Role Of Neuropeptide Y Research Articles

Neuropeptide Y inhibits the trigeminovascular pathway through NPY Y1 receptor: implications for migraine.

Migraine is a painful neurologic disorder with premonitory symptomatology that can include disturbed appetite. Migraine pathophysiology involves abnormal activation of trigeminocervical complex (TCC) neurons. Neuropeptide Y (NPY) is synthesized in the brain and is involved in pain modulation. NPY receptors are present in trigeminal ganglia and trigeminal nucleus caudalis suggesting a role in migraine pathophysiology. The present study aimed to determine the effect of systemic administration of NPY on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We performed in vivo electrophysiology in anesthetized rats, administered NPY (10, 30, and 100 µg·kg), and investigated the receptors involved by studying NPY Y1 (30 µg·kg), Y2 (30 µg·kg), and Y5 receptor agonists (100·µg·kg), and NPY Y1 receptor antagonist (30 µg·kg). NPY (30 and 100 µg·kg) significantly reduced TCC neuronal firing in response to dural-evoked trigeminovascular activation, but only NPY (30 µg·kg) significantly reduced spontaneous trigeminal firing. NPY Y1 receptor agonist also significantly reduced dural-evoked and spontaneous TCC neuronal firing. NPY (10 µg·kg), NPY Y2, and Y5 receptor agonists, and the NPY Y1 receptor antagonist had no significant effects on nociceptive dural-evoked neuronal firing in the TCC or spontaneous trigeminal firing. This study demonstrates that NPY dose dependently inhibits dural-evoked trigeminal activity, through NPY Y1 receptor activation, indicating antinociceptive actions of NPY in a migraine animal model. Based on the role of NPY in appetite regulation, it is possible that disruption of the NPY system might explain changes of appetite in migraineurs.

High Plasma Levels of Neuropeptide Y Correlate With Good Clinical Outcome But are not Correlated to Cerebral Blood Flow or Vasospasm After Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage. Treatments with convincing effect are lacking and the pathophysiology behind DCI remains poorly understood. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor and a role of NPY in the development of DCI has been proposed. This study investigated the relationship between plasma-NPY and cerebral blood flow (CBF), cerebral vasospasm, DCI, and clinical outcome. In 90 patients with subarachnoid hemorrhage, NPY was measured in peripheral blood days 2 to 11. Any occurrence of DCI was recorded and CBF was quantified day 3 and day 8 using computed tomography (CT) perfusion. CT angiography was performed day 8. Clinical outcome was assessed after 3 months. No correlation was found between plasma-NPY and CBF or angiographic vasospasm. The correlation between reduced plasma-NPY and DCI reached borderline statistical significance (P=0.05). Increased levels of NPY measured on days 2 to 4 were correlated to good outcome (P=0.006). Our findings in peripheral blood were not supportive of a causal relationship between NPY secretion and DCI. Although high levels of plasma-NPY were correlated with good clinical outcome, NPY did not show promise as a clinically useful biomarker.

Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment.

The sympathetic nervous system (SNS) or neurotransmitters in the bone marrow microenvironment has been known to regulate hematopoietic stem cell (HSC) functions such as self-renewal, proliferation and differentiation. However, the specific role of neuropeptide Y (NPY) in this process remains relatively unexplored. In this study, we demonstrated that NPY deficient mice have significantly reduced HSC numbers and impaired bone marrow regeneration due to apoptotic destruction of SNS fibers and/or endothelial cells. Moreover, NPY treatment prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while conditional knockout mice lacking the Y1 receptor in macrophages did not restore bone marrow dysfunction in spite of NPY injection. Transforming growth factor-beta (TGF-β) secreted by NPY-mediated Y1 receptor stimulation in macrophages plays a key role in neuroprotection and HSC survival in the bone marrow. Therefore, this study reveals a new role of NPY in bone marrow HSC microenvironment, and provides an insight into the therapeutic application of this neuropeptide. [BMB Reports 2015; 48(12): 645-646]

Effect of blockade of neuropeptide Y receptor on aortic intima-media thickness and adipose tissue characteristics in normal and obese mice.

Atherosclerosis is an important risk factor for coronary heart disease. Neuropeptide Y (NPY) and its receptors, located in peripheral tissue such as white adipose tissue, have been linked to obesity and fat storage. The role of NPY in atherosclerosis has not yet been fully studied, so this study was conducted to further investigate the effect of BIIE 0246, an NPY receptor antagonist, on aortic intima-media thickness and size and number of adipocyte cells in normal and obese mice. Tests were performed on 24 male C57BL/6 mice. The animals were divided into four groups as follows: control (normal), obese (high-fat diet), normal+NPY receptor antagonist (1 μM, 100 µl/Kg BIIE0246 intraperitoneally) and obese+NPY receptor antagonist (n=6 each). After 14 days, the animals were sacrificed and epididymal adipose tissue and thoracic aorta were removed. Evaluations were made for adipocyte cell number and size and for aortic intima-media thickness. The group on a high-fat diet showed a significantly decreased number of adipocyte cells and increased cell size (P<0.05). BIIE0246 application changed the cell number of adipocyte in normal mice (P=0.05); however, it did not change adipocyte cell size and aortic intima-media thickness in obese and normal mice (P>0.05). NPY receptor antagonist had no effect on adipocyte cell size and aortic intima-media thickness; however, it decreased cell number in the normal group indicating likely involvement in the progression of obesity.

Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow.

Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide.

Neuropeptide Y as a presynaptic modulator of norepinephrine release from the sympathetic nerve fibers in the pig pineal gland.

Norepinephrine (NE) released from the sympathetic nerve endings is the main neurotransmitter controlling melatonin synthesis in the mammalian pineal gland. Although neuropeptide Y (NPY) co-exists with NE in the pineal sympathetic nerve fibers it also occurs in a population of non-adrenergic nerve fibers located in this gland. The role of NPY in pineal physiology is still enigmatic. The present study characterizes the effect of NPY on the depolarization-evoked 3H-NE release from the pig pineal explants. The explants of the pig pineal gland were loaded with 3H-NE in the presence of pargyline and superfused with Tyrode medium. They were exposed twice to the modified Tyrode medium containing 60 mM of K+ to evoke the 3H-NE release via depolarization. NPY, specific agonists of Y1- and Y2- receptors and pharmacologically active ligands of α2-adrenoceptors were added to the medium before and during the second depolarization. The radioactivity was measured in medium fractions collected every 2 minutes during the superfusion. NPY (0.1-10 μM) significantly decreased the depolarization-induced 3H-NE release. Similar effect was observed after the treatment with Y2-agonist: NPY13-36, but not with Y1-agonist: [Leu31,Pro34]-NPY. The tritium overflow was lower in the explants exposed to the 5 μM NPY and 1 μM rauwolscine than to rauwolscine only. The effects of 5 μM NPY and 0.05 μM UK 14,304 on the depolarization-evoked 3H-NE release were additive. The results show that NPY is involved in the regulation of NE release from the sympathetic terminals in the pig pineal gland, inhibiting this process via Y2-receptors.

Pancreatic islet neuropeptide Y overexpression has minimal effect on islet morphology and β-cell adaptation to high-fat diet.

Neuropeptide Y (NPY) is highly expressed in the hypothalamus, where it regulates feeding and energy homeostasis. Interestingly, NPY and its receptors are also expressed in peripheral tissues with roles in metabolism, including pancreatic islets. In islets, NPY is known to suppress insulin secretion acutely. In addition, the role of NPY in β-cell de-differentiation has been postulated recently. Therefore, we studied transgenic mice expressing NPY under rat insulin promoter (TG) to determine the effects of chronic up-regulation of NPY on islet morphology and function. NPY levels were 25 times higher in islets of TG mice compared with wild-type (WT) littermates, whereas no differences in NPY expression were noted in the brains of TG and WT mice. Islet NPY secretion was 2.3-fold higher in TG compared with WT mice. There were no significant changes in body weight, glucose tolerance, or insulin sensitivity in TG mice fed regular rodent diet or high-fat diet (HF). Islet β-cell area was comparable between TG and WT mice both on regular rodent and HF diets, indicating that NPY overexpression is insufficient to alter β-cell maturation or the compensatory increase of β-cell area on HF. One abnormality noted was that the glucose-stimulated insulin secretion in islets isolated from TG was reduced compared with those from WT mice on HF diet. Overall, an increase in islet NPY level has little impact on islet function and is insufficient to affect glucose homeostasis in mice.

Levels of neuropeptide Y in synovial fluid relate to pain in patients with knee osteoarthritis

The precise etiology of knee osteoarthritis (KOA) pain remains highly controversial and there is no known effective treatment. Due to the known and suggested effects of neuropeptide Y (NPY) on pain, we have sought to investigate the relationship between the concentration of NPY in synovial fluid of knee, pain of KOA, and structural severity of KOA. One hundred KOA patients and twenty healthy participants (control group) were recruited. The pain and the radiographic grade of KOA were assessed separately by Hideo Watanabe’s pain score and Tomihisa Koshino’s scoring system. Synovial fluid of knee from all participants was collected with arthrocentesis. Radioimmunoassay was used to examine the concentration of NPY in synovial fluid of knee. Concentrations of NPY in synovial fluid were significantly higher in KOA patients (124.7 ± 33.4 pg/mL) compared with controls (64.8 ± 26.3 pg/mL) (p = 0.0297). According to Hideo Watanabe’s pain score, 100 KOA patients were divided into 5 subgroups: no pain (n = 12), mild pain (n = 25), moderate pain (n = 37), strong pain (n = 19) and severe pain (n = 7). Within the KOA group, significantly higher concentrations of NPY were found in each subgroup as pain intensified (no pain 81.4 ± 11.7 pg/mL, mild pain 99.1 ± 23.2 pg/mL, moderate pain 119.9 ± 31.5 pg/mL, strong pain 171.2 ± 37.3 pg/mL and severe pain 197.3 ± 41.9 pg/mL). Meanwhile, according to Tomihisa Koshino’s scoring system, 100 KOA patients were divided into 3 subgroups: early stage (n = 30), middle stage (n = 53), advanced stage (n = 17). Concentrations of NPY in middle and advanced stage groups of KOA patients were significant higher than early stage group of KOA patients (early stage 96.4 ± 27.1 pg/mL, middle stage 153.3 ± 16.9 pg/mL, advanced stage 149.5 ± 36.7 pg/mL) (p = 0.0163, p = 0.0352). Concentrations of NPY in advanced stage group of KOA patients has no significant difference compare with middle stage group of KOA patients (p = 0. 2175). This study demonstrated the presence and variation of concentrations of NPY in the KOA joint fluid, suggesting a role for NPY as a putative regulator of pain transmission and perception in KOA pain.

Neuropeptide Y and Leptin Sensitivity is Dependent on Diet Composition

Rats on different free-choice (fc) diets for 1 week of either chow, saturated fat and liquid sugar (fcHFHS), chow and saturated fat (fcHF), or chow and liquid sugar (fcHS) have differential levels of neuropeptide Y (NPY) mRNA in the arcuate nucleus. Because these differences were not explained by plasma leptin levels but did predict subsequent feeding behaviour, in the present study, we first examined whether leptin sensitivity could explain these differences. Second, we focused on the role of NPY on feeding behaviour, and measured NPY mRNA levels and sensitivity to NPY after 4 weeks on the different choice diets. To determine leptin sensitivity, we measured food intake after i.p. leptin or vehicle injections in male Wistar rats subjected to the fcHFHS, fcHS, fcHF or Chow diets for 7 days. Next, we measured levels of arcuate nucleus NPY mRNA with in situ hybridisation in rats subjected to the choice diets for 4 weeks. Finally, we studied NPY sensitivity in rats subjected to the fcHFHS, fcHS, fcHF or Chow diet for 4 weeks by measuring food intake after administration of NPY or vehicle in the lateral ventricle. Leptin decreased caloric intake in rats on Chow, fcHS and fcHF but not in rats on the fcHFHS diet. After 4 weeks, rats on the fcHFHS diet remained hyperphagic, whereas fcHS and fcHF rats decreased caloric intake to levels similar to rats on Chow. By contrast to 1 week, after 4 weeks, levels of NPY mRNA were not different between the diet groups. Lateral ventricle administration of NPY resulted in higher caloric intake in fcHFHS rats compared to rats on the other choice diets or rats on Chow. Our data show that consuming a combination of saturated fat and liquid sugar results in leptin resistance and increased NPY sensitivity that is associated with persistent hyperphagia.

Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a T h 2 polarization

Neuropeptide Y (NPY), a major autonomic nervous system and stress mediator, is emerging as an important regulator of inflammation, implicated in autoimmunity, asthma, atherosclerosis, and cancer. Yet the role of NPY in regulating phenotype and functions of dendritic cells (DCs), the professional antigen-presenting cells, remains undefined. Here we investigated whether NPY could induce DCs to migrate, mature, and polarize naive T lymphocytes. We found that NPY induced a dose-dependent migration of human monocyte-derived immature DCs through the engagement of NPY Y1 receptor and the activation of ERK and p38 mitogen-activated protein kinases. NPY promoted DC adhesion to endothelial cells and transendothelial migration. It failed to induce phenotypic DC maturation, whereas it conferred a T helper 2 (Th2) polarizing profile to DCs through the up-regulation of interleukin (IL)-6 and IL-10 production. Thus, during an immune/inflammatory response NPY may exert proinflammatory effects through the recruitment of immature DCs, but it may exert antiinflammatory effects by promoting a Th2 polarization. Locally, at inflammatory sites, cell recruitment could be amplified in conditions of intense acute, chronic, or cold stress. Thus, altered or amplified signaling through the NPY-NPY-Y1 receptor-DC axis may have implications for the development of inflammatory conditions.-Buttari, B., Profumo, E., Domenici, G., Tagliani, A., Ippoliti, F., Bonini, S., Businaro, R., Elenkov, I., Riganò, R. Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization.

Neuropeptide Y – an early biomarker for cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Objectives:In the human brain, the potent vasoconstrictive neuropeptide Y (NPY) is abundantly expressed. Neuropeptide Y, which is stored in perivascular nerve fibers of the cerebral arteries, regulates the cerebral vascular diameter as well as cerebral blood flow. However, the role of NPY in the pathogenesis of cerebral vasospasm (CV) related to subarachnoid hemorrhage (SAH) is unclear. We prospectively analyzed and compared the release of endogenous NPY in the cerebrospinal fluid (CSF) of 66 patients with SAH to NPY release in a control group. Additionally, we correlated the levels of NPY with CV and consecutive ischemic stroke.Methods:Sixty-six consecutive patients (40 women, 26 men; mean age 53·1 years) with aneurysmal SAH were included. In the SAH group, CSF was drawn daily from day 1 to day 10 after the onset of SAH. The CSF of 29 patients undergoing spinal anesthesia for orthopedic surgery served as control samples. The NPY levels were determined in duplicate CSF samples by means of a competitive enzyme immunoassay (EIA). The levels of NPY in CSF were correlated with the development of CV over the 10-day period after the onset of SAH and to the occurrence of consecutive ischemic stroke. To evaluate CSF NPY levels as a predictive biomarker for vasospasm, we calculated the sensitivity and specificity as well as the positive and negative predictive values.Results:The NPY levels were significantly higher in the SAH group than in the control group (p < 0·001). The treatment modality (clip versus coil) did not influence the level of NPY in CSF (p > 0·05). Patients with CV showed significantly higher NPY levels than patients without CV during the entire observation period. The NPY levels of the non-CV group dissipated over time, whereas the CV group showed continuously increasing values. The NPY levels from day 4 to 10 were significantly higher in patients with CV-related stroke than in non-stroke patients. Using 0·3 ng/ml as a cut-off value, NPY levels on day 3 predicted the occurrence of CV with a sensitivity and specificity of 82% and 72%, respectively. High NPY levels, starting on day 4, significantly correlated with poor Glasgow Outcome Score grading at the follow-up (p < 0·05).Discussion:Our data indicate that NPY is involved in the pathogenesis of SAH-related CV and ischemia. Neuropeptide Y represents an early and reliable biomarker for the prediction of CV and consecutive stroke due to aneurysmal SAH.

Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms

Neuropeptide Y (NPY) exerts its functions through six subtypes of receptors (Y₁-Y₆). Biliary homeostasis is regulated by several factors through autocrine/paracrine signaling. NPY inhibits cholangiocarcinoma growth; however, no information exists regarding the autocrine/paracrine role of NPY on biliary hyperplasia during cholestasis. The aims of this study were to determine: 1) the expression of NPY and Y₁-Y₅ in cholangiocytes and 2) the paracrine/autocrine effects of NPY on cholangiocyte proliferation. Normal or bile duct ligation (BDL) rats were treated with NPY, neutralizing anti-NPY antibody, or vehicle for 7 days. NPY and NPY receptor (NPYR) expression was assessed in liver sections and isolated cholangiocytes. NPY secretion was assessed in serum and bile from normal and BDL rats, as well as supernatants from normal and BDL cholangiocytes and normal rat cholangiocyte cell line [intrahepatic normal cholangiocyte culture (NRICC)]. We evaluated intrahepatic bile ductal mass (IBDM) in liver sections and proliferation in cholangiocytes. With the use of NRICC, the effects of NPY or anti-NPY antibody on cholangiocyte proliferation were determined. The expression of NPY and all NPYR were increased after BDL. NPY levels were lower in serum and cholangiocyte supernatant from BDL compared with normal rats. NPY secretion from NRICC was detected at both the basolateral and apical domains. Chronic NPY treatment decreased proliferating cellular nuclear antigen (PCNA) expression and IBDM in BDL rats. Administration of anti-NPY antibody to BDL rats increased cholangiocyte proliferation and IBDM. NPY treatment of NRICC decreased PCNA expression and increased the cell cycle arrest, whereas treatment with anti-NPY antibody increased proliferation. Therapies targeting NPY-mediated signaling may prove beneficial for the treatment of cholangiopathies.

The Role of NPY and Ghrelin in Anorexia Nervosa

Complex mechanisms have evolved that control feeding and energy homeostasis in mammals. Centrally, particularly in the hypothalamus, numerous neurotransmitters have been identified that regulate appetite and energy homeostasis. On the other hand, hormones released from the gut signal states of hunger and satiety to the brain. From the large number of players involved in this interplay, peptides from the neuropeptide Y (NPY) family are unique, with the predominantly neuronally expressed NPY being one of the most strongly stimulating agents for food intake while its two other closely related family members peptide YY (PYY) and pancreatic polypeptide (PP) released from the gut induce satiety. Another major player in this circuitry is ghrelin, which is released from the stomach and is the only known hormone that signals hunger to the brain. It is doing this by stimulating hypothalamic NPY production and release, subsequently leading to increased appetite and feeding behaviour. Deregulation of these processes can lead to either the development of obesity or the other extreme, anorexia. The aim of this review is to summarize the recent literature on NPY and ghrelin and its involvement in anorexia nervosa.

Cell-specific expression of calcineurin immunoreactivity within the rat basolateral amygdala complex and colocalization with the neuropeptide Y Y1 receptor

Neuropeptide Y (NPY) produces potent anxiolytic effects via activation of NPY Y1 receptors (Y1r) within the basolateral amygdaloid complex (BLA). The role of NPY in the BLA was recently expanded to include the ability to produce stress resilience and long-lasting reductions in anxiety-like behavior. These persistent behavioral effects are dependent upon activity of the protein phosphatase, calcineurin (CaN), which has long been associated with shaping long-term synaptic signaling. Furthermore, NPY-induced reductions in anxiety-like behavior persist months after intra-BLA delivery, which together indicate a form of neuronal plasticity had likely occurred. To define a site of action for NPY-induced CaN signaling within the BLA, we employed multi-label immunohistochemistry to determine which cell types express CaN and if CaN colocalizes with the Y1r. We have previously reported that both major neuronal cell populations in the BLA, pyramidal projection neurons and GABAergic interneurons, express the Y1r. Therefore, this current study evaluated CaN immunoreactivity in these cell types, along with Y1r immunoreactivity. Antibodies against calcium-calmodulin kinase II (CaMKII) and GABA were used to identify pyramidal neurons and GABAergic interneurons, respectively. A large population of CaN immunoreactive cells displayed Y1r immunoreactivity (90%). Nearly all (98%) pyramidal neurons displayed CaN immunoreactivity, while only a small percentage of interneurons (10%) contained CaN immunoreactivity. Overall, these anatomical findings provide a model whereby NPY could directly regulate CaN activity in the BLA via activation of the Y1r on CaN-expressing, pyramidal neurons. Importantly, they support BLA pyramidal neurons as prime targets for neuronal plasticity associated with the long-term reductions in anxiety-like behavior produced by NPY injections into the BLA.

Neuropeptide Y potentiates beta-adrenergic stimulation of lipolysis in 3T3-L1 adipocytes

Recently, we have shown that neuropeptide Y (NPY) is produced and upregulated in visceral adipose tissue of an early-life programmed rat model of central obesity. Moreover, we have demonstrated that NPY promotes proliferation of adipocyte precursor cells and contributes to the pathogenesis of obesity. However, the role of NPY in regulating adipocyte metabolism is poorly understood. The present study was designed to examine the effects of NPY on adipocyte metabolic function using 3T3-L1 adipocytes as an in vitro cell model system. We found that although it did not affect basal lipolysis, NPY potentiated isoproterenol (a β-adrenergic receptor agonist) stimulated lipolysis. Furthermore, this potentiation occurred upstream of adenylyl cyclase, since NPY did not enhance forskolin (an activator of adenylyl cyclase) stimulated lipolysis. In addition, NPY also augmented isoproterenol-stimulated phosphorylation of hormone sensitive lipase. In contrast, NPY did not alter the expression of several key lipolytic and lipogenic enzymes/proteins. Taken together, our results revealed a novel cross talk between the NPY and β-adrenergic signaling pathways in regulating lipolysis. Thus, the present findings add a new dimension to the dynamic role NPY plays in regulating energy balance.

Mice lacking neuropeptide Y show increased sensitivity to cocaine

There is increasing data implicating neuropeptide Y (NPY) in the neurobiology of addiction. This study explored the possible role of NPY in cocaine-induced behavior using NPY knockout mice. The transgenic mice showed a hypersensitive response to cocaine in three animal models of cocaine addiction. Whether this is due to an observed compensatory increase in striatal dopamine transporter binding or an anxiogenic phenotype of the transgenic mice remains to be determined.

The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin

The effects of intracerebroventricular administration of neuropeptide Y (NPY), which is believed to play an important role in neuroprotection against excitotoxicity and in the modulation of adult neurogenesis, were evaluated in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy represented by trimethyltin (TMT) intoxication. A single TMT injection (8 mg/kg) causes, in the rat brain, massive neuronal death, selectively involving pyramidal neurons, accompanied by glial activation and enhanced hippocampal neurogenesis. Our data indicate that intracerebroventricular administration of exogenous NPY (at the dose of 2 μg/2 μL, 4 days after TMT-administration), in adult rats, exerts a protective role in regard to TMT-induced hippocampal damage and a proliferative effect on the hippocampal neurogenic niche through the up-regulation of Bcl-2, Bcl2l1, Bdnf, Sox-2, NeuroD1, Noggin and Doublecortin genes, contributing to delineate more clearly the role of NPY in in vivo neurodegenerative processes.

Neuropeptide Y promotes neurogenesis and protection against methamphetamine-induced toxicity in mouse dentate gyrus-derived neurosphere cultures

Methamphetamine (METH) is a psychostimulant drug of abuse that causes severe brain damage. However, the mechanisms responsible for these effects are poorly understood, particularly regarding the impact of METH on hippocampal neurogenesis. Moreover, neuropeptide Y (NPY) is known to be neuroprotective under several pathological conditions. Here, we investigated the effect of METH on dentate gyrus (DG) neurogenesis, regarding cell death, proliferation and differentiation, as well as the role of NPY by itself and against METH-induced toxicity. DG-derived neurosphere cultures were used to evaluate the effect of METH or NPY on cell death, proliferation or neuronal differentiation. Moreover, the role of NPY and its receptors (Y1, Y2 and Y5) was investigated under conditions of METH-induced DG cell death. METH-induced cell death by both apoptosis and necrosis at concentrations above 10 nM, without affecting cell proliferation. Furthermore, at a non-toxic concentration (1 nM), METH decreased neuronal differentiation. NPY's protective effect was mainly due to the reduction of glutamate release, and it also increased DG cell proliferation and neuronal differentiation via Y1 receptors. In addition, while the activation of Y1 or Y2 receptors was able to prevent METH-induced cell death, the Y1 subtype alone was responsible for blocking the decrease in neuronal differentiation induced by the drug. Taken together, METH negatively affects DG cell viability and neurogenesis, and NPY is revealed to be a promising protective tool against the deleterious effects of METH on hippocampal neurogenesis.

Elevated plasma levels of neuropeptide Y in female fibromyalgia patients.

Neuropeptide Y(NPY) co-exists with norepinephrine in the sympathetic nervous system, and NPY may represent the sympathetic-neuronal output. Fibromyalgia syndrome (FMS) patients have perturbations in the hypothalmic-pituitary-adrenal (HPA) axis and in the sympathetic stress axis as well. As opioid peptides, monoamines and sex steroids are integrated in the regulation of stress, it is interesting to further explore the role of NPY in FMS patients, as they show many symptoms that are related to perturbations of those systems.In this study, plasma NPY levels were assessed in subgroups of FMS patients: cyclic (regular menstrual cycles), non-cyclic (post-menopausal), depressed and non-depressed patients. In order to examine whether pain and other symptoms seen in FMS patients are correlated to the NPY levels, the patients were also registering 15 different symptoms daily during 28 days. Sex and age-matched healthy controls were recruited for comparisons. Non-parametric tests were used for the statistical analyses.The results showed that the NPY levels were significantly elevated in the patients compared to the controls. In the luteal phase of the cyclic patients, the levels of the peptide were higher than in the corresponding controls. For the non-cyclic patients, there was a positive correlation between physical symptoms and NPY levels, however, pain per se did not reach the significant level of correlation. The non-depressed patients had the same levels of NPY as the depressed FMS patients, who also had a positive correlation between anxiety and NPY levels.These results suggest that FMS patients have an altered activity in the NPY system, most likely due to prolonged and/or repeated stress, and that the hormonal state and time of the menstrual cycle also may be of importance in the complex pathophysiologic mechanism behind the development of FMS. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Involvement of Neuropeptide Y Signaling in the Antidepressant-Like Effect and Hippocampal Cell Proliferation Induced by Kososan, a Kampo Medicine, in the Stress-Induced Depression-Like Model Mice

Neuropeptide Y (NPY) and Orexin-A (OX-A), well-known neuropeptides associated with feeding and arousal, show antidepressant-like properties via hippocampal cell proliferation. Previous studies have revealed that kososan, a Kampo (Japanese herbal) medicine, has an antidepressant-like effect in behavioral animal models of depression; the mechanisms underlying this effect may involve the orexinergic system and subsequent upregulation of hippocampal cell proliferation. However, the roles of NPY in kososan's antidepressant-like effect remain unclear. Here we investigated whether the regulation of the NPY system could play crucial roles in this effect in the stress-induced depression-like model mice. The antidepressant-like effect of kososan administered orally (1.0 g/kg) for 28 d was abolished by a continuous intracerebroventricular injection of BIBO3304, a neuropeptide Y1 receptor antagonist, for 7 d. Likewise, BIBO3304 injection blocked the kososan-induced increases in hippocampal cell proliferation and cluster formation of neural progenitor cells. On the other hand, BIBO3304 injection did not affect kososan-induced increases in hypothalamic OX-A-producing cells or in serum OX-A levels. These results suggest that the control of the NPY system in the brain plays an essential role in kososan's antidepressant-like effect and facilitates hippocampal cell proliferation, both of which could be attributed, at least in part, to the control of the NPY system subsequent to the control of the OX-A system.