RESUMO
Introduction In addition to their role in regulation of the hypothalamic-pituitary-adrenal-axis, corticotropin-releasing factor (CRF) and its related peptides, the urocortins, are important mediators of physiological and pathophysiological processes of the central nervous, cardiovascular, gastrointestinal, immune, endocrine, reproductive, and skin systems. Altered regulation of CRF-mediated adaptive responses to various stressful stimuli disrupts healthy function and might confer vulnerability to several disorders, including depression and anxiety. Methodology This narrative review was conducted through search and analysis of studies retrieved from online databases using a snowball method. Results This review covers aspects beginning with the discovery of CRF, CRF binding protein and their actions via interaction with CRF receptors type 1 and type 2. These are surface plasma membrane receptors, activation of which is associated with conformational changes and interaction with a variety of G-proteins and signaling pathways. We also reviewed the pharmacology and mechanisms of the receptor signaling modulatory activity of these receptors. Conclusion This review compiles and presents knowledge regarding the CRFergic system, including CRF related peptides, CRF binding protein, and CRF receptors, as well as some evidence that is potentially indicative of the biological roles of these entities in several physiological and pathophysiological processes.
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Transdução de Sinais/fisiologia , Estresse Psicológico/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Humanos , Receptores de Hormônio Liberador da Corticotropina/metabolismoRESUMO
Abstract Introduction In addition to their role in regulation of the hypothalamic-pituitary-adrenal-axis, corticotropin-releasing factor (CRF) and its related peptides, the urocortins, are important mediators of physiological and pathophysiological processes of the central nervous, cardiovascular, gastrointestinal, immune, endocrine, reproductive, and skin systems. Altered regulation of CRF-mediated adaptive responses to various stressful stimuli disrupts healthy function and might confer vulnerability to several disorders, including depression and anxiety. Methodology This narrative review was conducted through search and analysis of studies retrieved from online databases using a snowball method. Results This review covers aspects beginning with the discovery of CRF, CRF binding protein and their actions via interaction with CRF receptors type 1 and type 2. These are surface plasma membrane receptors, activation of which is associated with conformational changes and interaction with a variety of G-proteins and signaling pathways. We also reviewed the pharmacology and mechanisms of the receptor signaling modulatory activity of these receptors. Conclusion This review compiles and presents knowledge regarding the CRFergic system, including CRF related peptides, CRF binding protein, and CRF receptors, as well as some evidence that is potentially indicative of the biological roles of these entities in several physiological and pathophysiological processes.
Assuntos
Animais , Humanos , Estresse Psicológico/metabolismo , Hormônio Liberador da Corticotropina/fisiologia , Transdução de Sinais/fisiologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismoRESUMO
Vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF) are anorexigenic neuropeptides that act in the hypothalamus to regulate food intake. Intracerebroventricular (ICV) microinjection of VIP promotes increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, indicating that VIP activates hypothalamic-pituitary-adrenal axis. The aim of this study was to evaluate the interaction between VIP and CRF, by verifying the effects of ICV administration of VIP on the activity of neurons and CRF mRNA expression in paraventricular nucleus of hypothalamus (PVN). In addition, it was evaluated the effects of pretreatment with CRF type 1 receptor (CRFR1) antagonist (Antalarmin, ANT) or CRF type 2 receptor (CRFR2) antagonist (Antisauvagine-30, AS30) on VIP-induced changes on food intake and plasma parameters of male rats. Compared to Saline group, VIP increased not only the number of Fos-related antigens (FRA)-immunoreactive neurons in the PVN but also CRF mRNA levels in this nucleus. Both ANT and AS30 treatment attenuated the inhibition of food intake promoted by VIP, ANT showing a more pronounced effect. Both antagonists also attenuated VIP-induced reduction and enhancement of free fatty acids and corticosterone plasma levels, respectively, and only AS30 was able to attenuate the hyperglycemia. These results suggest that CRF is an important mediador of VIP effects on energy balance, and CRFR1 and CRFR2 are involved in these responses.
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/sangue , Transtornos da Alimentação e da Ingestão de Alimentos/induzido quimicamente , Peptídeo Intestinal Vasoativo/efeitos adversos , Hormônio Adrenocorticotrópico/sangue , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Corticosterona/sangue , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ácidos Graxos/sangue , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Wistar , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
In teleosts, changes in swimming, exploring, general locomotor activity, and anxious state can be a response to stress mediated by the corticotropin-releasing hormone system activation and its effects on glucocorticoid levels. Zebrafish has been widely used to study neuropharmacology and has become a promising animal model to investigate neurobehavioral mechanisms of stress. In this report the animals were submitted to acute restraint stress for different time lengths (15, 60 and 90 min) for further evaluation of behavioral patterns, whole-body cortisol content, and corticotropin-releasing hormone expression. The results demonstrated an increase in the locomotor activity and an alteration in the swimming pattern during a 5-min trial after the acute restraint stress. Interestingly, all groups of fish tested in the novel tank test exhibited signs of anxiety as evaluated by the time spent in the bottom of the tank. Whole-body cortisol content showed a positive correlation with increased behavioral indices of locomotion in zebrafish whereas molecular analysis of corticotropin-releasing hormone showed a late reduction of mRNA expression (90 min). Altogether, we present a model of acute restraint stress in zebrafish, confirmed by elevated cortisol content, as a valid and reliable model to study the biochemical basis of stress behavior, which seems to be accompanied by a negative feedback of corticotropin-release hormone mRNA expression.
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Doença Aguda , Animais , Hormônio Liberador da Corticotropina/genética , Regulação da Expressão Gênica , Hidrocortisona/biossíntese , RNA Mensageiro/biossíntese , Restrição Física/efeitos adversos , Estresse Psicológico/genética , Peixe-ZebraRESUMO
Corticotropin-releasing hormone (CRH) plays a key role in adjusting the basal and stress-activated hypothalamic-pituitary-adrenal axis (HPA). CRH is also widely distributed in extrahypothalamic circuits, where it acts as a neuroregulator to integrate the complex neuroendocrine, autonomic, and behavioral adaptive response to stress. Hyperactive and/or dysregulated CRH circuits are involved in neuroendocrinological disturbances and stress-related mood disorders such as anxiety and depression. This review describes the main physiological features of the CRH network and summarizes recent relevant information concerning the molecular mechanism of CRH action obtained from signal transduction studies using cells and wild-type and transgenic mice lines. Special focus is placed on the MAPK signaling pathways triggered by CRH through the CRH receptor 1 that plays an essential role in CRH action in pituitary corticotrophs and in specific brain structures. Recent findings underpin the concept of specific CRH-signaling pathways restricted to specific anatomical areas. Understanding CRH action at molecular levels will not only provide insight into the precise CRH mechanism of action, but will also be instrumental in identifying novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders.
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Animais , Sistema Nervoso Central/fisiologia , Humanos , Camundongos , Modelos Animais , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Adrenalectomy-induced hypophagia is associated with increased satiety-related responses, which involve neuronal activation of the nucleus of the solitary tract (NTS). Besides its effects on the pituitary-adrenal axis, corticotrophin-releasing factor (CRF) has been shown to play an important role in feeding behaviour, as it possesses anorexigenic effects. We evaluated feeding-induced CRF mRNA expression in the paraventricular nucleus (PVN) and the effects of pretreatment with CRF(2) receptor antagonist (Antisauvagine-30, AS30) on food intake and activation of NTS neurons in response to feeding in adrenalectomised (ADX) rats. Compared to the sham group, ADX increased CRF mRNA levels in the PVN of fasted animals, which was further augmented by refeeding. AS30 treatment did not affect food intake in the sham and ADX+corticosterone (B) groups; however, it reversed hypophagia in the ADX group. In vehicle-pretreated animals, refeeding increased the number of Fos and Fos/TH-immunoreactive neurons in the NTS in the sham, ADX and ADX+B groups, with the highest number of neurons in the ADX animals. Similarly to its effect on food intake, pretreatment with AS30 in the ADX group also reversed the increased activation of NTS neurons induced by refeeding while having no effect in the sham and ADX+B animals. The present results show that adrenalectomy induces an increase in CRF mRNA expression in the PVN potentiated by feeding and that CRF(2) receptor antagonist abolishes the anorexigenic effect and the increased activation of NTS induced by feeding in the ADX animals. These data indicate that increased activity of PVN CRF neurons modulates brainstem satiety-related responses, contributing to hypophagia after adrenalectomy.
Assuntos
Adrenalectomia , Hormônio Liberador da Corticotropina/fisiologia , Ingestão de Alimentos/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Resposta de Saciedade , Adrenalectomia/reabilitação , Animais , Corticosterona/farmacologia , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/induzido quimicamente , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Expressão Gênica/efeitos dos fármacos , Antagonistas de Hormônios/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Resposta de Saciedade/efeitos dos fármacos , Resposta de Saciedade/fisiologiaRESUMO
OBJECTIVE: We reviewed previous studies that have described an association between abnormal functioning of the hypothalamic-pituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically reduced secretion of corticotropin releasing factor may result in pathological hypoarousal and an enhanced hypothalamic-pituitary-adrenal negative feedback. Patients with atypical depression, seasonal affective disorder and chronic fatigue syndrome fall in this category. METHOD: The literature data on the overlap between the key-words were reviewed, summarized and discussed. RESULTS: Many studies suggest that these conditions themselves overlap biologically, showing hypofunction of central corticotropin releasing factor neuronal systems. CONCLUSIONS: Therefore, in the real world of clinical practice, patients often present in a grey area between classical idiopathic fatigue and early chronic atypical depression and/or seasonal depression. This underscores the potential common biological links underpinning common symptom clusters not only between depression (atypical and seasonal) and chronic fatigue syndrome, but also other conditions characterized by the hypothalamic-pituitary-adrenal axis mainly diminished the corticotropin realising factor activity.
Assuntos
Transtorno Depressivo/fisiopatologia , Síndrome de Fadiga Crônica/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Transtorno Afetivo Sazonal/fisiopatologia , Hormônio Liberador da Corticotropina/fisiologia , Transtorno Depressivo/psicologia , Transtorno Depressivo Maior/fisiopatologia , Síndrome de Fadiga Crônica/psicologia , Humanos , Transtorno Afetivo Sazonal/psicologia , Estresse Psicológico/fisiopatologiaRESUMO
OBJETIVO: Foram revisados estudos que descrevem que as alterações na função do eixo hipotálamo-hipófise-adrenal são relacionadas com o estado psicopatológico em depressão. Além da depressão melancólica, uma série de condições podem ser associadas à hiperativação prolongada do eixo hipotálamo-pituitária-adrenal. Um outro grupo de psicopatologias é caracterizado por hipoativação do mesmo eixo com redução crônica na secreção do fator de liberação de corticotrofina. Pacientes com depressão atípica, doença afetiva sazonal e síndrome da fadiga crônica estão inclusos nesta categoria. MÉTODO: Foram revisados os dados da literatura que incluem a interseção entre estes descritores, resumidos e discutidos os principais e recentes achados. RESULTADOS: Muitos estudos têm enfatizado que estes quadros se sobrepõem biologicamente, demonstrando hipofunção no sistema relacionado ao fator de liberação de corticotrofina. CONCLUSÕES: Na prática clínica, os pacientes frequentemente se apresentam de forma intermediária entre a fadiga e a depressão atípica crônica e/ou a depressão sazonal. Isto enfatiza o potencial biológico comum que fundamenta o grupo de sintomas não somente entre depressão (atípica e sazonal) e a síndrome da fadiga crônica e as condições caracterizadas por alterações no eixo hipotálamo-pituitária-adrenal, principalmente hipofunção e, em particular, diminuição da atividade do fator de liberação de corticotrofina.
OBJECTIVE: We reviewed previous studies that have described an association between abnormal functioning of the hypothalamic-pituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically reduced secretion of corticotropin releasing factor may result in pathological hypoarousal and an enhanced hypothalamic-pituitary-adrenal negative feedback. Patients with atypical depression, seasonal affective disorder and chronic fatigue syndrome fall in this category. METHOD: The literature data on the overlap between the key-words were reviewed, summarized and discussed. RESULTS: Many studies suggest that these conditions themselves overlap biologically, showing hypofunction of central corticotropin releasing factor neuronal systems. CONCLUSIONS: Therefore, in the real world of clinical practice, patients often present in a grey area between classical idiopathic fatigue and early chronic atypical depression and/or seasonal depression. This underscores the potential common biological links underpinning common sympton clusters not only between depression (atypical and seasonal) and chronic fatigue syndrome, but also other conditions characterized by the hypothalamic-pituitary-adrenal axis mainly diminished the corticotropin realising factor activity.
Assuntos
Humanos , Transtorno Depressivo/fisiopatologia , Síndrome de Fadiga Crônica/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Transtorno Afetivo Sazonal/fisiopatologia , Hormônio Liberador da Corticotropina/fisiologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo/psicologia , Síndrome de Fadiga Crônica/psicologia , Transtorno Afetivo Sazonal/psicologia , Estresse Psicológico/fisiopatologiaRESUMO
Urocortin 1, highly conserved metazoan gene of the corticotropin-releasing hormone family, is a simple gene structured in two exons and the corresponding intron. The urocortin 1 prepropeptide is entirely coded in the second exon. Preliminary non-isotopic in situ hybridization experiments with an oligonucleotide complementary to an intron sequence of the urocortin 1 gene showed a significant cytoplasmic-like staining, suggesting the occurrence of an intron-retained urocortin 1 transcript. This observation prompted us to study whether the urocortin 1 gene presents alternative splicing by intron retention event. Confocal fluorescent in situ hybridization for urocortin 1 RNA and the use of the specific DNA dye TOPRO-3 allowed us to show significant expression of the intron-retained urocortin 1 transcript that did not colocalize with TOPRO-3 staining indicating a cytoplasmic localization for the intron-retained urocortin 1 transcript. The natural occurrence of a polyadenylated intron-retained urocortin 1 RNA was further documented by reverse transcriptase polymerase chain reaction (PCR), primed with oligo(dT), of total RNA extracted from three brain regions, a midbrain region containing the Edinger-Westphal nucleus, cerebellum and prefrontal cortex. In the three brain regions studied, it was possible to amplify both intron-less as well as intron-retained urocortin 1 transcripts. The use of PCR primers that simultaneously amplify both urocortin 1 transcripts allowed us to show that the expression of both urocortin 1 transcripts differs among the brain regions analyzed, suggesting a tissue specific regulation of this alternative splicing. In silico analysis of the five known mammalian urocortin 1 genomic sequences showed high conservation of the urocortin 1 intron sequence. Further studies should investigate the regulation of this intron retention event and its consequence for the functionality of the urocortin 1 gene.
Assuntos
Processamento Alternativo/genética , Hormônio Liberador da Corticotropina/genética , Variação Genética , Íntrons/genética , Animais , Cerebelo/metabolismo , Hormônio Liberador da Corticotropina/fisiologia , Masculino , Mesencéfalo/metabolismo , Córtex Pré-Frontal/metabolismo , RNA/biossíntese , RNA/genética , Ratos , Ratos Sprague-Dawley , UrocortinasRESUMO
The present study investigated the role of corticotropin-releasing hormone (CRH) in the lateral parabrachial nucleus (LPBN) in the behavioral control of body fluid homeostasis by determining the effect of bilateral injections of the CRH receptor antagonist, alpha-helical corticotropin-releasing factor (CRF)(9-41), and the CRH receptor agonist, CRH, on sodium chloride (salt appetite) and water (thirst) intake. Groups of adult, male Sprague-Dawley rats had stainless-steel cannulas implanted bilaterally into the LPBN and were sodium depleted or water deprived. Bilateral injections of alpha-helical CRF(9-41) into the LPBN significantly potentiated water and salt intake in the sodium-depleted rats when access to fluids was restored. Bilateral injections of alpha-helical CRF(9-41) into the LPBN (1.0 microg) also increased sodium appetite in water-deprived rats. Conversely, in sodium-depleted animals, bilateral injections of CRH inhibited sodium chloride intake. These results suggest that there is an endogenous CRH inhibitory mechanism operating in the LPBN to modulate the intake of sodium (salt appetite). This mechanism may contribute to the behavioral control of restoration of body fluid homeostasis in sodium-deficient states.