A new invertebrate NPY-like polypeptide, ZoaNPY, from the Zoanthus sociatus, as a novel ligand of human NPY Y2 receptor rescues vascular insufficiency via PLC/PKC and Src- FAK-dependent signaling pathways.

Our recent multi-omics studies have revealed rich sources of novel bioactive proteins and polypeptides from marine organisms including cnidarians. In the present study, we initially conducted a transcriptomic analysis to review the composition profile of polypeptides from Zoanthus sociatus. Then, a newly discovered NPY-like polypeptide-ZoaNPY was selected for further in silico structural, binding and virtually pharmacological studies. To evaluate the pro-angiogenic effects of ZoaNPY, we employed an in vitro HUVECs model and an in vivo zebrafish model. Our results indicate that ZoaNPY, at 1-100 pmol, enhances cell survival, migration and tube formation in the endothelial cells. Besides, treatment with ZoaNPY could restore a chemically-induced vascular insufficiency in zebrafish embryos. Western blot results demonstrated the application of ZoaNPY could increase the phosphorylation of proteins related to angiogenesis signaling including PKC, PLC, FAK, Src, Akt, mTOR, MEK, and ERK1/2. Furthermore, through molecular docking and surface plasmon resonance (SPR) verification, ZoaNPY was shown to directly and physically interact with NPY Y2 receptor. In view of this, all evidence showed that the pro-angiogenic effects of ZoaNPY involve the activation of NPY Y2 receptor, thereby activating the Akt/mTOR, PLC/PKC, ERK/MEK and Src- FAK-dependent signaling pathways. Furthermore, in an excision wound model, the treatment with ZoaNPY was shown to accelerate the wound healing process in mice. Our findings provide new insights into the discovery and development of novel pro-angiogenic drugs derived from NPY-like polypeptides in the future.

Long-term enhancements in antidepressant efficacy and neurogenesis: Effects of intranasal co-administration of neuropeptide Y 1 receptor (NPY1R) and galanin receptor 2 (GALR2) agonists in the ventral hippocampus.

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.

Enhancing Cognitive Functions and Neuronal Growth through NPY1R Agonist and Ketamine Co-Administration: Evidence for NPY1R-TrkB Heteroreceptor Complexes in Rats.

This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on cognitive functions and neuronal proliferation, against a backdrop where neurodegenerative diseases present an escalating challenge to global health systems. Utilizing male Sprague-Dawley rats in a physiological model, this research employed a single-dose administration of these compounds and assessed their impact 24 h after treatment on object-in-place memory tasks, alongside cellular proliferation within the dorsal hippocampus dentate gyrus. Methods such as the in situ proximity ligation assay and immunohistochemistry for proliferating a cell nuclear antigen (PCNA) and doublecortin (DCX) were utilized. The results demonstrated that co-administration significantly enhanced memory consolidation and increased neuronal proliferation, specifically neuroblasts, without affecting quiescent neural progenitors and astrocytes. These effects were mediated by the potential formation of NPY1R-TrkB heteroreceptor complexes, as suggested by receptor co-localization studies, although further investigation is required to conclusively prove this interaction. The findings also highlighted the pivotal role of brain-derived neurotrophic factor (BDNF) in mediating these effects. In conclusion, this study presents a promising avenue for enhancing cognitive functions and neuronal proliferation through the synergistic action of the NPY1R agonist and Ketamine, potentially via NPY1R-TrkB heteroreceptor complex formation, offering new insights into therapeutic strategies for neurodegenerative diseases.

The Roles of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response.

The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases.

Important role of NPY-Y4R signalling in the dual control of feeding and physical activity.

The control of feeding and physical activity is tightly linked and coordinated. However the underlying mechanisms are unclear. One of the major regulatory systems of feeding behaviour involves neuropeptide Y (NPY) signalling, with the signalling mediated through NPY Y4 receptor also known to influence activity. Here we show that mice globally lacking the Npy4r (Npy4r-/-) in the absence of access to a running wheel behaved WT-like with regards to food intake, energy expenditure, respiratory exchange ratio and locomotion regardless of being fed on a chow or high fat diet. Interestingly however, when given the access to a running wheel, Npy4r-/- mice while having a comparable locomotor activity, showed significantly higher wheel-running activity than WT, again regardless of dietary conditions. This higher wheel-running activity in Npy4r-/-mice arose from an increased dark-phase running time rather than changes in number of running bouts or the running speed. Consistently, energy expenditure was higher in Npy4r-/- than WT mice. Importantly, food intake was reduced in Npy4r-/-mice under wheel access condition which was due to decreased feeding bouts rather than changes in meal size. Together, these findings demonstrate an important role of Npy4r signalling in the dual control of feeding and physical activity, particularly in the form of wheel-running activity.

Topical Neuropeptide Y for Ischemic Skin Wounds.

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.

Effects of NPY-2 Receptor Antagonists, Semaglutide, PYY3-36, and Empagliflozin on Early MASLD in Diet-Induced Obese Rats.

(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY3-36, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY3-36) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.

Enhancement of neurogenesis and cognition through intranasal co-delivery of galanin receptor 2 (GALR2) and neuropeptide Y receptor 1 (NPY1R) agonists: a potential pharmacological strategy for cognitive dysfunctions.

BACKGROUND: Spatial memory deficits and reduced neuronal survival contribute to cognitive decline seen in the aging process. Current treatments are limited, emphasizing the need for innovative therapeutic strategies. This research explored the combined effects of intranasally co-administered galanin receptor 2 (GALR2) and neuropeptide Y1 receptor (NPY1R) agonists, recognized for their neural benefits, on spatial memory, neuronal survival, and differentiation in adult rats. After intranasal co-delivery of the GALR2 agonist M1145 and a NPY1R agonist to adult rats, spatial memory was tested with the object-in-place task 3 weeks later. We examined neuronal survival and differentiation by assessing BrdU-IR profiles and doublecortin (DCX) labeled cells, respectively. We also used the GALR2 antagonist M871 to confirm GALR2's crucial role in promoting cell growth. RESULTS: Co-administration improved spatial memory and increased the survival rate of mature neurons. The positive effect of GALR2 in cell proliferation was confirmed by the nullifying effects of its antagonist. The treatment boosted DCX-labeled newborn neurons and altered dendritic morphology, increasing cells with mature dendrites. CONCLUSIONS: Our results show that intranasal co-delivery of GALR2 and NPY1R agonists improves spatial memory, boosts neuronal survival, and influences neuronal differentiation in adult rats. The significant role of GALR2 is emphasized, suggesting new potential therapeutic strategies for cognitive decline.

Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Role of the intracerebroventricular injection of the visfatin and its interaction with neuropeptide Y and nitric systems on food intake in neonatal chicken.

Visfatin play an essential role in the central regulation of appetite in birds. This study aimed to determine role of intracerebroventricular (ICV) injection of the visfatin on food intake and its possible interaction with neuropeptide Y (NPY) and nitric oxide system in neonatal broiler chicken. In experiment 1, neonatal chicken received ICV injection visfatin (1, 2 and 4 µg). In experiment 2, chicken received ICV injection of B5063 (NPY1 receptor antagonist 1.25 µg), visfatin (4 µg) and co-injection of the B5063 + Visfatin. In experiments 3-6, SF22 (NPY2 receptor antagonist 1.25 µg), SML0891 (NPY5 receptor antagonist 1.25 µg), L-NAME (nitric oxide synthase inhibitor, 100 nmol) and L-arginine (Precursor of nitric oxide, 200 nmol) were injected instead of B5063. Then the amount of cumulative food was measured at 30, 60 and 120 min after injection. Obtained data showed, injection visfatin (2 and 4 µg) increased food intake compared to control group (P < 0.05). Co-injection of the B5063 + Visfatin decreased visfatin-induced hyperphagia compared to control group (P < 0.05). Co-injection of the L-NAME + Visfatin amplified visfatin-induced hyperphagia compared to control group (P < 0.05). The result showed that visfatin has hyperphagic role and this effect mediates via NPY1 and nitric oxide system in neonatal chicken.

Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective.

The neuropeptide Y4 receptor (Y4R), a rhodopsin-like G protein-coupled receptor (GPCR) and the hormone pancreatic polypeptide (PP) are members of the neuropeptide Y family consisting of four receptors (Y1R, Y2R, Y4R, Y5R) and three highly homologous peptide ligands (neuropeptide Y, peptide YY, PP). In this family, the Y4R is of particular interest as it is the only subtype with high affinity to PP over NPY. The Y4R, as a mediator of PP signaling, has a pivotal role in appetite regulation and energy homeostasis, offering potential avenues for the treatment of metabolic disorders such as obesity. PP as anorexigenic peptide is released postprandial from the pancreas in response to food intake, induces satiety signals and contributes to hamper excessive food intake. Moreover, this system was also described to be associated with different types of cancer: overexpression of Y4R have been found in human adenocarcinoma cells, while elevated levels of PP are related to the development of pancreatic endocrine tumors. The pharmacological relevance of the Y4R advanced the search for potent and selective ligands for this receptor subtype, which will be significantly progressed through the elucidation of the active state PP-Y4R cryo-EM structure. This review summarizes the development of novel PP-derived ligands, like Obinepitide as dual Y2R/Y4R agonist in clinical trials or UR-AK86c as small hexapeptide agonist with picomolar affinity, as well as the first allosteric modulators that selectively target the Y4R, e.g. VU0506013 as potent Y4R positive allosteric modulator or (S)-VU0637120 as allosteric antagonist. Here, we provide valuable insights into the complex physiological functions of the Y4R and PP and the pharmacological relevance of the system in appetite regulation to open up new avenues for the development of tool compounds for targeted therapies with potential applications in metabolic disorders.

Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

The role of NPY signaling pathway in diagnosis, prognosis and treatment of stroke.

Neuropeptide Y (NPY), an extensively distributed neurotransmitter within the central nervous system (CNS), was initially detected and isolated from the brain of a pig in 1982. By binding to its G protein-coupled receptors, NPY regulates immune responses and contributes to the pathogenesis of numerous inflammatory diseases. The hippocampus contained the maximum concentration in the CNS, with the cerebral cortex, hypothalamus, thalamus, brainstem, and cerebellum following suit. This arrangement suggests that the substance has a specific function within the CNS. More and more studies have shown that NPY is involved in the physiological and pathological mechanism of stroke, and its serum concentration can be one of the specific biomarkers of stroke and related complications because of its high activity, broad and complex effects. By summarizing relevant literature, this article aims to gain a thorough understanding of the potential clinical applications of NPY in the treatment of stroke, identification of stroke and its related complications, and assessment of prognosis.

Membrane-Mediated Allosteric Action of Serotonin on a Noncognate G-Protein-Coupled Receptor.

The structure and dynamics of the lipid membrane can affect the activity of membrane proteins. Therefore, small lipophilic molecules that alter membrane properties (such as the neurotransmitter serotonin) can potentially modulate receptor activity without binding to the receptor. Here, we investigated how the activity of neuropeptide Y type 4 receptor (Y4R, reconstituted in lipid bicelles) is modulated by serotonin, which has no known interaction with Y4R. We found a serotonin-concentration-dependent decrease (down to 0.1 mM of serotonin) in the ligand affinity of Y4R. This effect correlates with a serotonin-induced reduction of the resistance of the bilayer to indentation (measured by atomic force microscopy) and bilayer thickness (measured by solid state NMR) in two different types of zwitterionic lipid bicelles. Our findings indicate a "membrane-mediated allosteric effect" of serotonin on the activation of Y4R and suggest the potential for developing pharmacophores, which can modulate cellular signaling without directly interacting with any receptor.

The plasticity of neuropeptide Y-Y1 receptor system on Tac2 neurons contributes to mechanical hyperknesis during chronic itch.

Rationale: In the physiological states, the act of scratching protects the person from harmful substances, while in certain pathological conditions, the patient suffers from chronic itch, both physically and mentally. Chronic itch sufferers are more sensitive to mechanical stimuli, and mechanical hyperknesis relief is essential for chronic itch treatment. While neuropeptide Y-Y1 receptor (NPY-Y1R) system is known to play a crucial role in modulating mechanical itch in physiological conditions, it is elusive how they are altered during chronic itch. We hypothesize that the negative regulatory effect of Y1Rs on Tac2 neurons, the key neurons that transmit mechanical itch, declines during chronic itch. Methods: We combined transgenic mice, chemogenetic manipulation, immunofluorescence, rabies virus circuit tracing, and electrophysiology to investigate the plasticity of Y1Rs on Tac2 neurons during chronic itch. Results: We found that Tac2 neurons receive direct input from Npy neurons and that inhibition of Npy neurons induces activation of Tac2 neurons. Moreover, the expression of Y1Rs on Tac2 neurons is reduced, and the regulatory effect is also reduced during chronic itch. Conclusion: Our study clarifies the plasticity of Y1Rs on Tac2 neurons during chronic itch and further elucidates the mechanism by which NPY-Y1R system is responsible for modulating mechanical itch. We highlight Y1Rs as a promising therapeutic target for mechanical hyperknesis during chronic itch.

Valence-dependent effects of neuropeptide Y on the expression of conditioned fear and anxiety-like behavior: Involvement of the bed nucleus of the stria terminalis.

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We have previously shown that intracerebroventricular administration of NPY reduces the expression of social fear via simultaneous activation of Y1 and Y2 receptors in a mouse model of social fear conditioning (SFC). In the present study, we investigated whether the anteroventral bed nucleus of the stria terminalis (BNSTav) mediates these effects of NPY, given the important role of BNSTav in regulating anxiety- and fear-related behaviors. We show that while NPY (0.1 nmol/0.2 µl/side) did not reduce the expression of SFC-induced social fear in male CD1 mice, it reduced the expression of both cued and contextual fear by acting on Y2 but not on Y1 receptors within the BNSTav. Prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 µl/side) but not of the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 µl/side) blocked the effects of NPY on the expression of cued and contextual fear. Similarly, NPY exerted non-social anxiolytic-like effects in the elevated plus maze test but not social anxiolytic-like effects in the social approach avoidance test by acting on Y2 receptors and not on Y1 receptors within the BNSTav. These results suggest that administration of NPY within the BNSTav exerts robust Y2 receptor-mediated fear-reducing and anxiolytic-like effects specifically in non-social contexts and add a novel piece of evidence regarding the neural underpinnings underlying the effects of NPY on conditioned fear and anxiety-like behavior.

Basolateral amygdala neuropeptide Y system modulates binge ethanol consumption.

Neuropeptide Y (NPY) signaling regulation of corticolimbic communication is known to modulate binge-like ethanol consumption in rodents. In this work we sought to assess the impact of intra-BLA NPY system modulation on binge-like ethanol intake and to assess the role of the NPY1R+ projection from the BLA to the mPFC in this behavior. We used "drinking-in-the-dark" (DID) procedures in C57BL6J mice to address these questions. First, the impact of intra-BLA administration of NPY on binge-like ethanol intake was assessed. Next, the impact of repeated cycles of DID intake on NPY1R expression in the BLA was assessed with use of immunohistochemistry (IHC). Finally, chemogenetic inhibition of BLA→mPFC NPY1R+ projections was assessed to determine if limbic communication with the mPFC was specifically involved in binge-like ethanol intake. Importantly, as both the BLA and NPY system are sexually dimorphic, both sexes were assessed in these studies. Intra-BLA NPY dose-dependently decreased binge-like ethanol intake in males only. Repeated DID reduced NPY1R expression in the BLA of both sexes. Silencing of BLA→mPFC NPY1R+ neurons significantly reduced binge-like ethanol intake in both sexes in a dose-dependent manner. We provide novel evidence that (1) intra-BLA NPY reduces binge-like ethanol intake in males; (2) binge-like ethanol intake reduces NPY1R levels in the BLA; and (3) chemogenetic inhibition of BLA→mPFC NPY1R+ neurons blunts binge-like drinking in male and female mice. These observations provide the first direct evidence that NPY signaling in the BLA, and specifically BLA communication with the mPFC, modulates binge-like ethanol consumption.

A D-Y Shaped Neuropeptide Y Mimetic Peptide-Dye Self-Assembly with Maximal Emission Beyond 1300 nm and Glioma Mitochondrial Activity Modulation.

Neuropeptide Y (NPY), as one of the most abundant neuropeptides known, is widely distributed in the central and peripheral nervous system. However, most of the reported NPY-mimetic peptides are hard to cross the blood-brain barrier, target glioma mitochondria, and achieve self-assembly nanostructure in situ. Here, based on the α-helix structure of the novel chiral NPY-mimetic peptides D/LNPY(14), a Y-shaped peptide is designed with the sequences that can be recognized by enterokinase and achieved nanofibers conversion in glioma cell mitochondria. Coupling the Y-shaped NPY-mimetic peptide with the NIR-II fluorophore IR1048, a red-shifting of the fluorescence spectrum beyond 1300 nm is achieved through self-assembly. After the self-assembly in glioma mitochondria, the formed nanofibers can promote intracellular mitochondrial ROS production and extend the NIR-II fluorescence imaging time to at least 7 days in vivo. This work for the first time endows the self-assembly of α-helical-based chiral NPY-mimetic peptides, providing a novel strategy for glioma subcellular regulation enhanced antitumor treatment guided by NIR-II fluorescence imaging.

Effect of Adrenoreceptor Stimulation on Peptidergic Regulation of Cardiac Activity in Newborn Rats.

We studied the effect of adrenoreceptor stimulation on the frequency of spontaneous activity and amplitude-time parameters of isometric contraction of the atrial myocardial strips from newborn rats, as well as the effect of Y receptor stimulation against the background of adrenoreceptor activation. After addition of Y1,5 receptor agonist [Leu31, Pro34] NPY (10-7 M), a tendency to a decrease in the effect of ß1,2-adrenoreceptor agonist isoproterenol (10-5 M) on the frequency of spontaneous activity and atrial myocardial contractility was observed. The age-related features of the effect of NPY on the frequency of spontaneous activity and contractility of myocardial strips from newborn and adult rats were revealed.

Cross talk about the role of Neuropeptide Y in CNS disorders and diseases.

A peptide composed of a 36 amino acid called Neuropeptide Y (NPY) is employed in a variety of physiological processes to manage and treat conditions affecting the endocrine, circulatory, respiratory, digestive, and neurological systems. NPY naturally binds to G-protein coupled receptors, activating the Y-receptors (Y1-Y5 and y6). The findings on numerous therapeutic applications of NPY for CNS disease are presented in this review by the authors. New targets for treating diseases will be revealed by medication combinations that target NPY and its receptors. This review is mainly focused on disorders such as anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, Machado Joseph disease, multiple sclerosis, schizophrenia, depression, migraine, alcohol use disorder, and substance use disorder. The findings from the preclinical studies and clinical studies covered in this article may help create efficient therapeutic plans to treat neurological conditions on the one hand and psychiatric disorders on the other. They may also open the door to the creation of novel NPY receptor ligands as medications to treat these conditions.