Explore the vast range of titles available.

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y , Y , Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (Y R) . A number of peptides and small-molecule compounds have been characterized as Y R antagonists and have shown clinical potential in the treatment of obesity , tumour and bone loss . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability . Here we report crystal structures of the human Y R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y R can enable structure-based drug discovery that targets NPY receptors.

Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.

Peripheral nerve injury sensitizes a complex network of spinal cord dorsal horn (DH) neurons to produce allodynia and neuropathic pain. The identification of a druggable target within this network has remained elusive, but a promising candidate is the neuropeptide Y (NPY) Y1 receptor-expressing interneuron (Y1-IN) population. We report that spared nerve injury (SNI) enhanced the excitability of Y1-INs and elicited allodynia (mechanical and cold hypersensitivity) and affective pain. Similarly, chemogenetic or optogenetic activation of Y1-INs in uninjured mice elicited behavioral signs of spontaneous, allodynic, and affective pain. SNI-induced allodynia was reduced by chemogenetic inhibition of Y1-INs, or intrathecal administration of a Y1-selective agonist. Conditional deletion of Npy1r in DH neurons, but not peripheral afferent neurons prevented the anti-hyperalgesic effects of the intrathecal Y1 agonist. We conclude that spinal Y1-INs are necessary and sufficient for the behavioral symptoms of neuropathic pain and represent a promising target for future pharmacotherapeutic development of Y1 agonists.

Neuropeptide Y (NPY) is produced by the nerve system and may contribute to the progression of CKD. The present study found the new protective role for NPY in AKI in both patients and animal models. Interestingly, NPY was constitutively expressed in blood and resident kidney macrophages by co-expressing NPY and CD68+ markers, which was lost in patients and mice with AKI-induced by cisplatin. Unexpectedly, NPY was renoprotective in AKI as mice lacking NPY developed worse renal necroinflammation and renal dysfunction in cisplatin and ischemic-induced AKI. Importantly, NPY was also a therapeutic agent for AKI because treatment with exogenous NPY dose-dependently inhibited cisplatin-induced AKI. Mechanistically, NPY protected kidney from AKI by inactivating M1 macrophages via the Y1R-NF-κB-Mincle-dependent mechanism as deleting or silencing NPY decreased Y1R but increased NF-κB-Mincle-mediated M1macrophage activation and renal necroinflammation, which were reversed by addition of NPY or by silencing Mincle but promoted by blocking Y1R with BIBP 3226. Thus, NPY is renoprotective and may be a novel therapeutic agent for AKI. NPY may act via Y1R to protect kidney from AKI by blocking NF-κB-Mincle-mediated M1 macrophage activation and renal necroinflammation.

Identification of the cellular players and molecular messengers that communicate neuronal activity to the vasculature driving cerebral hemodynamics is important for (1) the basic understanding of cerebrovascular regulation and (2) interpretation of functional Magnetic Resonance Imaging (fMRI) signals. Using a combination of optogenetic stimulation and 2-photon imaging in mice, we demonstrate that selective activation of cortical excitation and inhibition elicits distinct vascular responses and identify the vasoconstrictive mechanism as Neuropeptide Y (NPY) acting on Y1 receptors. The latter implies that task-related negative Blood Oxygenation Level Dependent (BOLD) fMRI signals in the cerebral cortex under normal physiological conditions may be mainly driven by the NPY-positive inhibitory neurons. Further, the NPY-Y1 pathway may offer a potential therapeutic target in cerebrovascular disease. Unlike other cells in the body, brain cells contain almost no energy reserves and rely on blood vessels for continuous supply of oxygen. A change in the brain’s activity can cause these blood vessels to either dilate or constrict, which alters the supply to match the change in demand. However, it is not known which signals cause these changes in the blood vessels. Previous studies have shown that individual blood vessels in an intact brain tend to dilate when the brain’s activity increases, and constrict when brain activity is inhibited. However, these studies were based on correlations, and there was no direct evidence that the inhibitory cells cause blood vessels to constrict. Uhlirova, Kılıç et al. now provide such evidence. The experiments made use of mice that had been genetically modified such that the excitatory or inhibitory nerve cells in their brains could be selectively activated by shining a blue light on the brain’s surface. The vessels in the outer millimeter of the gray matter of each mouse’s brain were imaged in detail, both before and after the blue light was used to activate the nerve cells. The experiments reveal that both excitatory and inhibitory nerve cells can cause blood vessels in the brain to dilate. However, blood vessels in the brain will only constrict in response to inhibitory nerve cells. Uhlirova, Kılıç et al. went on to identify a molecule called Neuropeptide Y (or NPY short) as a signal that triggers the constriction of the blood vessels. This signaling molecule is released by a specific sub-type of inhibitory nerve cell and it binds to a receptor protein on the brain’s blood vessels to make them constrict. These findings suggest that NPY and its receptor on blood vessels may offer promising targets for drugs to treat diseases of the brain’s blood vessels. Further studies are now needed to identify the signals responsible for the dilation of blood vessels in the brain.

Abstract Background The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through 5 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 3 days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD. Methods Rats exposed to PSS or sham-PSS received a single dose of sitagliptin (10 or 30 mg/kg) or saline 1 hour post-exposure, or repeated doses over 3 days (20 mg/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 (30 mg/kg) or saline, and their brains were prepared for immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Results Sitagliptin did not attenuate anxiety-related behaviors or PTSD-related behavior prevalence compared to saline. Notably, the 30 mg/kg dose increased NPY levels in several brain regions without affecting NPY-Y1 levels. Conclusions 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.

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.

Our objective was to investigate the effects of topically applied neuropeptide Y (NPY) on ischemic wounds. Initially, the animal model for ischemic wound healing was validated using 16 male Sprague Dawley albino rats. In the intervention study, an additional 28 rats were divided into three groups: NPY (0.025%), the positive control insulin-like growth factor-I (IGF-I, 0.0025%), and the hydrogel carrier alone (control). The hydrogel was selected due to its capacity to prolong NPY release (p < 0.001), as demonstrated in a Franz diffusion cell. In the animals, an 8 mm full-thickness wound was made in a pedunculated dorsal ischemic skin flap. Wounds were then treated and assessed for 14 days and collected at the end of the experiment for in situ hybridization analysis (RNAscope®) targeting NPY receptor Y2R and for meticulous histologic examination. Wound healing rates, specifically the percentage changes in wound area, did not show an increase with NPY (p = 0.907), but there was an increase with rhIGF-I (p = 0.039) compared to the control. Y2R mRNA was not detected in the wounds or adjacent skin but was identified in the rat brain (used as a positive control). Light microscopic examination revealed trends of increased angiogenesis and enhanced inflammatory cell infiltration with NPY compared to control. An interesting secondary discovery was the presence of melanophages in the wounds. Our findings suggest the potential of NPY to enhance neovascularization under ischemic wound healing conditions, but further optimization of the carrier and dosage is necessary. The mechanism remains elusive but likely involves NPY receptor subtypes other than Y2R.

Abstract Background Since about one-third of patients with major depressive disorder (MDD) do not respond adequately to available antidepressants, there is a need for treatments based on novel mechanisms of action. Neuropeptide Y (NPY), a normal brain constituent, is reduced in cerebrospinal fluid of patients with MDD and post-traumatic stress disorder and in corresponding rodent models. Moreover, NPY administered centrally or intranasally rescues pathophysiology in these models. Consequently, we conducted the first, to our knowledge, controlled trial of NPY as a treatment for MDD. Methods Thirty MDD patients on a stable dose of a conventional antidepressant insufflated 6.8 mg NPY (n = 12) or placebo (n = 18) in a double blind randomized fashion. Effects were assessed at baseline, +1 hour, +5 hours, +24 hours, and +48 hours. The primary outcome was change in depression severity measured with the Montgomery-Åsberg Depression Rating Scale (MADRS). Results NPY was superior to placebo at +24 hours (change −10.3 [95% CI: −13.8; −6.8]) vs −5.6 (95% CI: −8.4; −2.7); group*time F = 3.26, DF = (1,28), P = .04; Cohen’s d = 0.67). At +5 hours MADRS decreased −7.1 ([95% CI: −10.0; −4.2] vs −3.5 [95% CI: −5.8; −1.2]; group*time F = 2.69, DF = (1,28), P = .05; Cohen’s d = 0.61). MADRS reduction at +48 hours was not significant. Conclusions Since no results regarding the trajectory of NPY effects existed prior to this study we extrapolated from the known NPY biology and predicted the effects will occur 5–48 hours post insufflation. We chose +48 hours as the primary endpoint and +1, +5, and +24 hours as secondary endpoints. The results, the first of their kind, indicate that insufflated NPY is antidepressant, despite not meeting the primary outcome, and call for dose ranging and repeated NPY insufflation trials. Clinical Trial Registration EudraCT Number: 2014-000129-19.

•Intermittent fasting improved cognitive performance after traumatic brain injury.•Intermittent fasting enhanced hippocampal proliferation of neural stems cells after traumatic brain injury.•Increased hippocampal neuropeptide Y contributed to the effects of intermittent fasting. Interventions for preventing cognitive dysfunction after traumatic brain injury (TBI) are limited. Given that adult hippocampal neurogenesis after brain injury contributes to cognitive recovery, and hippocampal neurogenesis is potentially affected by nutritional factors, the aim of this study was to examine whether fasting could promote hippocampal neurogenesis and thus ameliorate the cognitive defects after TBI. The present study used 8- to 10-wk-old C57 BL/6 N mice weighing 23 g, half males and half females. The mice were randomly assigned to each group, with 10 to 18 mice per group. All mice were housed in an approved animal facility with a 12-h light/dark cycle. In the metabolic study (food intake, body weight, blood glucose, triacylglycerol, total cholesterol, and β-hydroxybutyric acid ), 54 mice (male:female = 1:1) were randomized to the ad libitum (AL) group (n = 18) and the intermittent fasting (IF) group (n = 36). In the neurogenesis study, 45 mice (male:female = 1:1) were randomized to AL (n  = 18), IF (n  = 9), IF + scramble (n  = 9), and the IF + neuropeptide Y (NPY)_siRNA (n  = 9) groups. In the Morris water maze test, 48 mice (male:female = 1:1) were randomized to AL (n  = 12), IF (n  = 12), IF + scramble (n  = 12), and the IF + NPY_siRNA (n  = 12) groups. We showed that a 1-mo-long IF regimen enhanced the proliferation of neural stem cells in the subgranular zone of the hippocampus 3 d after TBI, in addition to improving the cognitive performance in the Morris water maze test. Furthermore, an increase in the hippocampal NPY expression was detected in the IF group after the injury, compared with the mice fed AL, and local knockdown of NPY in vivo attenuated the effects of IF on TBI. These findings suggest that IF promotes hippocampal neurogenesis after TBI by a mechanism that involves enhancement of NPY expression, to alleviate cognitive dysfunction caused by injury.