decline, and potentially catalyze morbidity and mortality risk in the elderly. Thus, a more detailed knowledge about the underlying mechanisms of late-life anxiety disorders is urgently warranted. Age-related genetic, neuroimaging, neuroendocrine, and neuropsychological markers as well as late-life specific psychosocial aspects, particularly loss and isolation, have been identified as prominent pathogenetically relevant and thus potentially targetable factors. Personalized treatments based on individual biological and biographic markers, innovative therapeutic approaches, and preventive strategies have great potential to alleviate the high individual and societal burden of late-life anxiety disorders.


Assuntos
Envelhecimento/psicologia , Transtornos de Ansiedade/psicologia , Idoso , Ansiedade/psicologia , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Envelhecimento Cognitivo/psicologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Comorbidade , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/psicologia , Isolamento Social/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
4.
Nat Rev Endocrinol ; 15(9): 525-534, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31249398

RESUMO

The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic-pituitary-adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway - cortisol - is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge in adrenocorticotropic hormone levels, if long-term inflammatory stress occurs, adrenocorticotropic hormone levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone-dominant to arginine vasopressin-dominant, and cortisol levels remain raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are beneficial to promoting survival of the fittest as part of the fight-or-flight response. However, chronic exposure to stress results in reversal of the beneficial effects, with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoid-based therapeutics are also discussed.


Assuntos
Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Ritmo Circadiano/fisiologia , Terapia de Reposição Hormonal/métodos , Humanos , Estresse Psicológico/psicologia , Estresse Psicológico/terapia
5.
Biomed Pharmacother ; 117: 109077, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177064

RESUMO

BACKGROUND: Prenatal stress (PS) leads to a wide variety of behavioral and emotional aberration observed in later life, particularly in the impairment of spatial learning and memory in offspring. Icariin (ICA) is a naturally occurring furanocoumarin and exhibits many pharmacological properties, including potent improvement on learning and memory. PURPOSE: We pretend to investigate the improvement of ICA on learning and memory impairment in PS. METHODS: Female PS offspring rats were used to explore the effects of ICA on learning and memory impairment. After 28 days of ICA (20, 40 and 80 mg/kg/day) treatment, we measured Morris water maze and 8-Arm Maze, the HPA axis and the related pathway in the hippocampus. RESULTS: We reported that ICA ameliorated the spatial learning and memory and working memory impairment in the female offspring rats. Correspondingly, ICA prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus. ICA significantly decreased the serum adrenocorticotropin, corticotropin-releasing hormone and corticosterone levels in offspring rats exposed to PS, associated with increased GR expression. Additionally, ICA treatment significantly increased the neurogranin (Ng) and c-fos protein expression of hippocampus in the offspring rats. Furthermore, the protein of relative content of p-EKR/ERK, p-CaMKIIα/CaMKIIα, p-CREB/CREB were remarkably increased after ICA treatment in the offspring rats. CONCLUSION: Taken together, ICA may be an effective therapeutic for learning and memory dysfunction in female offspring exposed to PS, its neuroprotective effect was mediated in part by normalizing the HPA axis and up-regulating of ERK/CaMKIIα/CREB signaling, Ng and c-fos protein.


Assuntos
Flavonoides/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo
6.
Neuropsychobiology ; 78(3): 145-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189176

RESUMO

BACKGROUND: Dysregulation of leptin secretion and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the pathophysiology of suicide. Preclinical and clinical studies have shown interactions between the HPA axis and leptin. There is also evidence for a negative relationship between leptin and anxiety in humans. However, these possible associations have not been studied in individuals with attempted suicide. OBJECTIVES: To examine the relationship between leptin, HPA axis activity, and anxiety in individuals with a recent suicide attempt. METHOD: Sixty-nine individuals with a recent suicide attempt (n = 37 females; n = 32 males) were recruited and subjected to the Dexamethasone Suppression Test (DST), lumbar puncture, and evaluation with the Comprehensive Psychopathological Rating Scale from which the Brief Scale for Anxiety (BSA) was derived. Leptin was analyzed in cerebrospinal fluid (CSF) and cortisol in serum. Leptin was corrected for body mass index (BMI) by dividing CSF-leptin by BMI (CSF-leptin/BMI). Due to gender-related differences in leptin secretion and HPA axis activity, calculations were made for males and females separately. RESULTS: Significant differences were only found among females; CSF-leptin/BMI levels correlated significantly and negatively with BSA (p < 0.05), pre-DST cortisol, and post-DST serum cortisol at 8 a.m. and 3 p.m. (all p < 0.05). Furthermore, CSF-leptin/BMI was significantly lower in nonsuppressors of dexamethasone as compared to suppressors (p < 0.05). CONCLUSIONS: These findings suggest that in females with a recent suicide attempt, low CSF leptin may be related to symptoms of anxiety and a hyperactive HPA axis.


Assuntos
Ansiedade/sangue , Ansiedade/líquido cefalorraquidiano , Sistema Hipotálamo-Hipofisário/metabolismo , Leptina/líquido cefalorraquidiano , Sistema Hipófise-Suprarrenal/metabolismo , Tentativa de Suicídio/psicologia , Adulto , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Caracteres Sexuais
7.
Psychopharmacology (Berl) ; 236(8): 2485-2500, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201478

RESUMO

BACKGROUND: Borderline personality disorder (BPD) is a pervasive psychiatric disorder characterized by emotion dysregulation, impulsivity, impaired self-perceptions, and interpersonal relationships and currently affects 1-3% of the US population as reported by Torgersen et al. (Arch Gen Psychiatry 58:590-596, Torgersen et al. 2001), Lenzenweger et al. (Biol Psychiatry 62:553-564, Lenzenweger et al. 2007), and Tomko et al. (J Personal Disord 28:734-750, Tomko et al. 2014). One major obstacle to our understanding of the neural underpinnings of BPD is a lack of valid animal models that translate the key known features of the disorder to a system that is amenable to study. OBJECTIVE: To summarize the etiology, major symptoms, and symptom triggers of BPD and then propose a blueprint for building an animal model of BPD by choosing key components of the disorder that can be implemented in rodents. RESULTS: We identify the role of early life stress and subsequent mild stress in adulthood as contributing etiological factors and the potential use of altered communication between frontal cortices and the amygdala in extinction and habituation, increased impulsivity, dysregulation of the hypothalamic pituitary axis (HPA), and increased neuroinflammation as biological markers of BPD. Building upon these features of BPD, we propose a two-hit animal model that uses maternal abandonment to alter maturation of the HPA axis and mild secondary adult stress to evoke behavioral symptoms such as increased impulsivity and impaired extinction, habituation, and social interactions. CONCLUSION: Through exploration of the etiology, symptom presentation, and altered neurological function, we propose an animal model of BPD. We believe that a number of existing animal paradigms that model other mental health disorders should be combined in a unique way to reflect the etiology, symptom presentation, and altered neurological function that is evident in BPD. These model, when compared with available human data, will inform research and treatment in humans for better understanding of systems from the micro-molecular level to more global physiology underlying BPD.


Assuntos
Transtorno da Personalidade Borderline/psicologia , Modelos Animais de Doenças , Comportamento Impulsivo/fisiologia , Relações Interpessoais , Tonsila do Cerebelo/metabolismo , Animais , Transtorno da Personalidade Borderline/genética , Transtorno da Personalidade Borderline/metabolismo , Emoções/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia
8.
Transl Psychiatry ; 9(1): 158, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164628

RESUMO

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ouabaína/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Injeções Intraventriculares , Compostos de Lítio/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos Wistar
9.
Endocrinology ; 160(7): 1719-1730, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166572

RESUMO

The control of steroidogenesis in the neonatal adrenal gland is of great clinical interest. We have previously demonstrated that the postnatal day (PD) 2 rat exhibits a large plasma corticosterone response to hypoxia in the absence of an increase in plasma ACTH measured by RIA, whereas the corticosterone response to exogenous ACTH is intact. By PD8, the corticosterone response to hypoxia is clearly ACTH-dependent. We hypothesized that this apparently ACTH-independent response to hypoxia in the newborn rat is due to an increase in a bioactive, nonimmunoassayable form of ACTH. To evaluate this phenomenon, we pretreated neonatal rats with a novel, specific, neutralizing anti-ACTH antibody (ALD1611) (20 mg/kg or 1 mg/kg IP) on the morning of PD1, PD7, and PD14. Twenty-four hours later, we measured hypoxia- or ACTH-stimulated plasma ACTH and corticosterone. For long-term effects, ALD1611 was given on PD1 and pups were studied on PD8 and PD15. Pretreatment with ALD1611 significantly decreased baseline corticosterone and completely blocked the corticosterone response to hypoxia and exogenous ACTH stimulation at all ages. The effect of 1 mg/kg ALD1611 on PD1 had dissipated by PD15. The decrease in corticosterone in ALD1611-treated pups was associated with decreases in baseline and hypoxia- and ACTH-stimulated adrenal Ldlr, Mrap, and Star mRNA expression at all ages. The adrenal response to hypoxia in the newborn rat is ACTH-dependent, suggesting the release of nonimmunoassayable, biologically active forms of ACTH. ALD1611 is useful as a tool to attenuate stress-induced, ACTH-dependent adrenal steroidogenesis in vivo.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Hormônio Adrenocorticotrópico/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Corticosterona/sangue , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipóxia/metabolismo , Masculino , Fosfoproteínas/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de LDL/metabolismo
10.
Eur J Endocrinol ; 181(2): 201-210, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31167165

RESUMO

Background: Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing's syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown. Methods: Cohort study included consecutive patients with Cushing's syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence and assessed the effect of better education in time on incidence of adrenal crisis. Results: We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval (CI): 6.7-12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2-4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies. Conclusions: The incidence of adrenal crises after treatment for Cushing's syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing's syndrome, which is probably the period of severest HPA axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.


Assuntos
Insuficiência Adrenal/metabolismo , Síndrome de Cushing/metabolismo , Síndrome de Cushing/cirurgia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Complicações Pós-Operatórias/metabolismo , Adolescente , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Síndrome de Cushing/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Adulto Jovem
11.
J Anim Sci ; 97(7): 2940-2951, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31081510

RESUMO

The present study used Escherichia coli lipopolysaccharide (LPS) to investigate whether maternal immune challenge during late gestation altered programming of the offspring hypothalamus and hypothalamic-pituitary-adrenal axis (HPAA). In addition, interactions of maternal diet, supplementation with fish oil (FO) or microalgae (AL), and complex vs. simple weaning diets were investigated. Briefly, Landrace × Yorkshire sows (N = 48) were randomly assigned to diets supplemented with FO, AL, or a standard gestation control diet (CON) from day 75 of gestation (gd 75) until parturition. On gd 112, half the sows from each dietary treatment were immune challenged with LPS (10 µg/kg BW) or saline as a control. At 21 d postpartum, the offspring were weaned, and half the animals from each maternal treatment were allocated to either a complex or simple weaning diet. At 28 d postpartum, the offspring's hourly fever and 2-h cortisol responses to LPS immune challenge (40 µg/kg BW) were measured to assess hypothalamus and HPAA function. Results indicated that the maternal temperature of sows on the FO diet returned to baseline levels faster than sows on the AL and CON diets after LPS immune challenge (P < 0.05). In contrast, there was no difference in the maternal cortisol response across the dietary treatments (P > 0.10). Regardless of the dietary treatments, the maternal LPS immune challenge induced a greater cortisol response in male offspring (P = 0.05) and a greater fever response in female offspring (P = 0.03) when they were LPS immune challenged post-weaning. Male offspring from LPS-immune-challenged sows fed the FO and AL diets had a greater fever response than male offspring from the maternal CON diet group (P ≤ 0.05). Last, no effect of the complex or simple weaning diets was observed for the nursery pig cortisol or fever responses to LPS immune challenge. In conclusion, LPS immune challenge during late pregnancy altered responsiveness of the offspring hypothalamus and HPAA to this same microbial stressor, and a sex-specific response was influenced by maternal dietary supplementation with FO and AL.


Assuntos
Suplementos Nutricionais , Óleos de Peixe/farmacologia , Microalgas , Suínos/fisiologia , Animais , Óleo de Milho/farmacologia , Dieta/veterinária , Escherichia coli/química , Feminino , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Projetos Piloto , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Distribuição Aleatória , Fatores Sexuais , Suínos/imunologia , Desmame
12.
PLoS One ; 14(5): e0216000, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116735

RESUMO

Hair is an emerging biological matrix in which to measure chronic HPA axis activity, offering a longer term view into an animal's life. We explored effects of exogenous (e.g. lifestyle, medications, social environment) and endogenous (e.g. disease, behaviour) stressors on hair cortisol concentration (HCC) in a population of Border Collies (BCs). Owners of BCs were recruited and reported their dog's lifestyle, clinical history, anxiety-related behaviour, and collected a white hair sample from their dog's dorsal neck region. HCC was determined using established methods with a commercial cortisol assay kit. Samples from 135 BCs were analysed, with 91 healthy controls and 44 diagnosed with epilepsy as a model disease. Factors associated with higher HCC included psychosocial stressors (living with three or more other dogs) and lifestyle (engaging in competitive flyball); while factors associated with lower HCC included anxiety (stranger-directed and non-social), health (epilepsy diagnosis, with number of seizures to date negatively correlated with HCC) and medication (certain anti-epileptic drugs were associated with elevated or reduced HCC). These novel results highlight the potential of chronic stress with frequent or persisting HPA-axis hyperactivity leading to a state of hypocortisolism, and the need to consider stressor recency and recurrence when interpreting HCC data.


Assuntos
Cabelo/metabolismo , Cabelo/fisiologia , Hidrocortisona/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Cães , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia
13.
J Assist Reprod Genet ; 36(6): 1273-1280, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31073722

RESUMO

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease's pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. PARTICIPANTS AND METHODS: We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. RESULTS: At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8 years, one female exhibited a spontaneous recovery of the hypothalamic-pituitary-adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). CONCLUSIONS: Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic-pituitary-gonadal, -adrenal, and -somatotropic axes.


Assuntos
Hipogonadismo/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Receptores de Kisspeptina-1/genética , Reprodução/genética , Adolescente , Corticosteroides/uso terapêutico , Adulto , Criança , Feminino , Hormônio Liberador de Gonadotropina/genética , Gonadotropinas/uso terapêutico , Humanos , Hipogonadismo/tratamento farmacológico , Hipogonadismo/patologia , Sistema Hipotálamo-Hipofisário/patologia , Masculino , Mutação , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
14.
Ther Adv Cardiovasc Dis ; 13: 1753944719851950, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31144599

RESUMO

Women are at increased risk for developing depression and cardiovascular disease (CVD) across the lifespan and their comorbidity is associated with adverse outcomes that contribute significantly to rates of morbidity and mortality in women worldwide. Immune-system activity has been implicated in the etiology of both depression and CVD, but it is unclear how inflammation contributes to sex differences in this comorbidity. This narrative review provides an updated synthesis of research examining the association of inflammation with depression and CVD, and their comorbidity in women. Recent research provides evidence of pro-inflammatory states and sex differences associated with alterations in the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system and the serotonin/kynurenine pathway, that likely contribute to the development of depression and CVD. Changes to inflammatory cytokines in relation to reproductive periods of hormonal fluctuation (i.e. the menstrual cycle, perinatal period and menopause) are highlighted and provide a greater understanding of the unique vulnerability women experience in developing both depressed mood and adverse cardiovascular events. Inflammatory biomarkers hold substantial promise when combined with a patient's reproductive and mental health history to aid in the prediction, identification and treatment of the women most at risk for CVD and depression. However, more research is needed to improve our understanding of the mechanisms underlying inflammation in relation to their comorbidity, and how these findings can be translated to improve women's health.


Assuntos
Doenças Cardiovasculares/imunologia , Depressão/imunologia , Sistema Imunitário/imunologia , Inflamação/imunologia , Reprodução/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Cinurenina/imunologia , Cinurenina/metabolismo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Sistema Renina-Angiotensina/imunologia , Serotonina/imunologia , Serotonina/metabolismo , Transdução de Sinais
15.
Neuroscience ; 409: 195-203, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31055007

RESUMO

Sex differences in neural structures are generally believed to underlie sex differences reported in anxiety, depression, and the hypothalamic-pituitary-adrenal axis, although the specific circuitry involved is largely unclear. Using a corticotropin-releasing factor receptor 1 (CRFR1) reporter mouse line, we report a sexually dimorphic distribution of CRFR1 expressing cells within the paraventricular hypothalamus (PVN; males > females). Relative to adult levels, PVN CRFR1-expressing cells are sparse and not sexually dimorphic at postnatal days 0, 4, or 21. This suggests that PVN cells might recruit CRFR1 during puberty or early adulthood in a sex-specific manner. The adult sex difference in PVN CRFR1 persists in old mice (20-24 months). Adult gonadectomy (6 weeks) resulted in a significant decrease in CRFR1-immunoreactive cells in the male but not female PVN. CRFR1 cells show moderate co-expression with estrogen receptor alpha (ERα) and high co-expression with androgen receptor, indicating potential mechanisms through which circulating gonadal hormones might regulate CRFR1 expression and function. Finally, we demonstrate that a psychological stressor, restraint stress, induces a sexually dimorphic pattern of neural activation in PVN CRFR1 cells (males >females) as assessed by co-localization with the transcription/neural activation marker phosphorylated CREB. Given the known role of CRFR1 in regulating stress-associated behaviors and hormonal responses, this CRFR1 PVN sex difference might contribute to sex differences in these functions.


Assuntos
Sistema Hipotálamo-Hipofisário/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Caracteres Sexuais , Estresse Psicológico/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação , Restrição Física
16.
Gac Med Mex ; 155(2): 184-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31056603

RESUMO

Polycystic ovary syndrome is the most common endocrine disease in reproductive age, characterized by menstrual alterations, clinical or biochemical hyperandrogenism, and ultrasound-identified ovarian cysts. The neuroendocrine and metabolic alterations that accompany this condition involve the desensitization of the hypothalamus-pituitary-ovary axis, steroidogenesis and hyperandrogenism; recently, the role of insulin resistance has been explored. Hyperandrogenism has been established to be the main cause of polycystic ovary syndrome, due to enzymatic alterations in the steroidogenic pathway that cause luteinizing hormone over-stimulation because of quick pulses generated by gonadotropin-releasing hormones. Various growth factors of and cytokines inhibit the conversion of androgens into estrogens; activin and prostaglandins are also involved, even high levels of insulin participate in the characteristic deregulation of this syndrome.


Assuntos
Hiperandrogenismo/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Resistência à Insulina , Hormônio Luteinizante/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo
17.
Acta Neuropsychiatr ; 31(4): 186-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31106715

RESUMO

OBJECTIVE: Depression is a disorder caused by genetics and environmental factors. The aim of this study was to perform a review investigating the interaction between genetic variations located in genes involved in hypothalamus-pituitary-adrenal axis (HPA-axis) and stressful life events (SLEs) in depression. METHODS: In this systematic review, we selected articles investigating the interaction between genes involved in the HPA-axis, such as Arginine Vasopressin (AVP), Angiotensin Converting Enzyme (ACE), Corticotrophin Releasing Hormone (CRH), Corticotrophin Releasing Hormone Receptor 1 (CRHR1), Corticotrophin Releasing Hormone Receptor 2 (CRHR2), FK506 binding protein (FKBP5), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Nuclear Receptor subfamily 3 group C member 2 (NR3C2), and SLE. The literature search was conducted using the Pubmed, Embase, and PsychINFO databases in adherence with the PRISMA guidelines. RESULTS: The search yielded 48 potentially relevant studies, of which 40 were excluded following screening. Eight studies were included in the final review. A total of 97 single nucleotide polymorphisms (SNPs) were examined in the eight included studies. The most prevalent gene was FKBP5, and the best studied polymorphism was FKBP5:rs1360780. Two of the five studies reported significant gene-environment (G × E) interactions between rs1360780 and SLE. Overall, four studies reported significant G × E interactions between FKBP5, CRH, or CRHR1 and SLE, respectively. No significant G × E interactions were found for the remaining genes. CONCLUSIONS: Our results suggest that genetic variation in three genes in the HPA-axis possibly moderate the effects of SLEs in depression.


Assuntos
Transtorno Depressivo/genética , Interação Gene-Ambiente , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/genética , Transtorno Depressivo/complicações , Humanos , Polimorfismo de Nucleotídeo Único , Estresse Psicológico/complicações , Proteínas de Ligação a Tacrolimo/genética
18.
Biofactors ; 45(4): 495-506, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30937979

RESUMO

Environmental noise is a well-recognized health risk and part of the external exposome-the World Health Organization estimates that 1 million healthy life years are lost annually in Western Europe alone due to noise-related complications, including increased incidence of hypertension, heart failure, myocardial infarction, and stroke. Previous data suggest that noise works through two paired pathways in a proposed reaction model for noise exposure. As a nonspecific stressor, chronic low-level noise exposure can cause a disruption of sleep and communication leading to annoyance and subsequent sympathetic and endocrine stress responses leading to increased blood pressure, heart rate, stress hormone levels, and in particular more oxidative stress, being responsible for vascular dysfunction and representing changes of the internal exposome. Chronic stress generates cardiovascular risk factors on its own such as increased blood pressure, blood viscosity, blood glucose, and activation of blood coagulation. To this end, persistent chronic noise exposure increases cardiometabolic diseases, including arterial hypertension, coronary artery disease, arrhythmia, heart failure, diabetes mellitus type 2, and stroke. The present review discusses the mechanisms of the nonauditory noise-induced cardiovascular and metabolic consequences, focusing on mental stress signaling pathways, activation of the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system, the association of these activations with inflammation, and the subsequent onset of oxidative stress and vascular dysfunction. © 2019 BioFactors, 45 (4):495-506, 2019.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Doença da Artéria Coronariana/induzido quimicamente , Diabetes Mellitus Tipo 2/induzido quimicamente , Poluentes Ambientais/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Hipertensão/induzido quimicamente , Acidente Vascular Cerebral/induzido quimicamente , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Coagulação Sanguínea/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Viscosidade Sanguínea/efeitos dos fármacos , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia
19.
J Endocrinol ; 241(3): 279-292, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31013474

RESUMO

Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5 to E15.5. To test the direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affected by dexamethasone treatment in either genotype. Dexamethasone treatment transiently decreased the myocardial deceleration index (MDI; a marker of diastolic function), in control fetuses at E15.5, with recovery by E17.5, 2 days after cessation of treatment. MDI was lower in SMGRKO than in control fetuses and was unaffected by dexamethasone. The transient decrease in MDI was associated with repression of cardiac GR in control fetuses following dexamethasone treatment. Measurement of glucocorticoid levels in fetal tissue and hypothalamic corticotropin-releasing hormone (Crh) mRNA levels suggest complex and differential effects of dexamethasone treatment upon the hypothalamic-pituitary-adrenal axis between genotypes. These data suggest potentially detrimental and direct effects of antenatal glucocorticoid treatment upon fetal heart function.


Assuntos
Dexametasona/farmacologia , Diástole/efeitos dos fármacos , Coração Fetal/efeitos dos fármacos , Exposição Materna , Animais , Peso Corporal , Feminino , Coração Fetal/diagnóstico por imagem , Genótipo , Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Tamanho do Órgão , Sistema Hipófise-Suprarrenal/metabolismo , RNA Mensageiro/metabolismo , Receptores de Glucocorticoides/metabolismo
20.
Depress Anxiety ; 36(6): 480-489, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31017373

RESUMO

BACKGROUND: The serotonin system and hypothalamic pituitary-adrenal (HPA)-axis are each implicated in the pathway to depression; human and animal research support these systems' cross-talk. Our work implicates a 5-variant additive serotoninergic multilocus genetic profile score (MGPS) and separately the cortisol awakening response (CAR) in the prospective prediction of depression; other work has shown that the serotonin transporter polymorphism 5HTTLPR predicts CAR and interacts with the CAR to predict depression. METHODS: We tested the hypothesis that a 6-variant MGPS (original plus 5HTTLPR) would interact with CAR to predict prospective depressive episode onsets in 201 emerging adults using four annual follow-up interviews. We also tested whether MGPS predicted CAR. We attempted replication of significant findings in a sample of 77 early adolescents predicting depression symptoms. RESULTS: In sample 1, MGPS did not significantly predict CAR. MGPS interacted with CAR to predict depressive episodes; CAR slopes for depression steepened as MGPS increased, for risk or protection. No single variant accounted for results, though CAR's interactions with 5HTTLPR and the original MGPS were both significant. In sample 2, the 6-variant MGPS significantly interacted with CAR to predict depression symptoms. CONCLUSIONS: Higher serotonergic MGPS appears to sensitize individuals to CAR level-for better and worse-in predicting depression.


Assuntos
Distinções e Prêmios , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Hidrocortisona/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina/metabolismo , Adolescente , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo Genético , Estudos Prospectivos , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
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