RESUMEN
Drugs with poor water and lipid solubility are termed "brick dust." We previously successfully developed a co-amorphous system of a novel neuropeptide Y5 receptor antagonist (AntiY5R), a brick dust molecule, using sodium taurocholate (NaTC) as a co-former. However, the maximum improvement in AntiY5R dissolution by the co-amorphous system was only approximately 10 times greater than that of the crystals. Therefore, in the current study, other bile salts, including sodium cholate (NaC), sodium chenodeoxycholate (NaCC), and sodium glycocholate (NaGC), were examined as co-formers to further improve AntiY5R dissolution. NaC, NaCC, and NaGC have glass transition temperatures above 150°C. All three co-amorphous systems prepared successfully retained the amorphous form of AntiY5R for 3 months at 40°C, but the co-amorphous system with NaGC (AntiY5R-NaGC; 1:9 molar ratio) provided the highest improvement in AntiY5R dissolution, which was approximately 50 times greater than that of the crystals. Possible intermolecular interactions via the glycine moiety of NaGC more than the other bile salts would contribute to the highest dissolution enhancement with AntiY5R-NaGC. Thus, NaGC would be a promising co-former for formulating stable co-amorphous systems to enhance the dissolution behavior of brick dust molecules.
Asunto(s)
Estabilidad de Medicamentos , Ácido Glicocólico , Receptores de Neuropéptido Y , Solubilidad , Agua , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Ácido Glicocólico/química , Agua/química , Neuropéptido Y/química , Cristalización , Ácidos y Sales Biliares/químicaRESUMEN
BACKGROUND: Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses. METHODS: Using structure-activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. RESULTS: Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 µM-a 100-fold improvement over the original reference compound. CONCLUSIONS: Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito-human host interactions that lead to pathogen transmission.
Asunto(s)
Aedes , Conducta Alimentaria , Mosquitos Vectores , Receptores de Neuropéptido Y , Animales , Aedes/efectos de los fármacos , Femenino , Conducta Alimentaria/efectos de los fármacos , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/agonistas , Mosquitos Vectores/efectos de los fármacos , Relación Estructura-Actividad , HumanosRESUMEN
INTRODUCTION: While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments. OBJECTIVE: As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance. METHODS: Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention. RESULTS: Upon conclusion at 28-d, body weight reduction compared to vehicle was -15.6%/-11.9% in response to GEP44, vs. -9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (-30%; p < 0.0001), vs. LIRA (-10%), and in male rats GEP44 (-39%; p < 0.0001), vs. LIRA (-20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA. CONCLUSION: The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance.
Asunto(s)
Ingestión de Alimentos , Receptor del Péptido 1 Similar al Glucagón , Liraglutida , Obesidad , Animales , Obesidad/tratamiento farmacológico , Masculino , Ratas , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Liraglutida/farmacología , Ingestión de Alimentos/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/metabolismo , Dieta Alta en Grasa/efectos adversos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Insulina/sangre , Prueba de Tolerancia a la GlucosaRESUMEN
Dysfunction of the sympathetic nervous system and increased epicardial adipose tissue (EAT) have been independently associated with the occurrence of cardiac arrhythmia. However, their exact roles in triggering arrhythmia remain elusive. Here, using an in vitro coculture system with sympathetic neurons, cardiomyocytes, and adipocytes, we show that adipocyte-derived leptin activates sympathetic neurons and increases the release of neuropeptide Y (NPY), which in turn triggers arrhythmia in cardiomyocytes by interacting with the Y1 receptor (Y1R) and subsequently enhancing the activity of the Na+/Ca2+ exchanger (NCX) and calcium/calmodulin-dependent protein kinase II (CaMKII). The arrhythmic phenotype can be partially blocked by a leptin neutralizing antibody or an inhibitor of Y1R, NCX, or CaMKII. Moreover, increased EAT thickness and leptin/NPY blood levels are detected in atrial fibrillation patients compared with the control group. Our study provides robust evidence that the adipose-neural axis contributes to arrhythmogenesis and represents a potential target for treating arrhythmia.
Asunto(s)
Adipocitos , Tejido Adiposo , Arritmias Cardíacas , Leptina , Miocitos Cardíacos , Neuropéptido Y , Pericardio , Humanos , Animales , Pericardio/metabolismo , Pericardio/patología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Neuropéptido Y/metabolismo , Leptina/metabolismo , Adipocitos/metabolismo , Masculino , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Neuronas/metabolismo , Neuronas/patología , Intercambiador de Sodio-Calcio/metabolismo , Femenino , Receptores de Neuropéptido Y/metabolismo , Persona de Mediana Edad , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/patología , Sistema Nervioso Simpático/metabolismo , Ratones , Tejido Adiposo EpicárdicoRESUMEN
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.
Asunto(s)
Proliferación Celular , Cognición , Proteína Doblecortina , Ketamina , Neuronas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido Y , Receptores de Neuropéptido , Animales , Masculino , Ketamina/farmacología , Ketamina/administración & dosificación , Cognición/efectos de los fármacos , Ratas , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proliferación Celular/efectos de los fármacos , Receptor trkB/agonistas , Receptor trkB/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Neurogénesis/efectos de los fármacosRESUMEN
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.
Asunto(s)
Cnidarios , Péptidos , Receptores de Neuropéptido Y , Animales , Humanos , Ratones , Movimiento Celular/efectos de los fármacos , Quinasa 1 de Adhesión Focal/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ligandos , Simulación del Acoplamiento Molecular , Neovascularización Fisiológica/efectos de los fármacos , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Péptidos/farmacología , Proteína Quinasa C/efectos de los fármacos , Proteína Quinasa C/metabolismo , Receptores de Neuropéptido Y/efectos de los fármacos , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/efectos de los fármacos , Familia-src Quinasas/metabolismo , Pez Cebra , Cnidarios/química , Fosfoinositido Fosfolipasa C/efectos de los fármacos , Fosfoinositido Fosfolipasa C/metabolismoRESUMEN
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.
Asunto(s)
Neuropéptido Y , Neuropéptidos , Ratas , Animales , Receptor de Galanina Tipo 2/agonistas , Receptor de Galanina Tipo 2/metabolismo , Administración Intranasal , Galanina/farmacología , Galanina/metabolismo , Hipocampo/metabolismo , Receptores de Neuropéptido Y/metabolismo , Neuropéptidos/farmacología , Antidepresivos/farmacología , NeurogénesisRESUMEN
BACKGROUND: Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD). RESEARCH DESIGN AND METHODS: In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain's ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871). Main outcome measures included long-term neuronal survival, differentiation, and behavioral. RESULTS: Co-administration of M1145 and NPYY1R agonist significantly enhanced neuronal survival and maturation in the ventral dentate gyrus, with a notable increase in Brain-Derived Neurotrophic Factor (BDNF) expression. This neurogenic effect was associated with an antidepressant-like effect, an outcome partially reversed by M871. CONCLUSIONS: GALR2 and NPYY1R agonists jointly promote hippocampal neurogenesis and exert antidepressant-like effects in rats without adverse outcomes, highlighting their therapeutic potential for MDD. The study's reliance on an animal model and intracerebroventricular delivery warrants further clinical exploration to confirm these promising results.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Supervivencia Celular , Trastorno Depresivo Mayor , Neuronas , Receptor de Galanina Tipo 2 , Receptores de Neuropéptido Y , Animales , Masculino , Ratas , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Modelos Animales de Enfermedad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Péptidos , Ratas Sprague-Dawley , Receptor de Galanina Tipo 2/metabolismo , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/antagonistas & inhibidoresRESUMEN
BACKGROUND: Major Depressive Disorder (MDD) poses a significant challenge to global health, with current treatments often limited by efficacy and onset delays. This study explores the synergistic antidepressant-like effects of an NPY1R agonist and Ketamine, targeting their neurobiological interactions within the ventral hippocampus. RESEARCH DESIGN AND METHODS: Utilizing a preclinical model, this study administered Neuropeptide Y receptor 1 (NPY1R) agonist and Ketamine, both separately and in combination, through intracerebroventricular (icv) and intranasal (i.n.) routes. The Forced Swimming Test (FST) was employed to assess antidepressant-like activity, while in situ Proximity Ligation Assay and immunohistochemistry were used to examine NPY1R/TrkB heteroreceptor complexes and BDNF expression in the ventral dentate gyrus (DG), along with neurogenesis markers. RESULTS: The combined treatment significantly reduced immobility in the FST, indicative of enhanced antidepressant-like effects, correlated with increased formation of NPY1R/TrkB complex and brain-derived neurotrophic factor (BDNF) expression in the ventral DG. These molecular alterations were associated with increased neurogenesis. CONCLUSIONS: The coadministration of an NPY1R agonist and Ketamine in a rodent model demonstrated potentiated antidepressant responses through synergistic neurobiological pathways, including TrkB signaling and hippocampal neurogenesis. This indicates a novel therapeutic strategy for MDD, warranting further clinical investigation to fully understand its implications.
Asunto(s)
Antidepresivos , Sinergismo Farmacológico , Hipocampo , Ketamina , Neurogénesis , Receptores de Neuropéptido Y , Transducción de Señal , Animales , Masculino , Ratones , Ratas , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ketamina/farmacología , Ketamina/uso terapéutico , Neurogénesis/efectos de los fármacos , Ratas Sprague-Dawley , Receptor trkB/agonistas , Receptor trkB/metabolismo , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal/efectos de los fármacos , NataciónRESUMEN
(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.
Asunto(s)
Benzamidas , Compuestos de Bencidrilo , Hígado Graso , Péptidos Similares al Glucagón , Glucósidos , Piperazinas , Receptores de Neuropéptido Y , Ratas , Masculino , Animales , Receptores de Neuropéptido Y/metabolismo , Ratas Wistar , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Dieta , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/prevención & control , Pérdida de Peso , InflamaciónRESUMEN
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.
Asunto(s)
Ingestión de Alimentos , Metabolismo Energético , Conducta Alimentaria , Ratones Noqueados , Neuropéptido Y , Receptores de Neuropéptido Y , Transducción de Señal , Animales , Ratones , Dieta Alta en Grasa , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Conducta Alimentaria/fisiología , Locomoción/fisiología , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Neuropéptido Y/metabolismo , Condicionamiento Físico Animal/fisiología , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/genética , Transducción de Señal/fisiologíaRESUMEN
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.
Asunto(s)
Polipéptido Pancreático , Receptores de Neuropéptido Y , Humanos , Polipéptido Pancreático/metabolismo , Receptores de Neuropéptido Y/metabolismo , Animales , LigandosRESUMEN
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.
Asunto(s)
Receptores Acoplados a Proteínas G , Serotonina , Receptores de Neuropéptido Y/metabolismo , Proteínas de la Membrana/química , Lípidos , Membrana Dobles de Lípidos/químicaRESUMEN
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.
Asunto(s)
Neuropéptido Y , Receptores de Neuropéptido Y , Accidente Cerebrovascular , Animales , Neuropéptido Y/metabolismo , Neuropéptido Y/uso terapéutico , Pronóstico , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Porcinos , HumanosRESUMEN
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.
Asunto(s)
Conducta Alimentaria , Hipotálamo , Neuronas , Neuropéptido Y , Ratas Sprague-Dawley , Animales , Femenino , Masculino , Ratas , Desoxiglucosa/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/efectos de los fármacos , Glucosa/metabolismo , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/efectos de los fármacos , Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Melaninas/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Neuropéptidos/metabolismo , Orexinas/metabolismo , Hormonas Hipofisarias/metabolismo , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/genética , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Saporinas/farmacologíaRESUMEN
AIMS: Cardiac dysfunction is commonly observed in patients with subarachnoid haemorrhage (SAH). However, the specific timeline of cardiac remodelling and the underlying mechanisms responsible for this effect following SAH remain unknown. This study aims to explore the impact of SAH on cardiac dysfunction and its potential mechanisms over time. METHODS AND RESULTS: In Protocol 1, we investigated cardiac function and potential mechanisms in a Sprague-Dawley rat model of SAH at six time points (baseline and Days 1, 3, 7, 14, and 28) while exploring the underlying mechanisms. Our assessments included the haemodynamic profile, echocardiography, and the concentrations of plasma biomarkers at various time points post-SAH. We determined neuropeptide Y (NPY) 1-5 receptor protein expression levels through western blotting. In Protocol 2, we administered an NPY1 receptor antagonist to evaluate the effects of cardiac dysfunction induced by SAH on Day 3. In Protocol 1, SAH gradually provoked cardiac systolic dysfunction during the acute phase, reaching its peak on Day 3 without concurrent alterations in wall thickness. However, no significant changes were observed from Days 14 to 28 compared with Day 0. The changes in cardiac dysfunction were consistent with myocardial injury, inflammatory biomarkers, and NPY levels. SAH resulted in a heightened heart rate and systolic blood pressure, correlating with elevated epinephrine and norepinephrine levels. In Protocol 2, the administration of the NPY1 receptor antagonist effectively ameliorated cardiac dysfunction. CONCLUSIONS: SAH induces transient cardiac dysfunction in the acute phase, and the underlying mechanisms for this response involve the NPY-NPY1 receptor pathway, otherwise known as catecholamines.
Asunto(s)
Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Receptores de Neuropéptido Y , Hemorragia Subaracnoidea , Animales , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/fisiopatología , Ratas , Masculino , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Factores de Tiempo , Ecocardiografía , Biomarcadores/sangre , Neuropéptido Y/metabolismo , Remodelación Ventricular/fisiologíaRESUMEN
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.
Asunto(s)
Núcleos Talámicos Anteriores , Ansiolíticos , Núcleos Septales , Masculino , Ratones , Animales , Neuropéptido Y/farmacología , Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/metabolismo , Ansiolíticos/farmacología , Núcleos Septales/metabolismo , Ansiedad/tratamiento farmacológico , Miedo , Núcleos Talámicos Anteriores/metabolismoRESUMEN
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.
Asunto(s)
Neuropéptido Y , Receptores de Neuropéptido Y , Humanos , Ratones , Animales , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Receptores de Neuropéptido Y/genética , Receptores de Neuropéptido Y/metabolismo , Neuronas/metabolismo , Prurito/metabolismoRESUMEN
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 BLAâmPFC 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 BLAâmPFC 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 BLAâmPFC 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.
Asunto(s)
Complejo Nuclear Basolateral , Consumo Excesivo de Bebidas Alcohólicas , Ratones , Masculino , Femenino , Animales , Complejo Nuclear Basolateral/metabolismo , Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/metabolismo , Etanol , Neuronas/metabolismo , Consumo Excesivo de Bebidas Alcohólicas/metabolismoRESUMEN
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.