Neuropeptide Y Research Articles

Exploring the Anxiolytic Potential of NPY by a dipeptidyl peptidase-IV inhibitor in an animal model of PTSD.

The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through five receptor subtypes, with Y1 and Y2 receptors being predominantly expressed in the rat brain. Activation of Y1 by full-length NPY1-36 induces anxiolytic effects, whereas Y2 binds truncated peptides, eliciting region-specific anxiogenic responses. Dipeptidyl peptidase IV (DPP-IV) cleaves NPY, thereby modulating its functionality. Sitagliptin, a DPP-IV inhibitor (DPP-IV-I), inhibits the degradation of various vasoactive peptides, including cerebral NPY. As such, the therapeutic potential of DPP-IV-I following a traumatic event remains inconclusive. We assessed the effects of a highly selective DPP-IV-I, administered either shortly after the stressor or intermittently over three days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD. Rats exposed to PSS or sham-PSS received a single dose of sitagliptin (10 or 30mg/kg) or saline 1h post-exposure, or repeated doses over three days (20mg/kg). Behavioral outcomes were evaluated using the elevated plus-maze and acoustic startle response at 7 days post-exposure. Additionally, rats exposed to PSS or sham-PSS were treated with sitagliptin (30mg/kg) or saline, and their brains were prepared for immunofluorescence and ELISA. Sitagliptin did not attenuate anxiety-related behaviors or PTSD-related behavior prevalence compared to saline. Notably, the 30mg/kg dose increased NPY levels in several brain regions without affecting NPY-Y1 levels. The findings suggest that sitagliptin-induced upregulation of NPY levels shortly after PSS is insufficient to prevent the development of post-traumatic responses. The effectiveness of NPY signaling may be influenced by factors beyond peptide concentration alone, potentially limiting its therapeutic efficacy. Activation of NPY-Y1 receptors, rather than merely increasing NPY levels, appears to be crucial for modulating anti-anxiety and post-traumatic responses.

MicroRNA-34a-5p regulates agouti-related peptide via krüppel-like factor 4 and is disrupted by bisphenol A in hypothalamic neurons

Obesity is a complex disease marked by increased adiposity and impaired metabolic function. While diet and lifestyle are primary causes, endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), significantly contribute to obesity. BPA, found in plastic consumer products, accumulates in the hypothalamus and dysregulates energy homeostasis by disrupting the neuropeptide Y (NPY)/agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons.However, the precise molecular mechanisms of how BPA disrupts neuropeptide expression remains unclear. We hypothesized that microRNAs (miRNAs), which regulate approximately 60% of the human protein-coding genome and are crucial for hypothalamic energy regulation, may mediate the effects of BPA on Agrp. Using the TargetScanMouse 8.0 and DIANA microT bioinformatics tools, we identified miR-501-5p as a potential miRNA that directly regulates Agrp and the miR-34 family as miRNAs that indirectly regulate Agrp through its transcription factor krüppel-like factor 4 (KLF4). We found that in an immortalized NPY/AgRP-expressing cell line, mHypoE-41, miR-501-5p unexpectedly upregulated Agrp, while miR-34a-5p reduced Klf4 and Agrp mRNA levels. Serum starvation reduced miR-34a-5p levels and elevated Agrp mRNA levels, suggesting a potential role in AgRP regulation. Inhibiting the miR-34a-5p interaction with the Klf4 3′UTR using a specific target site blocker prevented the downregulation of both Klf4 and Agrp, suggesting miR-34a-5p alters Agrp mRNA levels via regulation of KLF4. BPA treatment increased Agrp and Klf4 expression while simultaneously decreasing miR-34a-5p levels, indicating miR-34a-5p may play a role in BPA-mediated dysregulation of Agrp. Overall, this study highlights indirect miRNA-based regulation of Agrp, which can also be dysregulated by obesogens, such as BPA.

Role of differential food treatment on hypothalamic NPY expression and migratory phenology of redheaded bunting (Emberiza bruniceps)

ABSTRACT The present study explores the effect of differential food treatment on the migratory phenology of redheaded bunting (Emberiza bruniceps). Birds were divided into four groups (N = 10 each) on the basis of the food provided. Group I was fed with seeds of Setaria italica (kakuni), while group II was provided with protein-rich diet (combination of; 3 parts egg white and 1 part kakuni seeds). Likewise, group III birds received fat-rich food (i.e. 3 parts sesame seeds and 1 part kakuni seeds). Birds in group IV were provided with all three food items mentioned above separately. The experiment continued until the appearance of 7 cycles of zugunruhe. The results reveal a significant impact of food on locomotor activity and food intake behavior of birds, although the physiological response as demonstrated by a gain in body mass, fat score, and gonadal recrudescence was mainly influenced by the LHS. Besides the behavioral and physiological responses, the hypothalamic expression of neuropeptide Y (NPY) in infundibular complex (INc) was significantly high for group IV, highlighting the importance of “variety” in food intake. Thus, the present study suggests a significant role of food in influencing seasonal responses via hypothalamic NPY stimulation.

Plasma neuropeptide Y levels and adverse clinical outcomes after acute ischaemic stroke.

Neuropeptide Y (NPY) has been reported to be involved in the pathophysiology of several cardiovascular disease processes and might contribute to the incidence of stroke, but the prognostic utility of circulating NPY after acute ischaemic stroke is unclear. This study aimed to prospectively examine the association between plasma NPY levels and adverse clinical outcomes after acute ischaemic stroke. Plasma NPY levels were measured in 3250 patients (2066 men and 1184 women) from the China Antihypertensive Trial in Acute Ischaemic Stroke. The primary outcome was the combination of death and major disability (modified Rankin Scale score ≥3) at 12 months after stroke onset, and secondary outcomes included major disability, death and cardiovascular events. During the 12-month follow-up, 702 participants (21.6%) experienced major disability or died. After multivariable adjustment, odds ratio (95% confidence interval) for the highest quartile of NPY was 1.56 (1.19-2.04) for the primary outcome, compared to the lowest quartile. Each standard deviation (0.27 ng/mL) higher log-transformed NPY was associated with an odds ratio (95% confidence interval) of 1.18 (1.07-1.30) for the primary outcome, 1.28 (1.15-1.42) for major disability. The addition of NPY to a conventional risk factors model improved risk prediction of the composite outcome of death and major disability (category-free net reclassification index 8.82%, p = 0.040; integrated discrimination improvement 0.38%, p = 0.011). Elevated plasma NPY levels in the acute phase of ischaemic stroke were associated with increased risk of poor clinical outcomes after ischaemic stroke, suggesting that plasma NPY may be a potential prognostic biomarker for ischaemic stroke.

'The effect of neuropeptide Y1 receptor agonist on hypothalamic neurogenesis in rat experimental depression model'.

Depression is responsible for neuropathies such as decreased neurogenesis and increased dendritic atrophy. There is information that antidepressant treatments have an effect by increasing hippocampal neurogenesis and neurotrophic factor expression. The neuropeptide Y1 (NPY1R) receptor agonist has been suggested to have anxiolytic effects. Based on this information, it was aimed to investigate the effect of NPY1R agonist on depression in rats with depression using the CMS model and to determine how depression affects cell proliferation in the hypothalamus and hypothalamic peptide levels. Forty-eight adult, male Wistar albino rats were divided into groups as Control, Depression (D), Depression + NPY1R and NPY1R. Various stressors were applied to D for 30 days. An open field test (OFT) and forced swim test (FST) were performed to check whether the animals were depressed. On the 16th day, an osmotic mini pump was placed under the skin and NPY1R (130 ul/kg/day) was applied for 15 days. Behavioral tests were performed, hypothalamic peptide gene expression levels were analyzed by quantitative RT-PCR and statistical evaluations were made using ANOVA. A decrease in the percentage of movement in the D and control groups were noted in the OFT, an increase in the immobility time in the D group in the FST, and an increase in swimming behavior in the DNPY1R group. The animals did not display any anxiety behavior based on the elevated plus maze test results. It caused a decrease in IGF1R, FGF2, POMC, NPY and GLUT2 gene expression in the hypothalamus of depression group animals, and an increase in NPY gene expression in NPY1R treatment. This study compellingly demonstrated that exposure to chronic mild stress simultaneously downregulates gene expression in the hypothalamus; we observed that NPY receptor NPY1R treatment increased the effect of NPY. Therefore, adjunctive treatments with appropriate molecules such as NPY, Y1 receptor agonists or pharmacological derivatives may have significant potential in the treatment of depression.

Bioelectronic block of stellate ganglia mitigates pacing-induced heterogeneous release of catecholamine and neuropeptide Y in the infarcted pig heart.

The sympathetic nervous system modulates cardiac contractile and electrophysiological function and contributes to adverse remodelling following myocardial infarction (MI). Axonal modulation therapy (AMT), directed at the sympathetic chain, blocks efferent sympathetic outflow to the heart and is a strategy to transiently and controllably mitigate chronic MI-associated sympatho-excitation. In porcine models, we evaluated scalable AMT, directed at the paravertebral chain, in blocking reflex-mediated pacing-induced sympatho-excitation post-MI. The level of sympatho-excitation was assessed by dynamic interstitial measurement of noradrenaline (NA) and neuropeptide Y (NPY). In anaesthetized normal (n=5) and age-matched pigs 6weeks post-MI induction (n=10), we electrically stimulated the right sympathetic chain and determined levels of direct current block applied at the T1-T2 level sufficient to reduce the evoked changes in heart rate and/or contractility by 25-75%. Reflex-mediated neural release of NA and NPY into the interstitial space during programmed pacing (PP) was assessed using fast-scanning cyclic voltammetry and capacitive immunoprobes. Normal animals demonstrated homogeneous NA and NPY release profiles during PP. In contrast, for MI animals PP evoked differential NA and NPY release in remote and MI border zones of the left ventricle. Right-sided AMT mitigated NA and NPY pacing-induced release in the remote left ventricle with a positive correlation to increasing AMT levels. Pacing-induced NA and NPY release in the MI border zone was not mitigated by AMT. Differential effects of AMT on NA and NPY may underlie the anti-arrhythmic effects of partial stellate ganglion block in the setting of chronic MI. KEY POINTS: Programmed cardiac pacing evokes homogeneous noradrenaline (NA) and neuropeptide Y (NPY) release in equivalent areas (e.g. medial and lateral aspects) of the normal left ventricle. Programmed cardiac pacing evokes differential NA and NPY release in remote and border zones of the infarcted left ventricle. Axonal modulation therapy (AMT), using a graded direct current block applied to the stellate ganglia, can proportionally modulate cardiac sympathetic reflexes. Unilateral AMT mitigates NA and NPY release in remote left ventricular tissue, with release negativelycorrelated to increasing AMT levels. Heterogeneities in NA and NPY between the border and remote tissues are reduced by progressive AMT.

Central administration of galanin-like peptide (GALP) causes short-term orexigenic effects in broilers: Mediatory role of NPY1 and D1 receptors

Studies conducted on mammalian models have indicated the role of galanin-like peptide (GALP) in appetite regulation. For the first time, the present study examines the effects of this peptide on feed consumption and behavioral changes, as well as its interaction with dopaminergic and neuropeptide Y (NPY) systems in broilers. In experiment 1, broilers were injected with GALP (0.5, 1, and 2 μg) and saline. In experiment 2, saline, NPY1 receptor antagonist (BIBO-3304), GALP (2 μg), and BIBO-3304 + GALP were administrated. Experiments 3–6 were identical to experiment 2, except that NPY2 receptor antagonist (BIIE 0246), NPY5 receptor antagonist (CGP 71683A), D1 receptor antagonist (SCH39166), and D2 receptor antagonist (L-741,626) were injected instead of BIBO-3304. After that, cumulative meal consumption was recorded for 2 h. Also, behavioral changes in the broilers receiving GALP (0.5, 1, and 2 μg) were monitored for thirty minutes after infusion. Following the administration of GALP (1 and 2 μg), food intake and the number of feeding and exploratory pecks of chicks increased (P < 0.05), while other behaviors did not change significantly (P ≥ 0.05). Co-infusion of BIBO-3304 + GALP suppressed the orexigenic effect of GALP (P < 0.05). Infusion of BIIE 0246, CGP 71683A, and L-741,626 with GALP, had no significant effect on GALP-induced hyperphagia (P ≥ 0.05). However, the orexigenic effects of GALP were stimulated following the co-administration of SCH39166A + GALP (P < 0.05). These findings indicate that NPY1 and D1 receptors can mediate GALP-induced hyperphagia in broilers.

Easy-to-Engineer Flexible Nanoelectrode Sensor from an Inexpensive Overhead Projector Sheet for Sweat Neuropeptide-Y Detection.

In this paper, we report an inexpensive and easy-to-engineer flexible nanobiosensor electrode platform by exploring a nonconductive overhead projector (OHP) sheet for sweat Neuropeptide-Y (NPY) detection, a potential biomarker for stress, cardiovascular regulation, appetite, etc. We converted a nonconductive OHP sheet into a conductive nanobiosensor electrode platform with a hybrid polymerization method, which consists of interfacial polymerization of pyrrole and a template-free electropolymerization technique to decorate the electrode platform with poly(EDOT-COOH-co-EDOT-EG3) nanotubes. The selection of poly(EDOT-COOH) features an easy conjugation of NPY antibody (NPY-Ab) through EDC/Sulfo-NHS coupling chemistry, while poly(EDOT-EG3) is best known to reduce nonspecific binding of biomolecules. The antibody conjugation on the polymer surface was characterized by a quartz crystal microbalance, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and chronoamperometry techniques. The OHP nanosensor platform exhibited the successful detection of NPY analyte through a chronoamperometry method in phosphate-buffered saline with a wide range of concentrations from 1 pg/mL to 1 μg/mL with a limit of detection of 0.68 pg/mL having good linearity (R2 = 0.9841). The sensor platform exhibited excellent stability, reproducibility, repeatability, and a shelf-life of 13 days. Furthermore, the sensor showed superior selectivity to a 100 pg/mL NPY analyte among other interfering compounds such as tumor necrosis factor α, cortisol, and Interleukin-6. The clinical practicality of the sensor was confirmed through the detection of 100 pg/mL NPY spiked artificial perspiration, highlighting the possibility of integrating the sensor platform to wearable healthcare applications.

Transforming growth factor β-2 is rhythmically expressed in both WT and BMAL1-deficient hypothalamic neurons and regulates neuropeptide Y: Disruption by palmitate

The hypothalamus contains neuropeptide Y (NPY)-expressing neurons that control food intake and regulate energy homeostasis. During the development of obesity, neuroinflammation occurs in the hypothalamus before peripheral tissues, but the cytokines involved have not been thoroughly studied. Among them is the transforming growth factor beta (TGF-β) family of cytokines. Herein, we demonstrate that Tgfb 1–3, as well as its receptors Tgfbr1 and Tgfbr2, exhibit high levels of expression in the whole hypothalamus, primary hypothalamic culture, and immortalized hypothalamic neurons. Of interest, only Tgfb2 mRNA displays circadian expression in the immortalized hypothalamic neurons and maintains this rhythmicity in BMAL1-KO-derived hypothalamic neurons that are deficient of inherent clock gene rhythmicity. Although BMAL2 may serve as an alternative rhythm generation mechanism in the absence of BMAL1, its knockdown did not affect Tgfb2 expression. Treatment of immortalized NPY-expressing neurons with TGF-β2 upregulates the core circadian oscillators Bmal1 and Nr1d1, and importantly, also Npy mRNA expression. With obesity, the hypothalamus is exposed to elevated levels of palmitate, a saturated fatty acid that promotes neuroinflammation by upregulating pro-inflammatory cytokines. Palmitate treatment disrupts the expression of TGF-β signaling components, increases BMAL1 binding to the Tgfb2 5’ regulatory region, and upregulates Npy mRNA, whereas antagonizing TGFBRI attenuates the upregulation of Npy. These results suggest that hypothalamic neuronal TGF-β2 lies at the intersection of circadian rhythms, feeding neuropeptide control, and neuroinflammation. A better understanding of the underlying mechanisms that link nutrient excess to hypothalamic dysfunction is critical for the development of effective prevention and treatment strategies.

Higher Preoperative Serum Neuropeptide Y Concentration May Be Associated with a Better Prognosis After Surgery for Colorectal Cancer.

The early identification of patients at risk of peri-procedural complications and poor prognosis is particularly important. We conducted our study to determine whether serum orexigenic neuropeptide Y (NPY) concentration is associated with nutritional status and prognosis among patients undergoing surgery for colorectal cancer (CRC). A cohort study with a 3-month follow-up was conducted with 84 consecutive inpatients who underwent elective surgery in one center between 2016 and 2019 for primary CRC. The clinical characteristics and nutritional status of all patients were assessed. In long-term follow-ups (median; IQR: 1322; 930-1788 days; average 3.6 years), the patients' survival status was also checked during a telephone consultation. Before CRC surgery, patients with serum NPY concentrations equal to or higher than the median value (661.70 pg/mL) had higher scores in their Mini Nutritional Assessment, Barthel, and Instrumental Activities of Daily Living (IADL) questionnaires, greater handgrip strength, a lower score in the Patient-Generated Subjective Global Assessment, and almost a three-times lower risk of perioperative complications, as well as higher Barthel and IADL scores and larger calf circumference at the 3-month follow-up visit in comparison to individuals with lower serum NPY concentrations. A higher serum NPY concentration was predictive of a low Nutritional Risk Screening 2002 score at the 3-month visit, and this was also found to have significantly influenced the patients' survival during the 1200 days after CRC surgery. A higher preoperative serum NPY concentration may be related to lower nutritional risk, more favorable patient nutritional and functional status, and better survival, but further studies are required.

Stable and Minimum Size Solubilization of Membrane Proteins with Cocktails of Phospholipid Analogues.

Membrane proteins (MPs) play important roles in various cellular processes and are major targets for drugs. Solubilization of MPs is often needed for structural and biophysical studies. For high-resolution nuclear magnetic resonance measurements, there is a size limit of the sample (<100 kDa), and a high thermal stability at an increased temperature is required. Furthermore, lipid bilayer-like environments are desirable to preserve the native states of MPs. However, existing solubilization techniques do not fulfill these requirements at the same time. In this study, we combined two phospholipid analogues as a solubilizer and stabilizer to isolate MPs. This method maintained bacteriorhodopsin (bR) extracted from purple membranes in its native state for 7 d at 40 °C. The solubility was comparable to that of conventional detergents for MPs, and the thermal stability of the solubilizate was the best among them. The increase in the molecular size caused by the solubilization of bR was only 20 kDa, indicating that 20 phospholipid analogue molecules were sufficient to solubilize one bR molecule. 15N-1H heteronuclear single quantum coherence spectra of solubilized 2H- and 15N-labeled bR gave ∼80% of the expected peaks. In addition, the lysate of human neuropeptide Y2 receptor-expressing mammalian cells exhibited ligand recognition for 7 d at 37 °C, suggesting that this technique can be used for ligand screening. Moreover, the structure of the single membrane-spanning M2 protein of the influenza A virus expressed in Escherichia coli was stably maintained for 7 d at 40 °C. Thus, our method is promising for various MP studies.

A sympathetic paradigm shift for the role of NPY in obesity

Neuropeptide Y (NPY) is a powerful orexigenic factor in the brain. However, mice lacking NPY or NPY receptor Y1 (NPY1R) have minimal changes in basal food intake. In a study published in Nature, Zhu etal.1 demystify this paradox and show that central and peripheral NPY have antipodal roles in energy homeostasis.

The cardiac sympathetic co-transmitter neuropeptide-Y is pro-arrhythmic in human cardiomyocytes by lengthening activation-recovery interval

Abstract Background Myocardial infarction (MI) is associated with sympathetic overactivity, during which the co-release of neuropeptide-Y (NPY) is prominent. NPY is associated with arrhythmia risk and mortality following ST-elevation MI, although the exact mechanisms for this in human cardiomyocytes remains unclear. Purpose We therefore tested the hypothesis that NPY signalling would alter the electrophysiology of human induced-pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in a way that would promote arrhythmia, and that in patients being treated for MI, high NPY concentrations previously associated with ventricular arrhythmia (&amp;gt;27.3 pg.mL-1) would be associated with comparable ECG changes. Methods Immunohistochemistry and western blot were performed on hiPSC-CMs and ventricular biopsies from human patients undergoing valve surgery. The FRET-based sensor Epac-SH187 was expressed in hiPSC-CMs to monitor the cyclic adenosine 3’,5’-monophosphate (cAMP) response to NPY. A micro-electrode array was used to investigate the effects of NPY on a confluent layer of iPSC-CMs, measuring changes in activation, recovery, conduction velocity and spontaneous automaticity. Additionally, patients presenting with ST-elevation MI had peripheral venous [NPY] measured and compared to 12-lead ECGs recorded following stenting. Results hiPSC-CMs expressed Y1 and Y5 receptor mRNA and protein, which are also expressed in ventricular biopsies from human patients. NPY (1-100 nM) significantly reduced intracellular cAMP levels (n=65), most effectively prevented by Y5 receptor inhibition (1µM CGP71683A, n=40). In a confluent layer of hiPSC-CM, NPY (100 nM) slowed late-repolarisation represented by T-wave peak-end duration (p=0.04), which could be prevented by Y1-receptor inhibition (1 μM BIBO 3304, n=6), and caused prolongation of rate corrected activation-recovery interval (ARIc) (p=0.009, n=6) which could be abolished by Y5-receptor inhibition (n=7). NPY significantly increased automaticity to more than one site of initiation in 4/6 (66.7%) compared to 2/14 (14.3%) control plates (p=0.037), despite no change in conduction velocity. Moreover, in 65 patients being treated for ST elevation MI, those with high peripheral venous NPY concentrations were well matched in terms of cardiovascular risk factors, medications on admission, and pain to balloon times, but had significantly longer corrected QT interval (QTc) on the 12 lead ECG (p=0.04) despite no differences in PR interval, heart rate or electrolyte concentrations. Conclusions NPY slowed late repolarisation and caused ARIc prolongation, which was associated with increased automaticity in human iPSC-CMs. NPY also correlated with QTc-prolongation in patients being treated for MI and may contribute to the increased incidence of ventricular arrhythmia observed in these patients. Antagonists of Y1 and Y5 receptors may therefore offer an adjunct to β-blockade therapy to reduce the risk of ventricular arrhythmia.

Relation of plasma neuropeptide-Y with myocardial function and infarct severity in acute ST-elevation myocardial infarction

Abstract Background Acute myocardial infarction is associated with high levels of cardiac sympathetic stimulation, which leads to the release of the co-transmitter neuropeptide-Y (NPY). NPY acts as a potent vasoconstrictor and an association with increased risk for heart failure and microvascular dysfunction after acute ST-elevation myocardial infarction (STEMI) has been suggested. Purpose This study aims to comprehensively evaluate the association of plasma NPY with myocardial function and infarct severity, visualized by cardiac magnetic resonance (CMR) imaging, in STEMI patients revascularized by primary percutaneous coronary intervention (PCI). Methods In this observational study, we included 260 STEMI patients treated with primary PCI. Plasma NPY concentrations were measured by an immunoassay 24h after PCI from peripheral venous blood samples. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), infarct size (IS) and microvascular obstruction (MVO) were determined using CMR imaging 4 days and 4 months after PCI. Results Median plasma concentrations of NPY were 70 [interquartile range (IQR): 35-115] pg/ml. NPY levels above median were significantly associated with lower LVEF (48% vs. 52%, p=0.004), decreased GLS (-8.8% vs. -12.6%, p&amp;lt;0.001) and larger IS (17% vs. 13%, p=0.041) in the acute phase after infarction as well as in the chronic stage (LVEF: 50% vs. 52%, p=0.030, GLS: -10.5 vs. -12.9, p&amp;lt;0.001, IS: 13% vs. 10%, p=0.011). In addition, NPY levels were significantly related to presence of MVO (58% vs. 52%, p=0.041). Moreover, in multivariable linear regression analysis, NPY remained significantly associated with all investigated CMR parameters (LVEF: p&amp;lt;0.001, GLS: p&amp;lt;0.001, IS: p=0.003, MVO: p=0.042) independent of other established clinical variables including high-sensitivity cardiac troponin T, pre-interventional TIMI flow 0 and left anterior descending artery as culprit lesion location. Conclusion High plasma levels of NPY, measured 24h after STEMI, were independently associated with lower LVEF, decreased GLS, larger IS as well as presence of MVO, indicating plasma NPY as a valuable biomarker for optimized risk stratification.

Human sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y bioavailability.

What is the purpose of sympathetic neuronal action potential (AP) discharge and recruitment patterns for human vascular regulation? This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. We used microneurography to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to detect sympathetic APs during a baseline condition and intravenous dexmedetomidine infusion (α2-adrenergic agonist, 10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in six healthy individuals (5 females, 27 ± 6 years). Arterial blood samples provided NPY (enzyme-linked immunosorbent assay) and norepinephrine (Liquid Chromatography Tandem Mass Spectrometry) levels during baseline and the dexmedetomidine maintenance infusion. Linear mixed model regressions assessed the relationships between AP discharge, recruitment, and neurotransmitter levels. Across baseline and the dexmedetomidine condition, NPY levels were positively related to mean arterial pressure (β = 1.63 [0.34], P = 0.002), total AP clusters (β = 0.90 [0.22], P = 0.005), and AP frequency (β = 0.11 [0.03], P = 0.003). Norepinephrine levels were not related to mean arterial pressure (β = 0.03 [0.02], P = 0.133) but were positively related to total AP clusters (β = 19.50 [7.07], P = 0.030) and AP frequency (β = 2.66 [0.81], P = 0.014). These data suggest that sympathetic neuronal discharge and recruitment patterns regulate NPY and norepinephrine bioavailability in healthy adults. As such, sympathetic neuronal firing strategies are important for human vascular regulation.

Olfactory and gustatory chemical sensor systems in the African turquoise killifish: Insights from morphology

Smell and taste are extensively studied in fish species as essential for finding food and selecting mates while avoiding toxic substances and predators. Depending on the evolutionary position and adaptation, a discrete variation in the morphology of these sense organs has been reported in numerous teleost species. Here, for the first time, we approach the phenotypic characterization of the olfactory epithelium and taste buds in the African turquoise killifish (Nothobranchius furzeri), a model organism known for its short lifespan and use in ageing research. Our observations indicate that the olfactory epithelium of N. furzeri is organized as a simple patch, lacking the complex folding into a rosette, with an average size of approximately 600 µm in length, 300 µm in width, and 70 µm in thickness. Three main cytotypes, including olfactory receptor neurons (CalbindinD28K), supporting cells (β-tubulin IV), and basal cells (Ki67), were identified across the epithelium. Further, we determined the taste buds’ distribution and quantification between anterior (skin, lips, oral cavity) and posterior (gills, pharynx, oesophagus) systems. We identified the key cytotypes by using immunohistochemical markers, i.e. CalbindinD28K, doublecortin, and neuropeptide Y (NPY) for gustatory receptor cells, glial fibrillary acidic protein (GFAP) for supporting cells, and Ki67, a marker of cellular proliferation for basal cells. Altogether, these results indicate that N. furzeri is a microsmatic species with unique taste and olfactory features and possesses a well-developed posterior taste system compared to the anterior. This study provides fundamental insights into the chemosensory biology of N. furzeri, facilitating future investigations into nutrient-sensing mechanisms and their roles in development, survival, and ageing.

PTZ KINDLING MODEL: EVALUATION OF EEG FACTOR AND BIOCHEMISTRY PARAMETERS UNDER THE INFLUENCE OF RAMELTEON

Many selective synthetic melatonin receptor agonists have anticonvulsant/anti-epileptogenic properties. These agonists bind to melatonin receptor 1 (MT1) and receptor 2 (MT2), causing their activation. Therefore, we evaluated the anticonvulsant effect of Ramelteon (RMLT) as a melatonin agonist in the PTZ (Pentylenetetrazol)-kindling model. In the study, 36 male Wistar Albino rats were assessed in 6 groups (Sham, PTZ, dimethylsulphoxide (DMSO), Valproic acid (VPA) (150 mg/kg) + PTZ, RMLT (30 mg/kg)+PTZ, VPA+RMLT+PTZ). Cortical electroencephalography (EEG) data were recorded for all groups. Seizures were scored according to the Racine scale. Seizure scores and onset times of the first myoclonic movements were compared in EEG traces. Total antioxidant status (TAS), total oxidant status (TOS), catalase, myeloperoxidase (MPO), and Thiol levels were measured in serum samples. Also, Calcineurin (CaN), Neuropeptide-Y (NPY), Neuron Specific Enolase (NSE), and S100B levels were measured in brain tissue samples. There was a significant difference between the PTZ and PTZ+Valproic acid+RMLT groups for the onset of the first myoclonic movements and the rate of spikes in the EEG traces in Racine's convulsion stages (P 0.05). RMLT has anticonvulsant properties. Additionally, the receptor preference of RMLT can be investigated.

Neuropeptide Y Y2 receptors in acute and chronic pain and itch

Pain and itch are regulated by a diverse array of neuropeptides and their receptors in superficial laminae of the spinal cord dorsal horn (DH). Neuropeptide Y (NPY) is normally expressed on DH neurons but not sensory neurons. By contrast, the Npy2r receptor (Y2) is expressed on the central and peripheral terminals of sensory neurons but not on DH neurons. Neurophysiological slice recordings indicate that Y2-selective agonists inhibits spinal neurotransmitter release from sensory neurons. However, behavioral pharmacology studies indicate that Y2 agonists exert minimal changes in nociception, even after injury. Additional discrepancies in the behavioral actions of the Y2-antagonist BIIE0246 – reports of either pronociception or antinociception – have now been resolved. In the normal state, spinally-directed (intrathecal) administration of BIIE0246 elicits ongoing nociception, hypersensitivity to sensory stimulation, and aversion. Conversely, in the setting of nerve injury and inflammation, intrathecal BIIE024 reduced not only mechanical and thermal hypersensitivity, but also a measure of the affective dimension of pain (conditioned place preference). When administered in chronic pain models of latent sensitization, BIIE0246 produced a profound reinstatement of pain-like behaviors. We propose that tissue or nerve injury induces a G protein switch in the action of NPY-Y2 signaling from antinociception in the naïve state to the inhibition of mechanical and heat hyperalgesia in the injured state, and then a switch back to antinociception to keep LS in a state of remission. This model clarifies the pharmacotherapeutic potential of Y2 research, pointing to the development of a new non-opioid pharmacotherapy for chronic pain using Y2 antagonists in patients who do not develop LS.

A randomized phase I study of BI 1820237, a novel neuropeptide Y receptor type 2 agonist, alone or in combination with low-dose liraglutide in otherwise healthy men with overweight or obesity.

Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight. This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD. In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m2) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying. BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive.

Cellular and metabolic function of GIRK1 potassium channels expressed by arcuate POMC and NPY/AgRP neurons

It is well known that the G protein-gated inwardly rectifying K+ (GIRK) channels are critical to maintain excitability of central neurons. GIRK channels consist of 4 subunits and GIRK1/GIRK2 heterotetramers are considered to be the neuronal prototype. We previously reported the metabolic significance of GIRK2 subunits expressed by the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARH). However, the role of GIRK1 subunits expressed by the neurons of ARH remains to be determined. In this study, we delineated the contribution of GIRK1 channel subunits to the excitability of the pro-opiomelanocortin (POMC) and NPY/AgRP neurons of the ARH. We further assessed the metabolic function of GIRK1 subunits expressed by these neurons. Our results provide insight how GIRK channels regulate arcuate POMC and NPY/AgRP neurons and shape metabolic phenotypes.