RESUMO
Previous work has established that the hormone ghrelin engages the hypothalamic-pituitary-adrenal neuroendocrine axis via activation of corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN). The neuronal circuitry that mediates this effect of ghrelin is currently unknown. Here, we show that ghrelin-induced activation of PVN CRF neurons involved inhibition of γ-aminobutyric acid (GABA) inputs, likely via ghrelin binding sites that were localized at GABAergic terminals within the PVN. While ghrelin activated PVN CRF neurons in the presence of neuropeptide Y (NPY) receptor antagonists or in arcuate nucleus (ARC)-ablated mice, it failed to do it so in mice with ghrelin receptor expression limited to ARC agouti gene related protein (AgRP)/NPY neurons. These data support the notion that ghrelin activates PVN CRF neurons via inhibition of local GABAergic tone, in an ARC-independent manner. Furthermore, these data suggest that the neuronal circuits mediating ghrelin's orexigenic action vs. its role as a stress signal are anatomically dissociated.
Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Grelina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Corticosterona/sangue , Antagonistas GABAérgicos , Técnicas de Silenciamento de Genes , Grelina/administração & dosagem , Infusões Intraventriculares , Masculino , Camundongos , Muscimol/farmacologia , Neuropeptídeo Y/antagonistas & inibidores , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Grelina/efeitos dos fármacos , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-ß (Aß) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234 µmol/µL) 15 min prior to the i.c.v. injection of aggregated Aß1-40 peptide (400 pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aß1-40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aß1-40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aß1-40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aß1-40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aß1-40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aß1-40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.
Assuntos
Peptídeos beta-Amiloides/administração & dosagem , Depressão/induzido quimicamente , Depressão/prevenção & controle , Transtornos da Memória/prevenção & controle , Neuropeptídeo Y/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intraventriculares , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos , Atividade Motora/efeitos dos fármacos , Neuropeptídeo Y/administração & dosagem , Neuropeptídeo Y/antagonistas & inibidores , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/antagonistas & inibidoresRESUMO
Neuropeptide Y (NPY) inhibits TRH neurons in fed state, and hypothalamic NPY higher expression during fasting has been proposed to be involved in fasting-induced suppression of the hypothalamus-pituitary-thyroid (HPT) axis. We investigated the role of central Y5 receptors in the control of thyrotropin (TSH) and thyroid hormone (TH) secretion. Fed and fasting rats received twice daily central injections (3rd ventricle) of Y5 receptor antagonist (CGP71683; 15nmol/rat) for 72h. Fasted rats also received a single central injection of CGP71683 (15nmol/rat) at the end of 72h of fasting. In fed rats, Y5 receptor blockade reduced total food intake by 32% and body mass by almost 10% (p<0.01), corroborating the role of this receptor in food intake control. 72h-fasted rats exhibited a 4-fold increase in serum TSH (p<0.001), 1h after a single injection of Y5 antagonist. Also with multiple injections during 72h of fasting, Y5 blockade resulted in activation of thyroid axis, as demonstrated by a 3-times rise in serum T4 (p<0.001), accompanied by unchanged TSH and T3. In fed rats, the chronic central administration of CGP71683 resulted in reduced total serum T4 without changes in free T4 and TSH. Serum leptin and PYY were not altered by the NPY central blockade in both fed and fasted rats, suggesting no role of these hormones in the alterations observed. Therefore, the inhibition of central Y5 neurotransmission resulted in activation of thyroid axis during fasting suggesting that NPY-Y5 receptors contribute to fasting-induced TSH and TH suppression.
Assuntos
Jejum/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Receptores de Neuropeptídeo Y/metabolismo , Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo , Animais , Jejum/efeitos adversos , Hipotálamo/metabolismo , Hipotálamo/patologia , Leptina/sangue , Naftalenos/farmacologia , Neuropeptídeo Y/antagonistas & inibidores , Neuropeptídeo Y/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Pirimidinas/farmacologia , Ratos , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Hormônios Tireóideos/sangue , Tireotropina/sangueRESUMO
This study investigated the role of neuropeptide Y (NPY) in mediating cardiovascular responses to reduced oxygenation in the late gestation ovine fetus by: (1) comparing the effects on the cardiovascular system of an exogenous infusion of NPY with those elicited by moderate or severe reductions in fetal oxygenation; and (2) determining the effect of fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist on the fetal cardiovascular responses to acute moderate hypoxaemia. Under general anaesthesia, 14 sheep fetuses (0.8-0.9 of gestation) were surgically prepared with vascular and amniotic catheters. In 5 of these fetuses, a Transonic flow probe was also implanted around a femoral artery. Following at least 5 days of recovery, one group of fetuses (n = 9) was subjected to a 30 min treatment period with exogenous NPY (17 microg kg(-1) bolus plus 0.85 microg kg(-1) min(-1) infusion). In this group, fetal blood pressure and heart rate were monitored continuously and the distribution of the fetal combined ventricular output was assessed via injection of radiolabelled microspheres before and during treatment. The second group of fetuses instrumented with the femoral flow probe (n = 5) were subjected to a 3 h experiment consisting of 1 h of normoxia, 1 h of hypoxaemia, and 1 h of recovery during a slow I.V. infusion of vehicle. One or two days later, the acute hypoxaemia protocol was repeated during fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist (50 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion). In these fetuses, fetal arterial blood pressure, heart rate and femoral vascular resistance were recorded continuously. The results show that fetal treatment with exogenous NPY mimics the fetal cardiovascular responses to asphyxia, and that treatment of the sheep fetus with a selective NPY-Y(1) receptor antagonist does not affect the fetal cardiovascular response to acute moderate hypoxaemia. These results support a greater role for NPY in mediating the fetal cardiovascular responses to acute asphyxia than to acute moderate hypoxaemia.
Assuntos
Sistema Cardiovascular/fisiopatologia , Hipóxia Fetal/fisiopatologia , Neuropeptídeo Y/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sangue Fetal , Hipóxia Fetal/sangue , Feto , Frequência Cardíaca Fetal/efeitos dos fármacos , Injeções Intravenosas , Neuropeptídeo Y/administração & dosagem , Neuropeptídeo Y/antagonistas & inibidores , Neuropeptídeo Y/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Ovinos/embriologia , Resistência Vascular/efeitos dos fármacosRESUMO
We studied the effect of GW1229, a novel neuropeptide Y Y1 receptor antagonists, on the vasoconstriction induced by neuropeptide Y and structurally related analogs in the hamster cheek pouch microcirculation. Changes in arteriolar diameter and microvascular conductance were assessed by intravital microscopy and measurement of sodium22 clearance. GW1229 did not affect basal vascular conductance but inhibited, concentration dependently, the reduction in arteriolar diameter and vascular conductance induced by 100 nM neuropeptide Y. GW1229 also counteracted the vasoconstrictor effect of 100 nM [Leu31,Pro34]neuropeptide Y, and that of 300 nM neuropeptide Y-[(13-36). In contrast, GW1229 had no effect on the vasoconstriction induced by noradrenaline. We conclude that the vasoconstrictor effect on neuropeptide Y in the hamster cheek pouch is mediated by neuropeptide Y Y1 receptors. The maintenance of physiological tone in this vascular bed does not involve the participation of endogenous neuropeptide Y.