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.

Neuropeptide Y protects kidney from acute kidney injury by inactivating M1 macrophages via the Y1R-NF-κB-Mincle-dependent mechanism.

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.

Ligands of the Neuropeptide Y Y2 Receptors as a Potential Multitarget Therapeutic Approach for the Protection of the Neurovascular Unit Against Acute Ischemia/Reperfusion: View from the Perspective of the Laboratory Bench.

Ischemic stroke is the third leading cause of death and disability worldwide, with no available satisfactory prevention or treatment approach. The current treatment is limited to the use of "reperfusion methods," i.e., an intravenous or intra-arterial infusion of a fibrinolytic agent, mechanical removal of the clot by thrombectomy, or a combination of both methods. It should be stressed, however, that only approximately 5% of all acute strokes are eligible for fibrinolytic treatment and fewer than 10% for thrombectomy. Despite the tremendous progress in understanding of the pathomechanisms of cerebral ischemia, the promising results of basic research on neuroprotection are not currently transferable to human stroke. A possible explanation for this failure is that experiments on in vivo animal models involve healthy young animals, and the experimental protocols seldom consider the importance of protecting the whole neurovascular unit (NVU), which ensures intracranial homeostasis and is seriously damaged by ischemia/reperfusion. One of the endogenous protective systems activated during ischemia and in neurodegenerative diseases is represented by neuropeptide Y (NPY). It has been demonstrated that activation of NPY Y2 receptors (Y2R) by a specific ligand decreases the volume of the postischemic infarction and improves performance in functional tests of rats with arterial hypertension subjected to middle cerebral artery occlusion/reperfusion. This functional improvement suggests the protection of the NVU. In this review, we focus on NPY and discuss the potential, multidirectional protective effects of Y2R agonists against acute focal ischemia/reperfusion injury, with special reference to the NVU.

Serum levels of neuropeptide Y in patients with chronic schizophrenia during treatment augmentation with sarcosine (results of the double-blind randomized controlled PULSAR study).

OBJECTIVE: Modulation of glutamatergic neurotransmission in schizophrenia by sarcosine leads to a reduction in primary negative symptoms, while its metabolic profile is safe. In order to extend research in the area, we assessed serum levels of neuropeptide Y (NPY), a hypothalamic hormone related to anxiety and depression, also involved in mechanisms inducing weight gain. Additionally, we analyzed associations between NPY concentrations and its changes with severity of symptoms and metabolic parameters. METHODS: A prospective 6-month, randomized, double-blind placebo-controlled trial was completed by 57 subjects with chronic schizophrenia with predominant negative symptoms and stable antipsychotic treatment. The participants received 2 g of sarcosine (n = 28) or placebo (n = 29) daily. We assessed serum NPY concentrations and severity of symptoms (with the Positive and Negative Syndrome Scale [PANSS] and Calgary Depression Scale for Schizophrenia) at the beginning of the study, after 6 weeks and 6 months. RESULTS: Sarcosine did not affect NPY levels in all time points. The highest decrease in NPY concentrations was observed in the subjects who were initially depressed, who became euthymic at the last visit. We noticed an improvement in the total PANSS score, and negative symptom and general psychopathology subscales in the sarcosine group, however, without any correlation with NPY levels. CONCLUSION: The use of sarcosine does not change NPY levels. Peripheral NPY concentrations may be related to depressive symptoms in schizophrenia.

Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear.

In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM-/-) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM-/- mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM-/- mice, while the same treatment reduced social fear in ASM+/- mice and completely reversed social fear in ASM+/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM-/- mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM-/- mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments.

Neuroimmunomodulation in the mucosa of the alimentary tract / Neuroimmun-moduláció az emésztocsatorna nyálkahártyájában.

Neuropeptides synthetised in the enteric nervous system can change the function of the immunocells and play a role in inflammatory processes. In our review the effects of inflammation on the neuropeptide content of nerves and immune cells were compared. Inflamed tissue samples (human gastritis and animal models with experimental colitis and streptozotocin-induced diabetes mellitus) were examined. The number and contacts of neuropeptide-containing nerves and immune cells were studied using immunohistochemistry, confocal laser microscopy and electronmicroscopy. In inflammation, the number of substance P, vasoactive intestinal polypeptide and neuropeptide Y nerve fibres was increased significantly in parallel with the strongly increased number of immunocompetent cells (p<0.001). In inflammatory diseases, a large number of lymphocytes and mast cells were also positive for these neuropeptides. Very close morphological relationship between substance P and neuropeptide Y immunoreactive nerve fibres and immunocells could be demonstrated only in inflamed mucosa. Some of the substance P immunoreactive immunocells were also immunoreactive for tumor necrosis factor alpha and nuclear factor kappa B in the case of inflammation. The increased number of tumor necrosis factor alpha and nuclear factor kappa B immunoreactive immune cells correlated with the increased number of substance P-containing nerve fibres. Substance P, vasoactive intestinal polypeptide and neuropeptide Y released from nerve fibres and immunocells can play a role in inflammation. Our results suggest that using substance P antagonists or vasoactive intestinal polypeptide and neuropeptide Y peptides might be a novel therapeutic concept in the management of inflammation. Orv Hetil. 2020; 161(35): 1436-1440.

[Preliminary study of antimicrobial peptide cathelicidin-PY therapy in mice with acute liver failure].

Objective: To investigate the feasibility of cationic antimicrobial peptide cathelicidin-PY(PY) therapy through a mouse model of acute liver failure. Methods: The ability of different concentrations of antimicrobial peptide PY to neutralize endotoxin / lipopolysaccharide (LPS) in vitro was detected by Limulus Amebocyte Lysate (LAL) assay. Cell counting kit-8 (CCK-8) was used to detect the toxic effect of different concentrations of antimicrobial peptide PY on mouse monocyte macrophages (RAW264.7). An in vitro hemolysis experiment was used to evaluate the activity of antimicrobial peptide PY on healthy human erythrocytes. D-galactosamine combined with LPS- induced mouse model of acute liver failure was constructed. The antimicrobial peptide PY effect on survival rate of mouse model was observed. HE staining was used to observe the pathological changes of liver tissue. Immunohistochemistry and Western blotting were used to detect the expression of apoptosis-associated protein caspase-3. Intra-group comparisons were performed using t-test and analysis of variance. χ (2) test was used for the comparison of rates. Results: An in vitro experiment showed that the endotoxin neutralization rate was higher at very low dose (0.01 µmol/L), and exceeded 70% at medium-dose (10-40 µmol/L), and the difference between groups with different concentration was statistically significant (F = 569.22, P < 0.05). Medium-dose antimicrobial peptide PY had strong endotoxin neutralizing effect, low cytotoxicity and hemolytic activity. Moreover, in vivo experiments showed that the degree of liver injury and survival rate of mouse model was significantly improved with the medium-dose of antimicrobial peptide PY. Immunohistochemistry results showed that the expression of caspase-3 in the liver tissue was significantly depleted in the medium-dose group than that of the liver failure group, and the results were consistent with protein immunoblotting testing. Conclusion: Antimicrobial peptide PY possesses a strong ability to neutralize endotoxin and few toxic side effects. A specific dose of antimicrobial peptide PY can attenuate hepatocyte apoptosis and significantly improve the survival rate of animal model, and thus provides a new idea for the liver failure treatment.

Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells.

Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

Preclinical findings on the potential of intranasal neuropeptide Y for treating hyperarousal features of PTSD.

Acoustic startle response (ASR) assesses hyperarousal, a core symptom of posttraumatic stress disorder (PTSD). Intranasal neuropeptide Y (NPY) administration was shown to prevent hyperarousal in single prolonged stress (SPS) rodent PTSD model. However, it is unclear how ASR itself alters responses to stress. Rats (A-S-A) were exposed to acoustic startle (AS) 1 day before SPS (ASR1) and 2 weeks afterward (ASR2). Other groups were exposed in parallel to either AS (A-A) or SPS or neither. SPS enhanced ASR2. In relevant brain areas, mRNA levels were determined by qRT-PCR. In mediobasal hypothalamus, AS or SPS each increased CRH mRNA levels without an additive effect. Exposure to AS appeared to dampen some responses to SPS. The SPS-triggered reduction of GR and FKBP5 gene expression was not observed in A-S-A group. In locus coeruleus, SPS increased CRHR1 and reduced Y2R mRNAs, but not in A-S-A group. In both regions, AS altered NPY receptor gene expression, which may mediate dampening responses to SPS. In second experiment, intranasal NPY administered 2 weeks after SPS reversed hyperarousal symptoms for at least 7 days. This study reveals important effects of AS on the NPY system and demonstrates that intranasal NPY elicits long-lasting reversal of traumatic stress-triggered hyperarousal.

Neuropeptide Y is Up-regulated and Induces Antinociception in Cancer-induced Bone Pain.

Pain remains a major concern in patients suffering from metastatic cancer to the bone and more knowledge of the condition, as well as novel treatment avenues, are called for. Neuropeptide Y (NPY) is a highly conserved peptide that appears to play a central role in nociceptive signaling in inflammatory and neuropathic pain. However, little is known about the peptide in cancer-induced bone pain. Here, we evaluate the role of spinal NPY in the MRMT-1 rat model of cancer-induced bone pain. Our studies revealed an up-regulation of NPY-immunoreactivity in the dorsal horn of cancer-bearing rats 17 days after inoculation, which could be a compensatory antinociceptive response. Consistent with this interpretation, intrathecal administration of NPY to rats with cancer-induced bone pain caused a reduction in nociceptive behaviors that lasted up to 150 min. This effect was diminished by both Y1 (BIBO3304) and Y2 (BIIE0246) receptor antagonists, indicating that both receptors participate in mediating the antinociceptive effect of NPY. Y1 and Y2 receptor binding in the spinal cord was unchanged in the cancer state as compared to sham-operated rats, consistent with the notion that increased NPY results in a net antinociceptive effect in the MRMT-1 model. In conclusion, the data indicate that NPY is involved in the spinal nociceptive signaling of cancer-induced bone pain and could be a new therapeutic target for patients with this condition.

Bone: Another potential target to treat, prevent and predict diabetes.

Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.

Potential of Intranasal Neuropeptide Y (NPY) and/or Melanocortin 4 Receptor (MC4R) Antagonists for Preventing or Treating PTSD.

There is a great need for effective treatment options for post-traumatic stress disorder (PTSD). Neuropeptide Y (NPY) is associated with resilience to traumatic stress. MC4R antagonists, such as HS014, also reduce response to stress. Both regulate stress-responsive systems - the hypothalamic-pituitary-axis (HPA) and the noradrenergic nervous system and their associated behaviors. Therefore, we examined if their intranasal delivery to brain could attenuate development of PTSD-related symptoms in single prolonged stress (SPS) rodent PTSD model. Three regimens were used: (1) prophylactic treatment 30 min before SPS stressors, (2) early intervention right after SPS stressors, (3) therapeutic treatment when PTSD behaviors are manifested 1 wk or more after the traumatic stress. NPY delivered by regimen 1 or 2 prevented SPS-triggered elevation in anxiety, depressive-like behavior, and hyperarousal and reduced dysregulation of HPA axis. Hypothalamic CRH mRNA and GR in ventral hippocampus were significantly induced in vehicle- but not NPY-treated group. NPY also prevented hypersensitivity of LC/NE system to novel mild stressor and induction of CRH in amygdala. Some of these impairments were also reduced with HS014, alone or together with NPY. When given after symptoms were manifested (regiment 3), NPY attenuated anxiety and depressive behaviors. This demonstrates strong preclinical proof of concept for intranasal NPY, and perhaps MC4R antagonists, for non-invasive early pharmacological interventions for PTSD and comorbid disorders and possibly also as therapeutic strategy.

Targeted Orexin and Hypothalamic Neuropeptides for Migraine.

The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together.

Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington's disease.

Huntington's disease (HD) is a monogenic inherited polyglutamine-mediated neurodegenerative disorder for which effective therapies are currently unavailable. Neuropeptide Y (NPY) has been implicated as a potential therapeutic target in several neurodegenerative diseases, including HD. However, its mechanisms of action in the context of HD pathology remain unknown. Here, we investigated the beneficial effects of Y2 receptor (Y2R) activation with NPY or Y2R selective agonist NPY13-36 in the R6/2 mouse and PC12 cell models of HD. Also, we explored the effects of selective pharmacological blockage of Y2R using selective non-peptide small molecule Y2R antagonist SF31 in vivo and in vitro. Our results showed that activation of Y2R with intranasal NPY or NPY13-36 led to an improved motor function in R6/2 mice as revealed by rotarod performance, vertical pole test, and hindlimb clasping behaviour. Also, intranasal NPY or NPY13-36 led to a decrease in aggregated mHtt and mediated increase in dopamine and cAMP-regulated phosphoprotein, 32kDa (DARPP-32), brain-derived neurotrophic factor (BDNF), and activated extracellular signal-regulated protein kinases (pERK1/2) levels in R6/2 mice. Intranasal NPY or NPY13-36 had no effect on body weight but showed positive effects on survival in R6/2 mice. Furthermore, intranasal NPY or NPY13-36 attenuated induction of proinflammatory cytokine and inflammatory mediators in R6/2 mice. In contrast, antagonizing by using SF31 exacerbates phenotypic severity in R6/2 mice and treatment effects with either intranasal NPY or NPY13-36 were significantly blocked.In vitro, using inducible PC12/HttQ103-EGFP cells, treatment with NPY or NPY13-36 protected against mHtt-mediated neuromorphological defects (neurite length and soma area) and neurotoxicity but had no effect on mHtt inclusion body formation. Conversely, co-treatment with SF31 significantly inhibited these effects. Together, our findings extend previous evidence of the beneficial effects of NPY in R6/2 mice, and more importantly, suggest that targeted activation of Y2R receptor might be a promising disease-modifying target for HD and other neurodegenerative diseases.

Neuropeptide Y and its Involvement in Chronic Pain.

Chronic pain is a serious condition that significantly impairs the quality of life, affecting an estimate of 1.5 billion people worldwide. Despite the physiological, emotional and financial burden of chronic pain, there is still a lack of efficient treatments. Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems of all mammals, which has been implicated in both pro- and antinociceptive effects. NPY is expressed in the superficial laminae of the dorsal horn of the spinal cord, where it appears to mediate its antinociceptive actions via the Y1 and Y2 receptors. Intrathecal administration of NPY in animal models of neuropathic, inflammatory or postoperative pain has been shown to cause analgesia, even though its exact mechanisms are still unclear. It remains to be seen whether these promising central antinociceptive effects of NPY can be transferred into a future treatment for chronic pain.

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

Background: Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Methods: Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Results: Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Conclusions: Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).

Analgesic and anxiolytic effects of [Leu31,Pro34]-neuropeptide Y microinjected into the periaqueductal gray in rats.

Several reports have demonstrated that neuropeptide Y (NPY) is involved in food intake, epilepsy, circadian rhythms, drug seeking, pain and anxiety, and other physiological or pathological conditions. On the other hand, periaqueductal gray (PAG) is a key brain center for modulating pain, anxiety and fear. It is the main structure implicated in integrated defensive behaviors. One such behavior, tonic immobility (TI), resembles fear and is able to induce analgesia. After microinjection of [Leu31,Pro34]-Neuropeptide Y ([Leu31,Pro34]-NPY) into the PAG dorsal (D) or ventrolateral (VL) of adult male Wistar rats, the following parameters were assessed: i) the analgesic effect by means of the tail-flick test (TF), ii) the duration of TI as a passive defensive behavioral response and as an anxiety/fear model (considering both TF and TI as single behaviors), iii) TI-induced analgesia by the combination of TF/TI, and iv) the anxious-like state through the elevated plus maze (EPM), and defensive burying behavior (DBB). The results show that the microinjection of [Leu31,Pro34]-NPY into the PAG produced an analgesic effect (increasing the TF latency); overall decreased the TI duration, which might represent an important anti-fear effect. Moreover, [Leu31,Pro34]-NPY microinjected into the PAG allows for a TI-induced analgesic effect, as well as, a substantial anxiolytic effect (evidenced by the EPM and DBB models). Hence, [Leu31,Pro34]-NPY microinjected into the PAG, especially at 0.47nmol/0.5µL produces both analgesic and anxiolytic effects, in a higher magnitude within ventrolateral area.

Neuropeptide Y-based recombinant peptides ameliorate bone loss in mice by regulating hematopoietic stem/progenitor cell mobilization.

Ovariectomy-induced bone loss is related to an increased deposition of osteoclasts on bone surfaces. We reported that the 36-amino-acid-long neuropeptide Y (NPY) could mobilize hematopoietic stem/progenitor cells (HSPCs) from the bone marrow to the peripheral blood by regulating HSPC maintenance factors and that mobilization of HSPCs ameliorated low bone density in an ovariectomy-induced osteoporosis mouse model by reducing the number of osteoclasts. Here, we demonstrated that new NPY peptides, recombined from the cleavage of the full-length NPY, showed better functionality for HSPC mobilization than the full-length peptide. These recombinant peptides mediated HSPC mobilization with greater efficiency by decreasing HSPC maintenance factors. Furthermore, treatment with these peptides reduced the number of osteoclasts and relieved ovariectomy-induced bone loss in mice more effectively than treatment with full-length NPY. Therefore, these results suggest that peptides recombined from full-length NPY can be used to treat osteoporosis. [BMB Reports 2017; 50(3): 138-143].

Neuropeptide Y, resilience, and PTSD therapeutics.

Resilience to traumatic stress is a complex psychobiological process that protects individuals from developing posttraumatic stress disorder (PTSD) or other untoward consequences of exposure to extreme stress, including depression. Progress in translational research points toward the neuropeptide Y (NPY) system - among others - as a key mediator of stress response and as a potential therapeutic focus for PTSD. Substantial preclinical evidence supports the role of NPY in the modulation of stress response and in the regulation of anxiety in animal models. Clinical studies testing the safety and efficacy of modulating the NPY system in humans, however, have lagged behind. In the current article, we review the evidence base for targeting the NPY system as a therapeutic approach in PTSD, and consider impediments and potential solutions to therapeutic development.

Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].