Changes In Neuropeptide Y Levels Research Articles

Neuropeptide Y in the medial habenula alleviates migraine-like behaviors through the Y1 receptor

BackgroundMigraine is a highly disabling health burden with multiple symptoms; however, it remains undertreated because of an inadequate understanding of its neural mechanisms. Neuropeptide Y (NPY) has been demonstrated to be involved in the modulation of pain and emotion, and may play a role in migraine pathophysiology. Changes in NPY levels have been found in patients with migraine, but whether and how these changes contribute to migraine is unknown. Therefore, the purpose of this study was to investigate the role of NPY in migraine-like phenotypes.MethodsHere, we used intraperitoneal injection of glyceryl trinitrate (GTN, 10 mg/kg) as a migraine mouse model, which was verified by light-aversive test, von Frey test, and elevated plus maze test. We then performed whole-brain imaging with NPY-GFP mice to explore the critical regions where NPY was changed by GTN treatment. Next, we microinjected NPY into the medial habenula (MHb), and further infused Y1 or Y2 receptor agonists into the MHb, respectively, to detect the effects of NPY in GTN-induced migraine-like behaviors.ResultsGTN effectively triggered allodynia, photophobia, and anxiety-like behaviors in mice. After that, we found a decreased level of GFP+ cells in the MHb of GTN-treated mice. Microinjection of NPY attenuated GTN-induced allodynia and anxiety without affecting photophobia. Furthermore, we found that activation of Y1—but not Y2—receptors attenuated GTN-induced allodynia and anxiety.ConclusionsTaken together, our data support that the NPY signaling in the MHb produces analgesic and anxiolytic effects through the Y1 receptor. These findings may provide new insights into novel therapeutic targets for the treatment of migraine.Graphical

Neuroprotective Effects of Neuropeptide Y against Neurodegenerative Disease.

Neuropeptide Y (NPY), a 36 amino acid peptide, is widely expressed in the mammalian brain. Changes in NPY levels in different brain regions and plasma have been described in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Machado-Joseph disease. The changes in NPY levels may reflect the attempt to set up an endogenous neuroprotective mechanism to counteract the degenerative process. Accumulating evidence indicates that NPY can function as an anti-apoptotic, anti-inflammatory, and pro-phagocytic agent, which may be used effectively to halt or to slow down the progression of the disease. In this review, we will focus on the neuroprotective roles of NPY in several neuropathological conditions, with a particular focus on the anti-inflammatory properties of NPY.

The Effects of Antidepressants on Neuropeptide Y in Patients with Depression and Anxiety.

This study aimed to investigate the neuropeptide Y (NPY) levels in patients with anxiety and depression and also the effects of antidepressants on this neuropeptide. The study included 40 outpatients who presented with depressive and anxiety symptoms, and 32 healthy controls. The patients received antidepressant treatment for 6 months. Serum levels of neuropeptide Y were measured before treatment in 40 patients, after 8 weeks of treatment in 32 patients, after 6 months in 10 patients, and once in the controls. Serum NPY levels were lower in the patients than in the controls. NPY levels were increased and normalized by antidepressant treatment. While there was no change in NPY levels in the patients using fluoxetine and sertraline for 8 weeks, an increase was found in patients using escitalopram and venlafaxine. Serum NPY levels were increased by treatment for 8 weeks in the patients with depression, but not in the patients with anxiety. The findings suggest that NPY may be related to pathophysiology in depression and anxiety, and antidepressants influence NPY levels.

Nerve growth factor retrieves neuropeptide Y and cholinergic immunoreactivity in the nucleus accumbens of old rats

The nucleus accumbens (NAc) contains high levels of neuropeptide Y (NPY), which is involved in the regulation of functions and behaviors that deteriorate with aging. We sought to determine if aging alters NPY expression in this nucleus and, in the affirmative, if those changes are attributable to the cholinergic innervation of the NAc. The total number and the somatic volume of NPY- and choline acetyltransferase-immunoreactive neurons, and the density of cholinergic varicosities were estimated in the NAc of adult (6 months old) and aged (24 months old) rats. In aged rats, the number of NPY neurons was reduced by 20% and their size was unaltered. The number of cholinergic neurons and the density of the cholinergic varicosities were unchanged, but their somas were hypertrophied. Nerve growth factor administration to aged rats further increased the volume of cholinergic neurons, augmented the density of the cholinergic varicosities, and reversed the age-related decrease in the number of NPY neurons. Our data show that the age-related changes in NPY levels in the NAc cannot be solely ascribed to the cholinergic innervation of the nucleus.

Neuropeptide Y receptor Y2 gene polymorphism interacts with plasma neuropeptide Y levels in predicting left ventricular hypertrophy in dialysis patients

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that acts on multiple receptors involved in cardiovascular remodelling and angiogenesis. Plasma levels of NPY are increased in patients with end-stage renal disease (ESRD) and are independently related to left ventricular hypertrophy (LVH) and incident cardiovascular events in these patients. To investigate the relationship between NPY receptor Y2 gene polymorphism and left ventricular mass index (LVMI) as well as the interaction between this polymorphism and plasma NPY in determining LVH in 189 ESRD patients. LVMI was significantly higher (+12%, P = 0.03) in patients carrying the C allele than in those without C allele and was linearly associated with plasma NPY (P = 0.01). Interaction analysis showed a significant NPY-LVMI relationship in patients with the C allele, both at univariate (r = 0.27, P = 0.001) and multivariate (r = 0.21, P = 0.01) analyses, whereas no such relationship existed in patients without this allele. In fully adjusted analyses, a 10 pmol/l increase in plasma NPY entailed a 4.9 g/m increase in LVMI in patients with C allele, whereas the same change in NPY levels did not modify the NPY-LVMI link in patients without such allele (P = 0.009). NPY receptor Y2 polymorphism is independently associated with LVMI and interacts with plasma levels of NPY in explaining the variability of LVH in ESRD. These results offer a genetic basis to the hypothesis that NPY is causally implicated in the pathogenetic pathway leading to LVH in ESRD patients.

Modulation of neuropeptide Y expression in adult mice does not affect feeding

Despite numerous experiments showing that administration of neuropeptide Y (NPY) to rodents stimulates feeding and obesity, whereas acute interference with NPY signaling disrupts feeding and promotes weight loss, NPY-null mice have essentially normal body weight regulation. These conflicting observations suggest that chronic lack of NPY during development may lead to compensatory changes that normalize regulation of food intake and energy expenditure in the absence of NPY. To test this idea, we used gene targeting to introduce a doxycycline (Dox)-regulated cassette into the Npy locus, such that NPY would be expressed until the mice were given Dox, which blocks transcription. Compared with wild-type mice, adult mice bearing this construct expressed approximately 4-fold more Npy mRNA, which fell to approximately 20% of control values within 3 days after treatment with Dox. NPY protein also fell approximately 20-fold, but the half-life of approximately 5 days was surprisingly long. The biological effectiveness of these manipulations was demonstrated by showing that overexpression of NPY protected against kainate-induced seizures. Mice chronically overexpressing NPY had normal body weight, and administration of Dox to these mice did not suppress feeding. Furthermore, the refeeding response of these mice after a fast was normal. We conclude that, if there is compensation for changes in NPY levels, then it occurs within the time it takes for Dox treatment to deplete NPY levels. These observations suggest that pharmacological inhibition of NPY signaling is unlikely to have long-lasting effects on body weight.

The Putative Neuroprotective Role of Neuropeptide Y in the Central Nervous System

Neuropeptide Y (NPY) is one of the most abundant and widely distributed neuropeptides in the mammalian central nervous system (CNS). An overview of the distribution of the G-protein coupled NPY receptor family (Y(1), Y(2), Y(4), Y(5) receptors) in the brain is described. The coexistence of NPY with other neurotransmitters and its wide distribution in several brain areas predict the high importance of NPY as a neuromodulator. Thus, the effect of NPY on the release of several neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), norepinephrine (NE), dopamine, somastotatin (SOM), serotonin (5-HT), nitric oxide (NO), growth hormone (GH) and corticotropin releasing factor (CRF) is reviewed. A neuroprotective role for NPY under physiological conditions and during hyperactivity such as epileptic-seizures has been suggested. We have shown previously that NPY inhibits glutamate release evoked from hippocampal nerve terminals and has a neuroprotective effect in rat organotypic hippocampal cultures exposed to an excitotoxic insult. Moreover, changes in NPY levels have been observed in different pathological conditions such as brain ischemia and neurodegenerative diseases (Huntington's, Alzheimer's and Parkinson's diseases). Taken together, these studies suggest that NPY and NPY receptors may represent pharmacological targets in different pathophysiological conditions in the CNS.

Changes in diurnal sympathoadrenal balance and pituitary hormone secretion in subjects with Leu7Pro polymorphism in the prepro-neuropeptide Y.

Neuropeptide Y (NPY) is an important neurotransmitter in the central and peripheral nervous systems. It has a regulatory role in cardiovascular and metabolic functions and control of hormone release. The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of prepro-NPY is associated with increased blood lipid levels, accelerated atherosclerosis, and diabetic retinopathy. This study elucidated the role of this polymorphism in diurnal cardiovascular, metabolic, and hormonal functions of healthy subjects during rest. The two study groups comprised individuals with different genotype, but they were matched for age and body mass index. Subjects with the Leu7Pro polymorphism had significantly lower plasma NPY and norepinephrine concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin-glucose ratio in plasma than the controls. Heart rate was significantly higher during daytime in the subjects with Leu7Pro polymorphism. Furthermore, these subjects had significantly lower prolactin concentrations in plasma. Systolic and diastolic blood pressure, serum free fatty acid and plasma leptin, ACTH, cortisol, LH, FSH, TSH, free thyroxin, and melatonin concentrations were similar during the 24-h period, compared with controls. These results show that genetically determined changes in NPY levels lead to widespread consequences in the control of sympathoadrenal, metabolic, and hormonal balance in healthy subjects.

Absence of increased neuropeptide Y neuronal activity before and during the luteinizing hormone (LH) surge may underlie the attenuated preovulatory LH surge in middle-aged rats.

A large body of evidence suggests that the neuroendocrine axis plays a major role in the reproductive aging of female rats. Since increased hypothalamic neuropeptide Y (NPY) neurosecretion is crucial in the preovulatory LH discharge in young rats, we tested the hypothesis that diminution in the preovulatory LH surge in middle-aged (MA) rats may be due to altered neurosecretory activity in NPYergic neurons. In Exp 1, we examined NPY levels in six microdissected hypothalamic nuclei, including median eminence (ME), arcuate nucleus (ARC), and medial preoptic area (MPOA), at 1000, 1200, 1400, 1600, 1800, 2000, or 2200 h on the day of proestrus in young (2.5- to 3-month old) and MA (7- to 9-month old) regularly cycling rats. At 1000 h, ME NPY levels in young rats were significantly lower than those in MA rats. In young rats, the ME NPY levels were significantly increased at 1400 h before the LH surge in the afternoon and thereafter decreased progressively during the interval of the LH surge. In MA rats, however, ME NPY levels decreased in the afternoon in association with an attenuated LH surge. In addition, in the ARC and MPOA, the other hypothalamic sites associated with induction of LH surge, NPY levels increased before and during the LH surge in young rats, no change in NPY levels in these nuclei was observed in association with the attenuated LH surge in MA rats. Also, NPY levels in the ARC and MPOA during the afternoon were significantly lower in MA compared with those in young animals. These results demonstrated the absence of an antecedent increase in NPY levels, specifically in the ME and ARC, during the afternoon of proestrus in MA animals. In a second experiment, we evaluated whether the absence of dynamic changes in NPY levels in the ME and ARC in MA rats was due to altered hypothalamic NPY gene expression. Regularly cycling young (2.5- to 3-month-old) and MA (8- to 10-month-old) rats were killed at 1000, 1200, 1400, 1600, 1800, 2000, or 2200 h on the day of proestrus. The medial basal hypothalamus was processed for prepro-NPY messenger RNA (mRNA) measurement by ribonuclease protection assay. In young rats, prepro-NPY mRNA levels were significantly increased at 1200 h and remained elevated throughout the afternoon. In contrast, in MA rats prepro-NPY mRNA levels remained unchanged before and during the attenuated LH surge. These results clearly indicate that the augmentation in NPY neuronal activity before and during the LH surge seen in young rats fails to manifest itself in middle-aged rats. As hypothalamic NPY participates in the induction of LHRH surge, our results suggest that reduced LHRH and LH surges in MA rats may be due to diminution in NPY secretion in these animals.

Neuropeptide Y (NPY) and its mRNA in discrete brain areas after subchronic administration of neuroleptics.

Classical (chlorpromazine, haloperidol) and atypical (sulpiride and clozapine) neuroleptics applied for a period of 2 weeks diminished neuropeptide Y (NPY) levels in nucleus accumbens, but not in striatum. These changes were correlated with NPY mRNA level. However, the effect of these neuroleptics on the level of NPY in hypothalamus was different. It is suggested that changes in NPY levels caused by neuroleptics are mediated by dopaminergic D1/D2 receptors.

Changes in plasma catecholamine and neuropeptide Y levels after sympathetic activation in dogs

1. Plasma levels of noradrenaline (NA) and neuropeptide Y (NPY) were evaluated in two experimental models associated with an increase in sympathetic tone: conscious dogs which were subject to either sinoaortic denervation or acute administration of the alpha 2-adrenoceptor antagonist yohimbine. 2. Dogs that had undergone sinoaortic denervation exhibited a two fold increase in plasma NA without any change in NPY levels. 3. Yohimbine (0.05 mg kg-1 i.v. as a bolus) produced similar effects. A higher dose of yohimbine (0.5 mg kg-1 i.v.) increased both plasma NA (7 fold) and NPY (6.5 fold) levels. 4. The present results indicate that changes in plasma catecholamines and NPY are not always concomitant. They suggest that the simultaneous release of NA and NPY is only observed under in vivo conditions for a marked increase in sympathetic tone.

Clonidine but not propranolol decreases plasma neuropeptide Y (NPY) levels

The effects of acute administration of two antihypertensive drugs, clonidine and propranolol, on plasma NPY and catecholamine levels were compared in sinoaortic denervated (a model associated with a marked increase in sympathetic tone and a rise in blood pressure) and normal conscious dogs. Clonidine decreased plasma noradrenaline and NPY concentrations in both groups of animals. Propranolol failed to change plasma noradrenaline and NPY levels in sinoaortic denervated dogs but elicited a decrease in plasma noradrenaline with no change in NPY levels in normotensive animals. The present experiments show that changes in plasma noradrenaline and NPY concentrations are not always simultaneous. The decrease in plasma NPY concentrations could contribute to the sympatholytic effect of clonidine.

Changes in brain neuropeptide Y induced by cholecystokinin peptides

Cholecystokinin (CCK) and neuropeptide Y (NPY) are two peptides with opposite effects on the regulation of feeding behaviour. The possible interaction between these two systems has always been controversial. In this study, rat brain NPY levels were assayed after treatment with CCK 8 S and with a potent CCK agonist (Boc-(Nle 28-Nle 31)-CCK 26–33). CCK 8 S and its agonist analogue (50 μg/kg i.p.) both decreased hypothalamic and hippocampal NPY levels. This result suggests a negative relationship between NPY and CCK-peptides which is not surprising given their opposite role in the control of feeding. The hypothalamus and secondarily the hippocampus appear to be the site of this interaction; no change in NPY levels was observed in other brain areas (striatum and cortex). The same pattern of variation was found in the plasma, suggesting a direct release from the brain via a mechanism which remains to be investigated. The effect appeared later with the CCK analogue than with CCK 8 S itself; this is not surprising with regard to other behavioural and biochemcial effects of the analogue and provides further characterization of its action.

Dynamic Changes in Neuropeptide Y Concentrations in the Median Eminence in Association with Preovulatory Luteinizing Hormone Release in the Rat

Abstract Neuropeptide Y (NPY) stimulates luteinizing hormone (LH) release in the rat by a dual action, one in the hypothalamus to excite LH-releasing hormone (LHRH) release and the other at the level of pituitary gonadotrophs to activate and/or potentiate LH release induced by LHRH. Because NPY produces effects similar to norepinephrine with which it may comprise an excitatory hypothalamic circuit, it was hypothesized that NPY concentrations in the hypothalamus would change in a time- and site-specific manner in association with the preovulatory LH surge on proestrus. Concentrations of NPY in individual nuclei of the preoptic-tuberal pathway and serum LH levels were estimated by radioimmunoassays in rats during diestrus 2 and proestrus. On proestrus, serum LH levels were basal between 1000 and 1400 h, rose significantly at 1500 h and plateaued between 1600 and 1800 h. Of the five neural sites examined, only NPY in the median eminence displayed marked fluctuations in close association with the LH surge. NPY concentrations were low between 1000 and 1300 h, and rose abruptly at 1400 h (P<0.05) preceding the onset of LH rise at 1500 h. These elevated levels were maintained until 1600 h, during which time serum LH rose to a plateau and then fell at 1800 h to the low range seen between 1000 and 1300 h. In contrast, the pattern of changes in NPY levels in the arcuate nucleus, suprachiasmatic nucleus and medial preoptic area, three additional sites in the preoptic-tuberal pathway known to participate in the preovulatory LH surge, were markedly different from that seen in the median eminence. In each of these three sites, NPY levels rose significantly at 1800 h from the values at 1000 to 1200 h with a slightly different time-course of increment. None of these areas exhibited changes in NPY concentrations on diestrus 2; NPY concentrations also were unaltered on diestrus 2 or proestrus in the ventromedial nucleus. The present observations of site-specific, dynamic changes in NPY levels on proestrus, in a manner previously documented for LHRH, support the hypothesis that a subset of NPY neurons terminating in the median eminence may be a component of excitatory neural circuitry that either independently or in co-action with the adrenergic system is responsible for the induction of preovulatory LH release.

Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus

We have studied the effects on neuropeptide Y (NPY) concentration in six hypothalamic nuclei, viz. medial preoptic area (MPOA), paraventricular nucleus (PVN), median eminence (ME), arcuate nucleus (ARC), ventromedial nucleus (VMN) and dorsomedial nucleus (DMN) of food deprivation (FD) for 2, 3, or 4 days or FD for 4 days followed by one day ad lib food intake (FI) in male rats. Hypothalamic nuclei were microdissected by the technique of Palkovits and processed for measurement of NPY immunoreactivity by RIA. NPY-like immunoreactivity in the ME, VMN and DMN was unaffected by FD or FI, but the remaining three nuclei—the ARC, MPOA and PVN—displayed a different pattern of changes in NPY levels in response to either FD or FD followed by FI. In the ARC, NPY levels rose significantly at day 3 and 4 after FD and remained elevated even after one day of FI. In the MPOA, while FD for 4 days had no effect, NPY concentration increased significantly in response to FI. In contrast, in the PVN, a site implicated in the control of feeding behavior, the NPY response to FD and FI was markedly different. FD elicited a gradual, time-related increase in NPY levels to reach highest concentration on day 4 and thereafter, following one day of FI, NPY levels fell dramatically to the range found in control satiated rats. These results show that (1) NPY levels display site-specific changes in response to FD and FI; (2) a dramatic reciprocal change in the PVN NPY levels occurred in response to disturbances in the daily food intake as produced by sequential FD and FI; (3) other hypothalamic sites, such as the ARC and MPOA, displayed only unidirectional increments in response to FD and FI. The observation of site-specific changes in the PVN NPY levels further support the hypothesis that NPY may be a physiological neurochemical signal in the PVN that normally evokes feeding in the rat.