Central NPY-Y5 sub-receptor partially functions as a mediator of NPY-induced hypothermia and affords thermotolerance in heat-exposed fasted chicks.

Exposure of chicks to a high ambient temperature (HT) has previously been shown to increase neuropeptide Y (NPY) mRNA expression in the brain. Furthermore, it was found that NPY has anti-stress functions in heat-exposed fasted chicks. The aim of the study was to reveal the role of central administration of NPY on thermotolerance ability and the induction of heat-shock protein (HSP) and NPY sub-receptors (NPYSRs) in fasted chicks with the contribution of plasma metabolite changes. Six- or seven-day-old chicks were centrally injected with 0 or 375 pmol of NPY and exposed to either HT (35 ± 1°C) or control thermoneutral temperature (CT: 30 ± 1°C) for 60 min while fasted. NPY reduced body temperature under both CT and HT NPY enhanced the brain mRNA expression of HSP-70 and -90, as well as of NPYSRs-Y5, -Y6, and -Y7, but not -Y1, -Y2, and -Y4, under CT and HT A coinjection of an NPYSR-Y5 antagonist (CGP71683) and NPY (375 pmol) attenuated the NPY-induced hypothermia. Furthermore, central NPY decreased plasma glucose and triacylglycerol under CT and HT and kept plasma corticosterone and epinephrine lower under HT NPY increased plasma taurine and anserine concentrations. In conclusion, brain NPYSR-Y5 partially afforded protective thermotolerance in heat-exposed fasted chicks. The NPY-mediated reduction in plasma glucose and stress hormone levels and the increase in free amino acids in plasma further suggest that NPY might potentially play a role in minimizing heat stress in fasted chicks.

NPY Impairs Cell Viability and Mitochondrial Membrane Potential Through Ca2+ and p38 Signaling Pathways in Neonatal Rat Cardiomyocytes.

NPY is involved in stress cardiomyopathy. However, the associated mechanism for NPY-induced stress cardiomyopathy remains unclear. In this study, we aimed to explore potential cell signaling pathways that are related to NPY-mediated cell viability in neonatal rat cardiomyocytes. We found that NPY induced cell viability suppression in cultured cardiomyocytes in a dose-dependent manner. After NPY treatment, expression of CaN and p-CAMKII increased significantly, and phosphorylation of p38 but not ERK and JNK was changed. Moreover, NPY treatment significantly increased PGC-1α (the key factor of mitochondrial biogenesis and energy metabolism) expression but decreased mitochondrial membrane potential in cultured cardiomyocytes. More importantly, the blockage of CaN, CAMKII, and p38 signaling pathways by their inhibitors could rescue the reduced cell viability and mitochondrial membrane potential in NPY-treated cardiomyocytes. Collectively, our data demonstrated that NPY mediated cell viability and mitochondrial membrane potential in cardiomyocytes through CaN, CAMKII, and p38 signaling pathways.

Neuropeptide Y Impairs Retrieval of Extinguished Fear and Modulates Excitability of Neurons in the Infralimbic Prefrontal Cortex.

Neuropeptide Y (NPY), a 36 aa peptide, regulates stress and emotional behaviors. Preclinical and clinical studies support an association of NPY with trauma-evoked syndromes such as posttraumatic stress disorder (PTSD), although the exact contribution of NPY is not clear. In the current study, we examined functional attributes of NPY in the infralimbic (IL) cortex, an area that regulates fear memories and is reported to be hypoactive in PTSD. Carriers of NPY gene polymorphism rs16147 have been reported to have elevated prefrontal NPY expression. Infusion of NPY into the IL cortex in rats significantly impaired fear extinction memory without affecting conditioned fear expression or acquisition of extinction. Neuroendocrine stress response, depression-like behavior, and working memory performance were not affected by NPY infusion into the IL. The NPY Y1 receptor antagonist BIBO3304 completely abolished NPY effects on fear extinction retrieval. Y1 receptor expression was localized on CaMKII-positive pyramidal projection neurons and GAD67-positive interneurons in the IL. Patch-clamp recordings revealed increased inhibitory synaptic transmission onto IL projection neurons in the presence of NPY. Thus, NPY dampens excitability of IL projection neurons and impairs retrieval of extinction memory by inhibiting consolidation of extinction. Of relevance to PTSD, elevation of prefrontal NPY attributable to the genetic polymorphism rs16147 may contribute to IL hypoactivity, resulting in impaired extinction memory and susceptibility to the disorder. SIGNIFICANCE STATEMENT: Neuropeptide Y (NPY), a stress modulatory transmitter, is associated with posttraumatic stress disorder (PTSD). Contribution of NPY to PTSD symptomology is unclear. PTSD patients have reduced activity in the infralimbic (IL) subdivision of the medial prefrontal cortex (mPFC), associated with compromised extinction memory. No information exists on fear modulation by NPY in the IL cortex, although NPY and NPY receptors are abundant in these areas. This study shows that IL NPY inhibits consolidation of extinction, resulting in impaired retrieval of extinction memory and modulates excitability of IL projection neurons. In addition to providing a novel perspective on extinction memory modulation by NPY, our findings suggest that elevated mPFC NPY in gene polymorphism rs16147 carriers or after chronic stress could increase susceptibility to PTSD.

Neuropeptide Y damages the integrity of mitochondrial structure and disrupts energy metabolism in cultured neonatal rat cardiomyocytes.

Neuropeptide Y (NPY) plays an important role in cardiovascular diseases including stress cardiomyopathy, hypertrophic cardiomyopathy, heart failure, diabetic cardiomyopathy, hypertension, and so on. However, inconsistent results related to the role of NPY in the different types of cardiomyopathies make the exact involvement of the peptide elusive. Considering these effects are known to be involved in energy balance, as the hearts energy producer, the mitochondria, should be investigated, and not only mitochondrial structure but also its potential. Up to now, the impact of NPY on energy metabolism and mitochondria in cultured neonatal rat cardiomyocytes has not been reported. The main objective of our study was to test the role of NPY in cultured neonatal rat cardiomyocytes. After 24-h stimulation of NPY, the ATP content and activity of the cardiomyocytes were determined by Cell Counting Kit-8 and ATP-dependent bioluminescence assay kit, respectively. To further measure these effects, mitochondrial membrane potential was measured by JC-1 staining, the change of mitochondrial structure was detected by transmission electron microscopy, and the levels of PGC-1α (a marker of mitochondrial energy metabolism) mRNA and protein expression were determined by real-time PCR and Western blotting, respectively. The results showed that after 24-h stimulation of NPY, ATP content and activity in the cardiomyocytes were decreased. Moreover, cardiomyocyte mitochondria were changed in morphology. Further, a decline of mitochondrial membrane potential was induced in a dose-dependent manner and the levels of PGC-1α mRNA and protein expression were up-regulated after being treated by different dose of NPY. The results indicate that energy metabolism is suppressed, mitochondrial structure and membrane potential damaged, and PGC-α is changed in cultured neonatal rat cardiomyocytes after being treated by NPY.

Histamine-independent modulation of the neuropeptide Y-induced pressor response by alpha-trinositol in the pithed rat.

The modulatory effects of alpha-trinositol (D-myo-inositol-1.2.6- trisphosphate; PP 56) on the systemic arterial blood pressor responses induced by neuropeptide Y, preganglionic nerve stimulation, phenylephrine and vasopressin were studied in pithed rats. Intravenous administration (within 2 min.) of alpha-trinositol reduced the neuropeptide Y-induced increase in mean arterial pressure within a defined dose range without altering the heart rate. The influence of alpha-trinositol on the neuropeptide Y-induced pressor response in the presence of non-selective as well as H1- and H2-selective histamine antagonists (diphenhydramine, mepyramine and cimetidine respectively) were investigated. The maximal increase in mean arterial pressure induced by neuropeptide Y as well as the duration of the pressor response was enhanced after nonselective (diphenhydramine) or H1-selective (mepyramine) histamine blockade. The enhancement of the neuropeptide Y-induced pressor response by the H1 specific antagonist mepyramine was significantly more pronounced compared to the H2-selective agent. The exaggerated increase in mean arterial pressure in response to neuropeptide Y after histamine blockade was inhibited by alpha-trinositol to a similar extent as without such pretreatment. We conclude that neuropeptide Y interacts with histamine in the pithed rat and that this action may partially offset the pressor actions of the peptide. The neuropeptide Y-induced pressor responses may be inhibited by alpha-trinositol within a defined dose range indicating that this non-peptide agent may act as a functional inhibitor to neuropeptide Y in vascular tissue.

Comparison of the effects of neuropeptide Y and noradrenaline on rat gastric mucosal blood flow and integrity.

1. The effects of neuropeptide Y (NPY) and noradrenaline on rat gastric mucosal blood flow, as estimated by laser Doppler flowmetry (LDF), have been examined. In addition, the ability of NPY and noradrenaline to induce acute mucosal haemorrhagic damage has also been assessed. 2. Close-arterial infusion of NPY (0.05-0.2 nmol kg-1 min-1) for 10 min in the anaesthetized rat induced a dose-dependent fall in LDF, but had minimal effects on systemic arterial blood pressure. Higher doses of NPY did not produce any further reduction in LDF. 3. Close-arterial infusion (0.1-0.4 nmol kg-1 min-1) of the structurally related peptide YY (PYY) or pancreatic polypeptide (PP), had inconsistent actions in decreasing LDF. 4. Close-arterial infusion of noradrenaline (30-90 nmol kg-1 min-1) dose-dependently reduced gastric LDF. 5. Local infusion of NPY (0.1 and 0.2 nmol kg-1 min-1) or noradrenaline (45 and 60 nmol kg-1 min-1) resulted in dose-related increases in the area of mucosal hemorrhagic damage. 6. Pretreatment with the alpha 1-adrenoceptor antagonist, prazosin (0.1 mg kg-1, i.v.) significantly reduced the effect of noradrenaline, but not NPY, on both LDF and mucosal damage. 7. These findings indicate that NPY and noradrenaline act directly on the gastric microvasculature to induce vasoconstriction and both can induce acute mucosal damage. Therefore endogenous NPY, like noradrenaline could play a modulatory role in regulating vascular tone and may influence mucosal integrity.

Centrally administered neuropeptide Y enhances the hypothermia induced by peripheral administration of adrenoceptor antagonists.

The distribution of neuropeptide Y in the brain includes extensive coexistence within adrenaline- and noradrenaline-containing neurons and many of its actions are often associated with adrenergic systems. Since neuropeptide Y immunoreactivity is particularly intense in the preoptic area, one of the principal sites for thermoregulation, we have tested the effects of neuropeptide Y on core temperature in normothermic rats, and rats rendered hypothermic by systemic treatment with adrenergic antagonists. In the normothermic rat, intracerebroventricular administration of 1 microgram of neuropeptide Y did not have a significant effect on core temperature. Intraperitoneal treatment with the alpha 1-adrenoceptor antagonist, prazosin, or the beta-adrenoceptor antagonist, propranolol, caused an immediate and significant hypothermia; the intracerebroventricular administration of 1 microgram of neuropeptide Y, 10 minutes after these drugs, strongly potentiated their hypothermic effect. Although intraperitoneal treatment with the alpha 2-adrenoceptor antagonist, idazoxan, had no hypothermic effect per se, the intracerebroventricular administration of NPY 10 minutes after this antagonist led to a significant decrease in core temperature.

Long-term stimulatory effect of neuropeptide-Y on the growth and steroidogenic capacity of rat adrenal zona glomerulosa.

A prolonged infusion with neuropeptide-Y (NPY) caused a notable hypertrophy of the adrenal zona glomerulosa and its parenchymal cells in rats whose hypothalamo-hypophyseal axis and renin-angiotensin system were pharmacologically interrupted. Zona glomerulosa hypertrophy was associated with a significant rise in both basal and stimulated plasma levels of aldosterone. Zona fasciculata cells and the blood concentration of corticosterone were not affected. These findings suggest that NPY is specifically involved in the stimulation of the growth and steroidogenic capacity of rat adrenal zona glomerulosa.