RESUMO
RFamide-related peptide (RFRP)-3 reduces luteinising hormone (LH) secretion in rodents. Stress has been shown to upregulate the expression of the RFRP gene (Rfrp) with a concomitant reduction in LH secretion, but an effect on expression of the gonadotrophin-releasing hormone (GnRH) gene (Gnrh1) has not been shown. We hypothesised that lipopolysaccharide (LPS)-induced stress affects expression of Rfrp, the gene for kisspeptin (Kiss1) and/or Gnrh1, leading to suppression of LH levels in rats. Intracerebroventricular injections of RFRP-3 (0.1, 1, 5 nmol) or i.v. LPS (15µgkg-1) reduced LH levels. Doses of 1 and 5 nmol RFRP-3 were then administered to analyse gene expression by in situ hybridisation. RFRP-3 (5 nmol) had no effect on Gnrh1 or Kiss1 expression. LPS stress reduced GnRH and Kiss1 expression, without affecting Rfrp1 expression. These data indicate that LPS stress directly or indirectly reduces Gnrh1 expression, but this is unlikely to be due to a change in Rfrp1 expression.
Assuntos
Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/efeitos dos fármacos , Kisspeptinas/metabolismo , Lipopolissacarídeos/farmacologia , Neuropeptídeos/farmacologia , Animais , Hormônio Liberador de Gonadotropina/genética , Humanos , Hipotálamo/metabolismo , Kisspeptinas/genética , Hormônio Luteinizante/sangue , Ovariectomia , Ratos , Ratos Sprague-DawleyRESUMO
Stress reduces GnRH and gonadotropin secretion in sheep, but the central mechanism for this suppressive effect is unknown. Gonadotropin-inhibitory hormone (GnIH) negatively regulates GnRH neurons and gonadotropes. Here, we measured activity of GnIH neurons and contact of GnIH fibers on GnRH neurons during either chronic "pseudostress" or acute stress in sheep. We also measured GnIH secretion into hypophysial portal blood during pseudostress and acute stress. The pseudostress was daily im injections (0.5 mg) of Synacthen Depot (adrenocorticotropin) or vehicle for 4 weeks, which increased the GnIH cell number and gene expression/cell in the hypothalamus, measured by in situ hybridization. Double label immunohistochemistry showed that Synacthen Depot treatment increased the percentage of GnRH cells in close contact with GnIH fibers but did not alter GnIH levels in hypophysial portal blood. Acute stress protocols were either sequential audiovisual predator stress, followed by insulin-induced hypoglycemia, or a single challenge with lipopolysaccharide (iv). Both of these acute stressors activated a c-Fos response in GnIH cells and increased the contacts of GnIH fibers to GnRH cells. Neither acute stress protocol increased GnIH secretion into hypophysial portal blood. These data show that chronic pseudostress and acute stressors increase the function of GnIH cells as well as the degree to which GnIH cells may provide input to GnRH cells. Thus, GnIH cells may provide a central mechanism whereby stress compromises reproduction. Neither chronic pseudostress nor acute stress elevates secretion of GnIH into portal blood, but stress effects mediated by GnIH cells are directed towards GnRH cell bodies.
Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Gonadotropinas/metabolismo , Hormônios Hipotalâmicos/metabolismo , Estresse Fisiológico/fisiologia , Animais , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hibridização In Situ , Lipopolissacarídeos/farmacologia , Hormônio Luteinizante/sangue , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Radioimunoensaio , OvinosRESUMO
Ependymal cell cilia help move cerebrospinal fluid through the cerebral ventricles, but the regulation of their beat frequency remains unclear. Using in vitro, high-speed video microscopy and in vivo magnetic resonance imaging in mice, we found that the metabolic peptide melanin-concentrating hormone (MCH) positively controlled cilia beat frequency, specifically in the ventral third ventricle, whereas a lack of MCH receptor provoked a ventricular size increase.
Assuntos
Ventrículos Cerebrais/anatomia & histologia , Cílios/fisiologia , Epêndima/anatomia & histologia , Hormônios Hipotalâmicos/farmacologia , Melaninas/farmacologia , Hormônios Hipofisários/farmacologia , Trifosfato de Adenosina/farmacologia , Animais , Encéfalo/citologia , Cálcio/metabolismo , Ventrículos Cerebrais/efeitos dos fármacos , Líquido Cefalorraquidiano/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Cílios/efeitos dos fármacos , Estimulação Elétrica , Feminino , Antagonistas de Hormônios/farmacologia , Hormônios Hipotalâmicos/deficiência , Técnicas In Vitro , Masculino , Melaninas/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hormônios Hipofisários/deficiência , Receptores de Somatostatina/deficiência , Receptores de Somatostatina/genética , Serotonina/farmacologiaRESUMO
Chemokines are small secreted proteins that chemoattract and activate immune and non-immune cells. Their role in the immune system is well-known, and it has recently been suggested that they may also play a role in the central nervous system (CNS). Indeed, they do not only act as immunoinflammatory mediators in the brain but they also act as potential modulators in neurotransmission. Although we are only beginning to be aware of the implication of chemokines in neuroendocrine functions, this review aims at summarizing what is known in that booming field of research. First we describe the expression of chemokines and their receptors in the CNS with a focus on the hypothalamo-pituitary system. Secondly, we present what is known on some chemokines in the regulation of neuroendocrine functions such as cell migration, stress, thermoregulation, drinking and feeding as well as anterior pituitary functions. We suggest that chemokines provide a fine modulatory tuning system of neuroendocrine regulations.
Assuntos
Quimiocinas/fisiologia , Sistemas Neurossecretores/fisiologia , Receptores de Quimiocinas/fisiologia , Animais , Quimiocinas/genética , Quimiocinas/metabolismo , Humanos , Modelos Biológicos , Sistemas Neurossecretores/metabolismo , Adeno-Hipófise/metabolismo , Adeno-Hipófise/fisiologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismoRESUMO
Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression.