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1.
Presse Med ; 48(11 Pt 1): 1229-1236, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31732360

RESUMO

Cannabis use is widespread among people at ultra-high risk (UHR) for psychosis. The causal link as well as the temporal link between cannabis use and further occurrence of psychosis in UHR people remain inconclusive. Current science data supported an increased risk of transition to psychosis in cannabis users who are genetically predisposed to psychosis. This risk would be even greater in the presence of a family history of psychosis, in case of a strong use and an early onset use. Several models have been cited to explain the link between cannabis use and the subsequent onset of psychosis or prepsychotic states: cannabis-induced modifications of some brain structures, a dysregulation of the hypothalamic-pituitary axis and an alteration of normal neurological development via the endocannabinoid system. Cannabis represents a modifiable risk for psychosis. Current interventions aim to reduce or stop the cannabis use in order to reduce the risk of transition to psychosis.


Assuntos
Cannabis/efeitos adversos , Abuso de Maconha/complicações , Psicoses Induzidas por Substâncias/etiologia , Fatores Etários , Encéfalo/efeitos dos fármacos , Endocanabinoides/fisiologia , Predisposição Genética para Doença , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Anamnese , Psicoses Induzidas por Substâncias/prevenção & controle , Risco
3.
Cell Prolif ; 52(6): e12696, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599060

RESUMO

OBJECTIVES: Panax ginseng, a well-known traditional Chinese medicine with multiple pharmacological activities, plays a crucial role in modulating mood disorders. Several recent studies have identified an underlying role of Panax ginseng in the prevention and treatment of depression. However, the cellular and molecular mechanisms remain unclear. MATERIALS AND METHODS: In this review, we summarized the recent progress of antidepressant effects and underlying mechanisms of Panax ginseng and its representative herbal formulae. RESULTS: The molecular and cellular mechanisms of Panax ginseng and its herbal formulae include modulating monoamine neurotransmitter system, upregulating the expression of neurotrophic factors, regulating the function of HPA axis, and anti-inflammatory action. CONCLUSIONS: Therefore, this review may provide theoretical bases and clinical applications for the treatment of depression by Panax ginseng and its representative herbal formulae.


Assuntos
Depressão/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Panax , Extratos Vegetais/farmacologia , Animais , Antidepressivos/uso terapêutico , Humanos , Panax/metabolismo
4.
Ecotoxicol Environ Saf ; 185: 109683, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31550567

RESUMO

Thiamethoxam has emerged as an environmental contaminant detected in aqueous environments, and its endocrine-disrupting effect at chronic exposure in teleosts remains unknown. In the present study, a docking experiment and an in vivo test were integrated to systematically explore the toxic mechanisms of thiamethoxam in fish. Histological analysis, plasma VTG and hormone level (E2, 11-KT, T3 and T4) determinations, and HPG and HPT gene expression quantification were performed after Chinese rare minnow (Gobiocypris rarus) was exposed to thiamethoxam (0, 0.5, 5, and 50 µg/L) for 90 days. According to the docking study, thiamethoxam had different interactions with ERα, AR and TRα via hydrogen bonding. A decrease in body length and plasma T4 was observed in both genders. The histological damage in liver and delayed gonadal development were observed in both genders at 50 µg/L thiamethoxam treatment. In males, the following HPG axis genes were upregulated: gnrh and cyp19b in the brain; vtg and cyp19a in the liver; and cyp17 and cyp19a in the gonad. In females, erɑ in the liver was significantly upregulated with 0.5 µg/L thiamethoxam treatment, and cyp17 in the gonad was upregulated with all treatment. The suppression of cyp19a, gnrh, cyp11a, and ttr was observed at the concentration of 5 µg/L in the female liver. Taken together, the endocrine system of Chinese rare minnow might be disrupted after chronic exposure to thiamethoxam.


Assuntos
Cyprinidae/metabolismo , Disruptores Endócrinos/toxicidade , Sistema Endócrino/efeitos dos fármacos , Hormônios/metabolismo , Tiametoxam/toxicidade , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Cyprinidae/genética , Sistema Endócrino/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Simulação de Acoplamento Molecular , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Regulação para Cima , Vitelogeninas/metabolismo
6.
Pestic Biochem Physiol ; 159: 68-79, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400786

RESUMO

Chlorpyrifos is a pesticide frequently detected in food and has been reported to disturb endocrine and gut health, which was regulated by gut microbiota and enteroendocrine cells. In this study, newly weaned (3 week) and adult (8 week) male rats fed a normal- or high- fat diet were chronically exposed to 0.3 mg chlorpyrifos/kg bodyweight/day. The effects of chlorpyrifos exposure on serum hormone levels, proinflammatory cytokines and gut microbiota were evaluated. Chronic exposure to chlorpyrifos significantly decreased the concentrations of luteinizing hormone, follicule stimulating hormone and testosterone, which was found only in the normal-fat diet. The counteracted effect of high-fat diet was also found in gut hormones and proinflammatory cytokines. Significantly higher concentrations of glucagon-like peptide-1, pancreatic polypeptide, peptide tyrosine tyrosine (PYY), ghrelin, gastric inhibitory poly-peptide, IL-6, monocyte chemoattractant protein-1, and TNF-α were found in rats exposed to chlorpyrifos beginning at newly weaned, whereas only the PYY, ghrelin and IL-6 concentrations increased significantly in rats exposed in adulthood. Furthermore, a decrease in epinephrine induced by chlorpyrifos exposure was found in rats exposed to chlorpyrifos beginning at newly weaned, regardless of their diet. Chlorpyrifos-induced disturbances in the microbiome community structure were more apparent in rats fed a high-fat diet and exposed beginning at newly weaned. The affected bacteria included short-chain fatty acid-producing bacteria (Romboutsia, Turicibacter, Clostridium sensu stricto 1, norank_f_Coriobacteriaceae, Faecalibaculum, Parasutterella and norank_f__Erysipelotrichaceae), testosterone-related genus (Turicibacter, Brevibacterium), pathogenic bacteria (Streptococcus), and inflammation-related bacteria (unclassified_f__Ruminococcaceae, Ruminococcaceae_UCG-009, Parasutterella, Oscillibacter), which regulated the endocrine system via the hypothalamic-pituitary-adrenal axis, as well as the immune response and gut barrier. Early exposure accelerated the endocrine-disturbing effect and immune responses of chlorpyrifos, although these effects can be eased or recovered by a high-fat diet. This study helped clarify the relationship between disrupted endocrine function and gut microbiota dysbiosis induced by food contaminants such as pesticides.


Assuntos
Clorpirifos/toxicidade , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/induzido quimicamente , RNA Ribossômico 16S/metabolismo , Envelhecimento , Animais , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos
7.
Physiol Biochem Zool ; 92(5): 445-458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365306

RESUMO

Hormones such as glucocorticoids (colloquially referred to as "stress hormones") have important effects on animal behavior and life-history traits, yet most of this understanding has come through correlative studies. While experimental studies offer the ability to assign causality, there are important methodological concerns that are often not considered when manipulating hormones, including glucocorticoids, in wild animals. In this study, we examined how experimental elevations of cortisol concentrations in wild North American red squirrels (Tamiasciurus hudsonicus) affected their hypothalamic-pituitary-adrenal (HPA) axis reactivity and life-history traits, including body mass, litter survival, and adult survival. The effects of exogenous cortisol on plasma cortisol concentrations depended on the time between treatment consumption and blood sampling. In the first 9 h after consumption of exogenous cortisol, individuals had significantly higher true baseline plasma cortisol concentrations, but adrenal gland function was impaired as indicated by their dampened response to capture and handling and to injections of adrenocorticotropic hormone compared to controls. Approximately 24 h after consumption of exogenous cortisol, individuals had much lower plasma cortisol concentrations than controls, but adrenal function was restored. Corticosteroid-binding globulin (CBG) concentrations were also significantly reduced in squirrels treated with cortisol. Despite these profound shifts in the functionality of the HPA axis, squirrel body mass, offspring survival, and adult survival were unaffected by experimental increases in cortisol concentrations. Our results highlight that even short-term experimental increases in glucocorticoids can affect adrenal gland functioning and CBG concentrations but without other side effects.


Assuntos
Glucocorticoides/farmacologia , Hidrocortisona/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sciuridae/sangue , Animais , Feminino , Glucocorticoides/administração & dosagem , Hidrocortisona/administração & dosagem , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiologia , Longevidade/efeitos dos fármacos , Masculino , Sistema Hipófise-Suprarrenal/fisiologia , Reprodução/efeitos dos fármacos , Sciuridae/fisiologia
8.
Environ Toxicol ; 34(11): 1255-1262, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31298479

RESUMO

Progesterone (P4) is a biologically active steroid hormone that is involved in the regulation of oocyte growth and maturation, as well as development of the endometrium and implantation in the uterus of humans. It can also stimulate oocyte maturation in female fish, as well as spermatogenesis and sperm motility in male fish. Thus, P4 has been extensively used in human and animal husbandry as a typical progestin. However, P4 remaining in the water environment will pose a potential hazard to aquatic organisms. For example, it can interfere with sex differentiation and reproduction in aquatic vertebrates such as fish. Therefore, we investigated the effects of prolonged progesterone exposure on the expression of genes related to circadian rhythm signaling and the hypothalamic-pituitary-gonadal (HPG) axes in Yellow River Carp, which may have a potential impact on their sex differentiation. Our results suggested that P4 exposure altered the expression of genes related to circadian rhythm signaling, which can lead to disorders in the endocrine system and regulate the HPG axes-related activities. Furthermore, the expression of genes related to the HPG axes was also altered, which might affect gonadal development and the reproductive systems of Yellow River Carp. In addition, these changes may provide a plausible mechanism for the observed shifts in their sex ratio toward females.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Progesterona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Razão de Masculinidade , Transcrição Genética/efeitos dos fármacos
9.
Georgian Med News ; (290): 127-131, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322529

RESUMO

Corticoliberin (CRF) isn't only regulates hypothalamic-pituitary-adrenal axis activity, but also functions as a neurotransmitter in extrahypothalamic brain regions like amygdala, implicated in the emotional responses to stress. The CRF system provides an input to orexin neurons and can modulate the activity of orexinergic neurons in stress response. Some data showed the role of orexin-A in extinction of aversive memory. The orexin system was shown to participate in stress-induced behavior connected with the extended amygdala structures, like central nucleus of the amygdala. The objective was to study the effects of orexin-A antagonist SB-408124 in rats after predator-induced stress using behavioral tests and its effects on CRF level in amygdala. In this study 30 male Wistar rats were used. The animals received an intranasally selective antagonist of Orexin receptor 1 type SB-408124. Posttraumatic stress disorder was modelled by single predator exposure. A group of 10-12 rats were placed in a terrarium with an indian python. 7 days after exposure to the predator, the behavior of animals was tested in the Open Field and Elevated Cross-Maze tests. Free motor activity of animals was studied in the "open field" test. To assess stress, we used the "elevated cross-maze " test. CRF concentrations in brain structures were measured by solid-phase ELISA using the Corticotropin Releasing Factor (CRF) test system. In the group of stressed rats receiving intranasally SB-408124, the time of stay in the light arm was restored, but did not reach the control values, the number of runs was restored to the control level, and the number of grooming acts increased in comparison with both the control group and the stressed animals. In the "open field" in the group of stressed rats receiving saline solution, the number of sniffs and rearing were decreased, but the number of peeks into holes was increased. In the group of stressed rats receiving SB-408124 20 µg intranasally, the number of sniffs was increased and the number of hole peeking decreased in comparison with the stressed rats receiving saline solution. The CRF level in the homogenates of amygdala in stressed rats was lower (0.44±0.07 ng/mg protein vs. 0.61±0.01 ng/mg in the control group). In the intranasal administration of SB408124 group this decrease was not recorded and the CRF level in the amygdala was 0.57±0.01 pg/mg protein. Orexin A antagonist SB-408124 reduced anxiety after psychotraumatic exposure. Predator induced acute psychotraumatic exposure decrease CRF level in the rat's amygdala. Intranasal administration of selective orexin 1 receptor antagonist SB408124 restored it closely to normal and has an anxiolytic effect on animal behaviour.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Receptores de Orexina , Compostos de Fenilureia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Tonsila do Cerebelo/fisiologia , Animais , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Wistar , Transtornos de Estresse Pós-Traumáticos/induzido quimicamente
10.
EBioMedicine ; 46: 411-422, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31358477

RESUMO

BACKGROUND: Severe energy deficits during military operations, produced by significant increases in exercise and limited dietary intake, result in conditions that degrade lean body mass and lower-body muscle function, which may be mediated by concomitant reductions in circulating testosterone. METHODS: We conducted a three-phase, proof-of-concept, single centre, randomised, double-blind, placebo-controlled trial (CinicalTrials.gov, NCT02734238) of non-obese men: 14-d run-in, free-living, eucaloric diet phase; 28-d live-in, 55% exercise- and diet-induced energy deficit phase with (200 mg testosterone enanthate per week, Testosterone, n = 24) or without (Placebo, n = 26) exogenous testosterone; and 14-d recovery, free-living, ad libitum diet phase. Body composition was the primary end point; secondary endpoints included lower-body muscle function and health-related biomarkers. FINDINGS: Following energy deficit, lean body mass increased in Testosterone and remained stable in Placebo, such that lean body mass significantly differed between groups [mean difference between groups (95% CI), 2.5 kg (3.3, 1.6); P < .0001]. Fat mass decreased similarly in both treatment groups [0.2 (-0.4, 0.7), P = 1]. Change in lean body mass was associated with change in total testosterone (r = 0.71, P < .0001). Supplemental testosterone had no effect on lower-body muscle function or health-related biomarkers. INTERPRETATION: Findings suggest that supplemental testosterone may increase lean body mass during short-term severe energy deficit in non-obese, young men, but it does not appear to attenuate lower-body functional decline. FUNDING: Collaborative Research to Optimize Warfighter Nutrition projects I and II, Joint Program Committee-5, funded by the US Department of Defence.


Assuntos
Composição Corporal/efeitos dos fármacos , Dieta , Suplementos Nutricionais , Exercício , Músculos/efeitos dos fármacos , Músculos/metabolismo , Testosterona/administração & dosagem , Adolescente , Adulto , Biomarcadores , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Estudo de Prova de Conceito , Adulto Jovem
11.
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
12.
J Agric Food Chem ; 67(50): 13790-13808, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31148444

RESUMO

Essential oils are usually used in aromatherapy to alleviate anxiety symptoms. In comparison to traditional drugs, essential oils have fewer side effects and more diversified application ways, including inhalation. This review provides a comprehensive overview of studies on anxiolytic effects of essential oils in preclinical and clinical trials. Most of the essential oils used in clinical studies have been proven to be anxiolytic in animal models. Inhalation and oral administration were two common methods for essential oil administration in preclinical and clinical trials. Massage was only used in the clinical trials, while intraperitoneal injection was only used in the preclinical trails. In addition to essential oils that are commonly used in aromatherapy, essential oils from many folk medicinal plants have also been reported to be anxiolytic. More than 20 compounds derived from essential oils have shown an anxiolytic effect in rodents, while two-thirds of them are alcohols and terpenes. Monoamine neurotransmitters, amino acid neurotransmitters, and the hypothalamic-pituitary-adrenal axis are thought to play important roles in the anxiolytic effects of essential oils.


Assuntos
Ansiolíticos/química , Óleos Voláteis/química , Óleos Vegetais/química , Animais , Ansiolíticos/farmacologia , Aromaterapia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Óleos Voláteis/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia
13.
Pharmacol Rep ; 71(4): 636-643, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176893

RESUMO

BACKGROUND: The inverse relationship between GnRH transcript level and GABA neurons activity has suggested that GABA at the hypothalamic level may exert a suppressive effect on subsequent steps of the GnRH biosynthesis. In the present study, we analyzed the effects of GABA type A receptor agonist (muscimol) or antagonist (bicuculline) on molecular mechanisms governing GnRH/LH secretion in follicular-phase sheep. METHODS: ELISA technique was used to investigate the effects of muscimol and/or bicuculline on levels of post-translational products of genes encoding GnRH ligand and GnRH receptor (GnRHR) in the preoptic area (POA), anterior (AH) and ventromedial (VMH) hypothalamus, stalk/median eminence (SME), and GnRHR in the anterior pituitary (AP). Real-time PCR was chosen for determination of the effect of drugs on kisspeptin (Kiss 1) mRNA level in POA and VMH including arcuate nucleus (VMH/ARC), and on Kiss1 receptor (Kiss1r) mRNA abundance in POA-hypothalamic structures. These analyses were supplemented by RIA method for measurement of plasma LH concentration. RESULTS: The study demonstrated that muscimol and bicuculline significantly decreased or increased GnRH biosynthesis in all analyzed structures, respectively, and led to analogous changes in plasma LH concentration. Similar muscimol- and bicuculline-related alterations were observed in levels of GnRHR. However, the expression of Kiss 1 and Kiss1r mRNAs in selected POA-hypothalamic areas of either muscimol- and bicuculline-treated animals remained unaltered. CONCLUSIONS: Our data suggest that GABAergic neurotransmission is involved in the regulatory pathways of GnRH/GnRHR biosynthesis and then GnRH/LH release in follicular-phase sheep conceivably via indirect mechanisms that exclude involvement of Kiss 1 neurons.


Assuntos
Ciclo Estral/metabolismo , Hormônio Liberador de Gonadotropina/biossíntese , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Kisspeptinas/metabolismo , Receptores de GABA-A/metabolismo , Receptores LHRH/biossíntese , Animais , Bicuculina/farmacologia , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Hormônio Liberador de Gonadotropina/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Muscimol/farmacologia , Neurônios/metabolismo , Ovinos
14.
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
15.
J Drugs Dermatol ; 18(6): 563, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251549

RESUMO

Clascoterone (cortexolone 17α-propionate, CB-03-01) 1% cream, a topical, androgen receptor (AR) inhibitor under investigation for the treatment of acne vulgaris, is rapidly metabolized to cortexolone in human plasma. The primary objectives of this study were to determine the pharmacokinetic (PK) properties and adrenal suppression potential of clascoterone topical cream, 1% in subjects with acne vulgaris. Study Design: This study was an open-label, multicenter study in 42 subjects ≥12 years of age with moderate-to-severe acne (Grade 3-4 on the Investigator's Global Assessment [IGA]), on the face, chest and/or back. Cohort 1(>18 years of age) and Cohort 2 (12-18 years of age) applied clascoterone topical cream, 1% twice daily (BID) for 14 days. Primary safety endpoints included hypothalamic-pituitary-adrenal (HPA) axis response to cosyntropin via a Cosyntropin Stimulation Test (CST) upon screening (day 1) and at day 14 (HPA axis suppression was defined as a post-stimulation serum cortisol level <18 µg/dL at day 14); and PK evaluation including concentration-time profiles of clascoterone and cortexolone in plasma­PK parameters were determined using "non-compartmental" analysis. Secondary safety endpoints included clinical laboratory testing, local and systemic adverse events (AEs), physical examination/vital signs, and electrocardiogram (ECG). Results: 42 subjects (Cohort 1=20, Cohort 2= 22) enrolled. Cohort 1 was comprised of 15 females (15/20, 75%) and 5 males (5/20, 25%), non-Hispanic/Latino (20/20, 100%), mean age is 24.4 years. Cohort 2 was comprised of 12 females (12/22, 54.5%) and 10 males (10/22, 45.5%), non-Hispanic/Latino (21/22, 95.5%), and mean age is 15.6 years. Three subjects (3/42,7%), 1 adult and 2 adolescents, demonstrated an abnormal HPA axis response with post-stimulation serum cortisol levels ranging from 14.9 to 17.7 µg/dL at day 14. All returned to normal HPA axis function, four weeks after day 14. None showed clinical evidence of adrenal suppression. Clascoterone plasma concentrations achieved PK steady-state by day 5. Clascoterone systemic exposure was similar between both cohorts. At steady-state, plasma concentrations increased ~1.8 to 2.1 fold versus first dose with mean (coefficient of variation [CV] %) maximum plasma concentrations of 4.4 ng/mL (67%) and 4.6 ng/mL (103%) in Cohort 1 and Cohort 2, respectively. Cortexolone plasma concentrations trended below the lower limit of quantitation (0.5 ng/mL) in both cohorts. Local skin reactions (LSRs) were mostly mild, with only one moderate case of pruritus. There were nine AEs categorized as follows: definitely related (N=2), probably related (N=4), unlikely/not related (N=3), to clascoterone. Conclusion: This study demonstrates the safety and tolerability of clascoterone topical cream, 1% in adolescents and adults with acne vulgaris treated BID for 14 consecutive days. J Drugs Dermatol. 2019;18(6):563-568.


Assuntos
Acne Vulgar/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/farmacocinética , Cortodoxona/análogos & derivados , Propionatos/farmacocinética , Creme para a Pele/farmacocinética , Acne Vulgar/sangue , Acne Vulgar/diagnóstico , Adolescente , Adulto , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Criança , Cortodoxona/administração & dosagem , Cortodoxona/efeitos adversos , Cortodoxona/farmacocinética , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Propionatos/administração & dosagem , Propionatos/efeitos adversos , Índice de Gravidade de Doença , Creme para a Pele/administração & dosagem , Creme para a Pele/efeitos adversos , Resultado do Tratamento , Adulto Jovem
16.
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
17.
S Afr Med J ; 109(5): 306-309, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31131795

RESUMO

A recently published approach to paediatric asthma management neither recommended screening for nor suggested any management of hypothalamic-pituitary-adrenal axis suppression in asthmatic children treated with corticosteroids. The existing literature on this topic was therefore reviewed and the quality of the evidence assessed. Recommendations for diagnosis, screening and management are made utilising the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.


Assuntos
Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Programas de Rastreamento/métodos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Guias de Prática Clínica como Assunto , Criança , Humanos
18.
Biomed Pharmacother ; 115: 108978, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102911

RESUMO

Post traumatic stress disorder (PTSD) is a mental illness that affected numerous people. The anti-PTSD-like effects of puerarin is unknown, although the antidepressant- and anxiolytic- like effects of puerarin have been reported. The PTSD behavioral deficits in rats were induced by single prolonged stress (SPS), mainly including the reduced time/entries in the open arms and the elevated time/entries in the closed arms in elevated plus maze test, increased freezing duration in contextual fear paradigm and lowered time/entries in the central zone in open field test. However, the behavioral deficits were attenuated by puerarin (50 and 100 mg/kg) without affecting the locomotor activity. For the evaluation of mechanism, the decreased levels of progesterone, allopregnanolone, and the increased levels of corticosterone, corticotropin releasing hormone, and adrenocorticotropic hormone in the brain or serum were induced by SPS, which is blocked by puerarin. In summary, the anti-PTSD-like effects of puerarin were associated with biosynthesis of neurosteroids and normalized levels of stress hormones in HPA axis.


Assuntos
Ansiolíticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Isoflavonas/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos/metabolismo
19.
Drug Alcohol Depend ; 199: 101-105, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029877

RESUMO

BACKGROUND: Dysregulation of glucocorticoid receptors has been implicated in addiction and stress-related disorders. FKBP5 is a co-chaperone of the glucocorticoid receptor and regulates receptor sensitivity. While FKBP5 is known to be involved in mood- and stress-related disorders, less is known regarding FKBP5 and cocaine abuse. This study investigated the regulation of FKBP5 expression in the extended amygdala and paraventricular nucleus of the hypothalamus, regions important in the control of stress-responses and HPA axis function, following chronic and acute cocaine administration. METHODS: Adult male and female rats received saline or cocaine three times per day for 1 or 14 days. Brain tissue was collected 30 min, 24 h, 48 h, 7 days or 14 days following the final injection. FKBP5 mRNA was measured by qRT-PCR in the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST) and paraventricular nucleus (PVN). RESULTS: FKBP5 mRNA levels were significantly elevated as a result of chronic cocaine administration in both males and females in the PVN and BNST 30 min and 24 h after the final injection. In females, FKBP5 was also elevated in the CeA. Following acute cocaine, FKBP5 gene expression was unaltered except for elevated levels in the BNST of females 24 h later. CONCLUSIONS: These results demonstrate that FKBP5 mRNA is regulated by cocaine administration. Increased FKBP5 expression may play a role in the dysregulation of the stress axis following chronic cocaine exposure, contributing to the negative affective symptoms of cocaine withdrawal.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Cocaína/administração & dosagem , Proteínas de Ligação a Tacrolimo/biossíntese , Regulação para Cima/efeitos dos fármacos , Animais , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Regulação para Cima/fisiologia
20.
Gen Comp Endocrinol ; 280: 147-157, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009603

RESUMO

Monitoring glucocorticoids in faeces and hair is increasingly used in ecological studies and provides a powerful and minimally intrusive mean to identify physiological challenges faced by wild animals. Using a cortisol and a corticosterone immunoassays, we conducted an adrenocorticotropic (ACTH) challenge with five weekly repeated injections to validate the use of faecal glucocorticoid metabolites and hair cortisol concentration as biological markers of the HPA-axis activity in captive mountain goats (Oreamnos americanus). We also investigated the effect of endogenous (age, sex, reproductive status) and methodological (faecal sample collection date, freezing delay and hair type) variables on cortisol values using faecal and hair samples collected from marked wild mountain goats during a long-term study. The cortisol enzyme immunoassay was reliable for mountain goat faeces and hair, and was sensitive enough to detect a clear rise in glucocorticoid concentration following ACTH injections for both matrices. Age and sex had no detectable effect on faecal glucocorticoid metabolites, but hair cortisol concentration was higher in kids and yearlings than in older goats, and lower in adult males compared to adult females. Reproductive status had no detectable effect on both faecal and hair measurements. Faecal metabolite concentrations increased with sample collection date in late spring until mid-summer and decreased afterward until early fall. Guard hair had nearly twice as much cortisol per gram as undercoat hair. Prolonged delay to freezing reduced the concentration of faecal glucocorticoid metabolites, but degradation seemed limited when samples were exposed to wind and sun or when ambient temperature was low. We conclude that faeces and hair can be used as valid biomarkers of the HPA-axis activity in mountain goat provided that confounding variables are taken into account when interpreting measurements.


Assuntos
Biomarcadores/metabolismo , Fezes/química , Cabras/metabolismo , Cabelo/metabolismo , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Metaboloma , Hormônio Adrenocorticotrópico/farmacologia , Envelhecimento/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Corticosterona/metabolismo , Feminino , Glucocorticoides/metabolismo , Cabelo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Técnicas Imunoenzimáticas , Masculino , Reprodutibilidade dos Testes , Reprodução
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