Administration Of Vasoactive Intestinal Peptide Research Articles

Sympathetic Neurotransmitter, VIP, Delays Intervertebral Disc Degeneration via FGF18/FGFR2-Mediated Activation of Akt Signaling Pathway.

Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and intervertebral disc (IVD) homeostasis remains unclear. Here, this study aimed to investigate the expression of postganglionic sympathetic nerve fiber-derived vasoactive intestinal peptide (VIP) system in human IVD tissue, and to assess the role of VIP-related neuromodulation in IVDD. Patient samples and in vitro cell experiments showed that the expression of receptors for VIP is negatively correlated with the severity of IVDD, and the administration of exogenous VIP can ameliorate interleukin 1β-induced nucleus pulposus (NP) cell apoptosis and inflammation. Further mRNA-seq analysis revealed that fibroblast growth factor 18- (FGF18)-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway is involved in the protective effects of VIP on inflammation-induced NP cell degeneration. Further analysis identified VIP via its receptor vasoactive intestinal peptide receptor 2 can directly result in decreased expression of miR-15a-5p, which targeted FGF18. Finally, in vivo mice lumbar IVDD model confirmed that focally exogenous administration of VIP can effectively ameliorated the progression of IVDD, as shown by the radiological and histological analysis. In conclusion, these results indicated that sympathetic neurotransmitter, VIP, delayed IVDD via FGF18/FGFR2-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway, which will broaden the horizon concerning how the neuromodulation correlates with IVDD and shed new light on novel therapeutical alternatives to IVDD.

Vasoactive intestinal peptide promotes hypophagia and metabolic changes: Role of paraventricular hypothalamic nucleus and nitric oxide

Vasoactive intestinal peptide (VIP), a neuromodulator present in the hypothalamus, plays an important role in the regulation of food intake. Paraventricular nucleus of the hypothalamus (PVN) is involved in ingestive responses and regulates the nitric oxide (NO) pathway. The main objectives of this study were to investigate metabolic changes established after different doses and times of VIP microinjection on the PVN, and the effect of VIP microinjection on the PVN on food intake and the role of NO in this control. In anesthetized rats, increased blood plasma glucose and insulin levels were observed following the doses of 40 and 80 ng/g of body weight. At the dose of 40 ng/g, VIP promoted hyperglycemia and hyperinsulinemia 5, 10, and 30 min after microinjection, and increased free fatty acids and total lipids plasma levels after 5 min, and triglycerides after 10 min. In awake animals, once again, VIP administration increased plasmatic levels of glucose, free fatty acids, corticosterone, and insulin 10 min after the microinjection. Moreover, VIP promoted hypophagia in the morning and night periods, and L-arginine (L-Arg) and monosodium glutamate (MSG) or a combination of both attenuated VIP-induced reduction on food intake. In addition, nitrate concentration in the PVN was decreased after VIP microinjection. Our data show that the PVN participates in the anorexigenic and metabolic effects of VIP, and that VIP-induced hypophagia is likely mediated by reduction of NO.

Inhibition of Vasoactive Intestinal Peptide Signaling with More Potent Inhibitors Augments T-Cell Activation and Prolongs Survival in Leukemic Mice

Introduction: Vasoactive intestinal peptide (VIP) is a 28-amino acid neuropeptide with immunosuppressive effects on T cells. Inhibition of VIP receptor (VIP-R) signaling by VIPhyb, a first-generation VIP-R antagonist, not only enhances T-cell activation and proliferation in vitro but also improves T cell dependent anti-tumor response in mouse models of acute myeloid leukemia (AML) and T lymphoblastic leukemia (Li et al. 2016; Petersen, Li, and Waller 2017). The goal of the project is to develop more potent VIP-R antagonists that generate a significantly more robust anti-tumor response in mouse models of AML, when compared to VIPhyb and validate a screening method to test the efficacy of novel peptides in activating human T cells in vitro. In this study, we report, for the first time, the activity of novel VIP-R antagonists on the activation profile of human T cells.Methods: We utilized in-silico-based modeling to identify 10 novel VIP-R antagonists from a library of 300 peptide sequences predicted to have increased binding affinity to VIP receptors VPAC1 and VPAC2 when compared to VIP or VIPhyb (Table 1). The library was generated from peptide sequences that contain the six charged N-terminal residues of the neurotensin present in VIPhyb with two or more amino acid substitutions within the C-terminal amino acid sequence of VIP. The ability of these peptides was tested in vitro using T cells from multiple healthy human donors activated using anti-CD3 monoclonal antibody coated plates. Activation status was assessed by flow cytometry of CD69, OX40, PD1, Tim3 and Lag3 expression relative to control cultures without added peptides. Potency of the novel antagonists in vivo was tested in a mouse AML model, by treating C1498- bearing mice with subcutaneous administration of VIP, VIPhyb, scrambled peptide (SCRAM1) or the second-generation VIP-R antagonists (labeled as ‘ANT‘) from day 6-12 after tumor implantation.Results: Inhibiting VIP-R signaling in human T cells using second-generation VIP-R antagonists ANT008, ANT308 and ANT195 showed approximately 1.5-to-2-fold increase in CD69, OX40, Tim3, Lag3 and OX40 expression in CD4+ T cells following 24-hour of drug exposure compared to control cultures (Figure 1A). A smaller effect of VIP-R antagonists on activation of CD8+ subsets was observed (Figure 1B). Among the peptides, ANT195 was superior to ANT008 and ANT308 which shows potency even at 1μM compared to 3μM for ANT008 and ANT308. However, significant increase in CD69 expression was observed in both CD4+ and CD8+ T cells in cultures treated with ANT308 (Figure 1 A&B, *p<0.05). Viability of the T cells was not affected by incubation with the queried peptides (Data not shown). These data corresponded to in vivo activity of the novel VIP-R antagonists such as ANT308 and ANT195 which rendered 40% of mice leukemia-free at day 60 compared to only 5% long-term survival with VIPhyb (Figure 2). Another candidate, ANT300, increased median survival time (MST) by up to 47 days compared to MST of 34 days with VIPhyb (Figure 2).Conclusions: Here, we report a simple and robust in vitro method to screen for immune activity potential of novel second-generation VIP-R antagonists using human T cells. Preliminary screen shows VIP-R antagonists augment activation of both CD4+ and CD8+ T cells. Our results indicate that ANT308 and ANT195 are more potent VIP-R antagonists with enhanced activity in vitro (human) and in vivo (mouse) than VIPhyb and ANT008, which demonstrate lower predicted binding affinities to VPAC1 and VPAC2. Our study supports the hypothesis that higher predicted binding affinity to VPAC1 and/or VPAC2 is associated with enhanced activity in stimulating human T cells and promoting anti-leukemia activity in mice. Further mechanistic studies on how inhibition of VIP-R signaling augments T cell activation and function are underway. These novel antagonists can lead to peptide-based immunotherapy for the treatment of various liquid cancers. Clinical development of this novel concept will require appropriate pre-clinical pharmacokinetic and toxicology studies. [Display omitted] DisclosuresWaller: Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Verastem Oncology: Consultancy, Research Funding.

Vasoactive Intestinal Peptide Promotes Fracture Healing in Sympathectomized Mice.

Vasoactive intestinal peptide (VIP) as a neuromodulator and neurotransmitter played a significant role in modulating bone homeostasis. Our previous study reported an essential role of VIP in in vitro BMSCs osteogenesis and in vivo bone defect repair. VIP was also revealed to have a promoting effect on embryonic skeletal element development. However, the role of VIP in fracture healing is not known yet. We hypothesized that the disorder of sympathetic nervous system impairs bone structure and fracture healing, whereas VIP may rescue the sympathetic inhibition effects and promote fracture healing. We employed a 6-hydroxydopamine(6-OHDA) induced sympathectomy mice model (sympathectomized mice), in which successful sympathetic inhibition was confirmed by a decreased level of norephedrine (NE) in the spleen. In the sympathectomized mice, the femoral micro-architecture, bone density and mechanical properties were all impaired compared to the vehicle control mice. The femoral fracture was created in the vehicle or sympathectomized mice. Vehicle mice were locally injected with PBS as a negative control, and the sympathectomized mice were treated with injection of PBS or VIP. VIP expression at the fracture site was significantly decreased in sympathectomized mice. The fracture healing was repressed upon 6-OHDA treatment and rescued by VIP treatment. Micro-CT examination showed that the femoral bone micro-architecture at the fracture sites and mechanical properties were all impaired. Simultaneously, the expression level of osteogenic markers OCN and OPN were reduced in sympathectomized mice compared with vehicle group. While the VIP treatment rescued the repression effects of 6-OHDA on bone remodeling and significantly promoted bone quality and mechanical properties as well as increased osteogenesis marker expression in the sympathectomized mice. VIP administration promoted bone fracture healing by inhibiting bone resorption, making it a putative new alternative treatment strategy for fracture healing.

Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts.

Formation of intrahepatic bile ducts (IHBDs) proceeds in accordance with their microenvironment. Particularly, mesenchymal cells around portal veins regulate the differentiation and ductular morphogenesis of cholangiocytes in the developing liver; however, further studies are needed to fully understand the arrangement of IHBDs into a continuous hierarchical network. This study aims to clarify the interaction between biliary and liver mesenchymal cells during IHBD formation. To identify candidate factors contributing to this cell–cell interaction, mesenchymal cells were isolated from embryonic day 16.5 matrix metalloproteinase 14 (MMP14)‐deficient (knockout [KO]) mice livers, in which IHBD formation is retarded, and compared with those of the wild type (WT). WT mesenchymal cells significantly facilitated the formation of luminal structures comprised of hepatoblast‐derived cholangiocytes (cholangiocytic cysts), whereas MMP14‐KO mesenchymal cells failed to promote cyst formation. Comprehensive analysis revealed that expression of vasoactive intestinal peptide (VIP) was significantly suppressed in MMP14‐KO mesenchymal cells. VIP and VIP receptor 1 (VIPR1) were mainly expressed in periportal mesenchymal cells and cholangiocytic progenitors during IHBD development, respectively, in vivo. VIP/VIPR1 signaling significantly encouraged cholangiocytic cyst formation and up‐regulated tight junction protein 1, cystic fibrosis transmembrane conductance regulator, and aquaporin 1, in vitro. VIP antagonist significantly suppressed the tight junction assembly and the up‐regulation of ion/water transporters during IHBD development in vivo. In a cholestatic injury model of adult mice, exogenous VIP administration promoted the restoration of damaged tight junctions in bile ducts and improved hyperbilirubinemia. Conclusion: VIP is produced by periportal mesenchymal cells during the perinatal stage. It supports bile duct development by establishing tight junctions and up‐regulating ion/water transporters in cholangiocytes. VIP contributes to prompt recovery from cholestatic damage through the establishment of tight junctions in the bile ducts.

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases.

The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP’s discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis

Background and PurposeExcessive inflammatory cell infiltration and accumulation in the intestinal mucosa are pathological features of necrotizing enterocolitis (NEC) leading to intestinal barrier disruption. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent that regulates intestinal epithelial barrier homeostasis. We previously demonstrated that VIP-ergic neuron expression is decreased in experimental NEC ileum, and this may be associated with inflammation and barrier compromise. We hypothesize that exogenous VIP administration has a beneficial effect in NEC. MethodsNEC was induced in C57BL/6 mice by gavage feeding, hypoxia, and lipopolysaccharide administration between postnatal day (P) 5 and 9. There were four studied groups: Control (n = 6): Breast feeding without stress factors; Control + VIP (n = 5): Breast feeding + intraperitoneal VIP injection once a day from P5 to P9; NEC (n = 9): mice exposed to NEC induction; NEC + VIP (n = 9): NEC induction + intraperitoneal VIP injection. Terminal ileum was harvested on P9. NEC severity, intestinal inflammation, (IL-6 and TNFα), and Tight junctions (Claudin-3) were evaluated. ResultsNEC severity and intestinal inflammation were significantly decreased in NEC + VIP compared to NEC. Tight junction expression was significantly increased in NEC + VIP compared to NEC. ConclusionVIP administration has a beneficial therapeutic effect in NEC by reducing inflammation and tight junction disruption.

Vasoactive intestinal peptide alleviates food allergy via restoring regulatory B cell functions.

The immune regulatory cell dysfunction is associated with many immune diseases including food allergy (FA). This study aims to investigate the role of vasoactive intestinal peptide (VIP) in the maintenance of regulatory B cell (Br cell)'s immune suppressive functions by stabilizing thrombospondin (TSP1) expression. In this study, blood samples were collected from patients with food allergy (FA) and healthy control (HC) subjects. Br cells were isolated from the samples through flow cytometry cell sorting and analyzed by immunological approaches to determine the immune regulatory capacity. We found that the immune suppressive functions of Br cells were impaired in FA patients. The serum VIP levels were associated with the production of immune suppressive function-related mediators (interleukin-10, IL-10) of Br cells in FA patients. VIP counteracted IL-10 mRNA decay in Br cells by up regulating the TSP1 expression. TSP1 inhibited tristetraprolin (TTP) to prevent IL-10 mRNA decay in Br cells. Administration of VIP inhibited FA response through restoration of immune suppressive functions in Br cells. In conclusion, administration of VIP can alleviate FA response through up regulating expression of TSP1 to stabilize IL-10 expression in FA Br cells and recover the immune regulatory functions. The results have translational potential for the treatment of FA and other disorders associated with immune regulatory dysfunction of Br cells.

Therapeutic effect of vasoactive intestinal peptide on form-deprived amblyopic kittens

BackgroundExploring the role of vasoactive intestinal peptide (VIP) in the lateral geniculate body (LGBd) in visual development and studying the therapeutic effect of VIP on amblyopic kittens.MethodsThree-week-old domestic cats were divided into a control group (n = 10) and a monocular deprivation group (n = 20), with an eye mask covering the right eye of those in the deprived group. After pattern visual evoked potential (PVEP) recording confirmed the formation of monocular amblyopia, the left LGBd was isolated from 5 kittens in each group. The remaining control kittens continued to be raised, and the remaining deprivation group was divided into a VIP intervention group (n = 5), Sefsol (caprylic acid monoglyceride, VIP solution) intervention group (n = 5) and amblyopia non-intervention group (n = 5) after removal of the eye mask. Three weeks later, PVEPs, VIP immunohistochemistry and VIP mRNA expression in the left LGBd were compared across groups.ResultsAt 6 weeks of age, there were significant differences in P100 wave latency and amplitude and VIP immunohistochemistry and in situ hybridization between the control group and the deprivation group (P < 0.05). After 3 weeks of the corresponding interventions, the latency and amplitude in the VIP intervention group were better than that in the Sefsol intervention group and amblyopia non-intervention group (P < 0.05). Furthermore, VIP treatment increased the number of immunohistochemical VIP-positive cells (P < 0.05) and the average optical density of positive cells (P > 0.05), as well as the number (P < 0.05) and average optical density of VIP mRNA-positive cells (P < 0.05).ConclusionsVIP plays an important role in visual development. Nasal administration of VIP can improve the function of neurons in the LGBd of kittens and has a certain therapeutic effect on amblyopia.

Immunomodulation by vasoactive intestinal peptide is associated with increased survival and growth of Salmonella Typhimurium in mice

Studies have shown that administration of vasoactive intestinal peptide (VIP) in mice rescues them from lethal endotoxaemia and that this is correlated with decreased concentration of inflammatory cytokines. VIP has, therefore, been proposed as a novel anti-inflammatory which could be used in the treatment of Gram negative sepsis. However, the effect of VIP has not been reported in mice infected with viable Gram negative bacteria.Here, we show that Salmonella enterica serovar Typhimurium 4/74 significantly increased expression of mRNA of a type 1 receptor (VPAC1) for anti-inflammatory vasoactive intestinal peptide (VIP) in murine ileum and mesenteric lymph nodes at day 6 post-infection (d6 pi) and in the spleen at d3 pi. When VIP (5 nmol/ml) was administered to S. Typhimurium-infected mice, there was a significant increase in the number of S. Typhimurium cultured from murine faeces and ileum at d3 and 6 pi and in MLN and spleen at d3 dpi, compared to faeces and tissues examined from mice infected with S. Typhimurium (without VIP administration). Administration of VIP to S. Typhimurium-infected mice also altered the splenic architecture, resulting in a lack of discernable periarterial lymphoid sheaths or marginal zones at d6 pi but liver histology appeared similar on both d3 and d6 pi. The effects of VIP administration were correlated with a significant decrease in expression of inflammatory cytokine mRNA, associated with systemic inflammatory response syndrome (SIRS) of bacteraemia and acute sepsis.We conclude that VIP inhibits expression of diagnostic/prognostic cytokine biomarkers of sepsis in S. Typhimurium-infected mice. However, this occurred with a concomitant increase in Salmonella growth in tissues and increased bacterial shedding in faeces. Thus, VIP may have potential as an adjunctive therapy to antibiotics in sepsis.

Adrenalectomy impairs vasoactive intestinal peptide-induced changes in food intake and plasma parameters.

The aim of this study is to evaluate the effects of adrenalectomy (ADX) and glucocorticoid in the changes induced by intracerebroventricular (ICV) administration of vasoactive intestinal peptide (VIP) on food intake and plasma parameters, as well as VIP receptor subtype 2 (VPAC2) mRNA expression in different hypothalamic nuclei of male rats. Male Wistar rats (260-280 g) were subjected to ADX or sham surgery, 7 days before the experiments. Half of ADX animals received corticosterone (ADX + CORT) in the drinking water. Animals with 16 h of fasting received ICV microinjection of VIP or saline (0.9% NaCl). After 15 min: (1) animals were fed, and the amount of food ingested was quantified for 120 min; or (2) animals were euthanized and blood was collected for biochemical measurements. Determination of VPAC2 mRNA levels in LHA, ARC, and PVN was performed from animals with microinjection of saline. VIP treatment promoted the anorexigenic effect, which was not observed in ADX animals. Microinjection of VIP also induced an increase in blood plasma glucose and corticosterone levels, and a reduction in free fatty acid plasma levels, but adrenalectomy abolished these effects. In addition, adrenalectomy reduced mRNA expression of VPAC2 in the lateral hypothalamic area and arcuate nucleus, but not in the paraventricular nucleus. These results suggest that adrenal glands are required for VIP-induced changes in food intake and plasma parameters, and these responses are associated with reduction in the expression of VPAC2 in the hypothalamus after adrenalectomy.

Vasoactive intestinal polypeptide synthesis by somatic tissues in transplant recipients limits GVHD in allo-BMT

Abstract Both donor and recipient hematopoietic cells regulate GvHD in allo-BMT, but the role of somatic host tissues in the induction and maintenance of GvHD is less clear. Vasoactive Intestinal peptide (VIP) is a neuropeptide with potent immune-regulatory activity. Our goal was to examine the role of VIP synthesis by recipient tissues on donor T cell activation and GvHD in allo-BMT. We used MHC mis-matched allo-BMT models, B10.BR--&amp;gt;B6 and Balb/c--&amp;gt;B6, irradiating WT and VIP-KO B6 mice with 11Gy on day −1 and transplanting with 5 × 10E6 T cell depleted (TCD) bone marrow (BM) plus 0, 1 × 10E6, or 3 × 10E6 T cells from MHC mis-matched donors. B6--&amp;gt;B6 radiation chimeras lacking VIP in either hematopoietic or non-hematopoietic cells were created by performing B6 WT--&amp;gt;VIP-KO and VIP-KO--&amp;gt;WT syngeneic transplants. Production of VIP in transplant recipients was visualized with immune-fluorescent staining of tissues using an anti-VIP antibody. Transplanting TCD BM plus 3 × 10E6 donor T cells from B10.BR or Balb/c donors in VIP KIO mice led significantly increased GVHD-mortality compared with WT recipients. Donor-derived T cells in VIP-KO recipients had significantly higher Th1 and Th17 polarization. B10.BR--&amp;gt;B6 second allogeneic transplantation of radiation chimeras caused lethal GVHD mortality in VIP-KO-- &amp;gt;VIP-KO and WT--&amp;gt;VIP-KO mice, but not in WT--&amp;gt;WT or VIP-KO--&amp;gt;WT B6 mice, demonstrating the protective effect of VIP was due to synthesis by somatic recipient cells. Immunofluorescent imaging of allo-BMT recipients showed up-regulation of VIP in lungs post-transplant and high VIP production within neurons innervating the lungs. Short-term administration of VIP from D0 to D10 prevented GvHD-mortality in VIP-KO recipients transplanted BM &amp; T cells.

Vasoactive intestinal peptide is required in the maintenance of immune regulatory competency of immune regulatory monocytes.

Dysfunction of the immune regulatory system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Vasoactive intestinal peptide (VIP) has multiple bioactivities. This study aims to investigate the role of VIP in the maintenance of the immune regulatory capacity of monocytes (Mos). Human peripheral blood samples were collected from RA patients and healthy control (HC) subjects. Mos and CD14+ CD71- CD73+ CD25+ regulatory Mos (RegMos) were isolated from the blood samples and characterized by flow cytometry. A rat RA model was developed to test the role of VIP in the maintenance of the immune regulatory function of Mos. The results showed that RegMos of HC subjects had immune suppressive functions. RegMos of RA patients expressed less interleukin (IL)-10 and showed an incompetent immune regulatory capacity. Serum levels of VIP were lower in RA patients, which were positively correlated with the expression of IL-10 in RegMos. In-vitro experiments showed that the IL-10 mRNA decayed spontaneously in RegMos, which could be prevented by the presence of VIP in the culture. VIP suppressed the effects of tristetraprolin (TTP) on inducing IL-10 mRNA decay in RegMos. Administration of VIP inhibited experimental RA in rats through restoring the IL-10 expression in RegMos. RegMos have immune suppressive functions. VIP is required in maintaining IL-10 expression in RegMos. The data suggest that VIP has translational potential in the treatment of immune disorders such as RA.

Vasoactive intestinal peptide stabilizes intestinal immune homeostasis through maintaining interleukin-10 expression in regulatory B cells.

Rationale: Immune dysfunction is thought to play an important role in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). However, the underlying mechanism requires further investigation. Vasoactive intestinal peptide (VIP) has immune regulatory functions, but its role in immune regulatory activities in the intestinal mucosa is not fully understood. This study aims to elucidate the role of VIP in the regulation of regulatory B cell (Breg) function in the intestine.Methods: Peripheral blood samples were collected from UC patients and healthy control (HC) subjects. Bregs were isolated from these samples and their immune regulatory function was analyzed. A murine colitis model was established to test the role of VIP in inhibiting inflammation in the intestine.Results: Serum IL-10 and VIP levels were lower in IgE+ (≥0.35 IU/mL) UC patients than that in HC subjects. The immune suppressive function of Bregs isolated from IgE+ UC patients was impaired. IL-10 mRNA decayed spontaneously in Bregs, which was reversed by VIP added to the culture. Tristetraprolin (TTP) bound IL-10 mRNA to speed its decay, which was blocked by VIP in the culture. Administration of VIP efficiently inhibited experimental colitis.Conclusions: Insufficient VIP levels in the microenvironment speeds IL-10 mRNA decay to cause Breg dysfunction. Administration of VIP can inhibit experimental colitis, suggesting the translational potential of VIP in the treatment of IgE+ UC.

Vasoactive Intestinal Peptide Decreases β-Amyloid Accumulation and Prevents Brain Atrophy in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of fibrillary β-amyloid (Aβ) plaques in the brain that initiate an inflammatory process resulting in neurodegeneration. The neuronal loss associated with AD results in gross atrophy of affected regions causing a progressive loss of cognitive ability and memory function, ultimately leading to dementia. Growing evidence suggests that vasoactive intestinal peptide (VIP) could be beneficial for various neurodegenerative diseases, including AD. The study investigated the effects of VIP on 5xFAD, a transgenic mouse model of AD. Toward this aim, we used 20 5xFAD mice in two groups (n = 10 each), VIP-treated (25ng/kgi.p. injection, three times per week) and saline-treated (the drug's vehicle) following the same administration regimen. Treatment started at 1month of age and ended 2months later. After 2months of treatment, the mice were euthanized, their brains dissected out, and immunohistochemically stained for Aβ40 and Aβ42 on serial sections. Then, plaque analysis and stereological morphometric analysis were performed in different brain regions. Chronic VIP administration in 5xFAD mice significantly decreased the levels of Aβ40 and Aβ42 plaques in the subiculum compared to the saline treated 5xFAD mice. VIP treatment also significantly decreased Aβ40 and Aβ42 plaques in cortical areas and significantly increased the hippocampus/cerebrum and corpus callosum/cerebrum ratio but not the cerebral cortex/cerebrum ratio. In summary, we found that chronic administration of VIP significantly decreased Aβ plaques and preserved against atrophy for related brain regions in 5xFAD AD mice.

Colonic levels of vasoactive intestinal peptide decrease during infection and exogenous VIP protects epithelial mitochondria against the negative effects of IFNγ and TNFα induced during Citrobacter rodentium infection

Citrobacter rodentium infection is a model for infection with attaching and effacing pathogens, such as enteropathogenic Escherichia coli. The vasoactive intestinal peptide (VIP) has emerged as an anti-inflammatory agent, documented to inhibit Th1 immune responses and successfully treat animal models of inflammation. VIP is also a mucus secretagogue. Here, we found that colonic levels of VIP decrease during murine C. rodentium infection with a similar time dependency as measurements reflecting mitochondrial function and epithelial integrity. The decrease in VIP appears mainly driven by changes in the cytokine environment, as no changes in VIP levels were detected in infected mice lacking interferon gamma (IFNγ). VIP supplementation alleviated the reduction of activity and levels of mitochondrial respiratory complexes I and IV, mitochondrial phosphorylation capacity, transmembrane potential and ATP generation caused by IFNγ, TNFα and C. rodentium infection, in an in vitro mucosal surface. Similarly, VIP treatment regimens that included the day 5–10 post infection period alleviated decreases in enzyme complexes I and IV, phosphorylation capacity, mitochondrial transmembrane potential and ATP generation as well as increased apoptosis levels during murine infection with C. rodentium. However, VIP treatment failed to alleviate colitis, although there was a tendency to decreased pathogen density in contact with the epithelium and in the spleen. Both in vivo and in vitro, NO generation increased during C. rodentium infection, which was alleviated by VIP. Thus, therapeutic VIP administration to restore the decreased levels during infection had beneficial effects on epithelial cells and their mitochondria, but not on the overall infection outcome.

Corticotrophin-releasing factor mediates vasoactive intestinal peptide-induced hypophagia and changes in plasma parameters

Vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF) are anorexigenic neuropeptides that act in the hypothalamus to regulate food intake. Intracerebroventricular (ICV) microinjection of VIP promotes increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, indicating that VIP activates hypothalamic-pituitary-adrenal axis. The aim of this study was to evaluate the interaction between VIP and CRF, by verifying the effects of ICV administration of VIP on the activity of neurons and CRF mRNA expression in paraventricular nucleus of hypothalamus (PVN). In addition, it was evaluated the effects of pretreatment with CRF type 1 receptor (CRFR1) antagonist (Antalarmin, ANT) or CRF type 2 receptor (CRFR2) antagonist (Antisauvagine-30, AS30) on VIP-induced changes on food intake and plasma parameters of male rats. Compared to Saline group, VIP increased not only the number of Fos-related antigens (FRA)-immunoreactive neurons in the PVN but also CRF mRNA levels in this nucleus. Both ANT and AS30 treatment attenuated the inhibition of food intake promoted by VIP, ANT showing a more pronounced effect. Both antagonists also attenuated VIP-induced reduction and enhancement of free fatty acids and corticosterone plasma levels, respectively, and only AS30 was able to attenuate the hyperglycemia. These results suggest that CRF is an important mediador of VIP effects on energy balance, and CRFR1 and CRFR2 are involved in these responses.

Vasoactive Intestinal Peptide Promotes Corneal Allograft Survival

Corneal transplantation is the most prevalent form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain graft transparency. CEnC density decreases significantly after corneal transplantation even in the absence of graft rejection. To date, different strategies have been used to enhance CEnC survival. The neuropeptide vasoactive intestinal peptide (VIP) improves CEnC integrity during donor cornea tissue storage and protects CEnCs against oxidative stress-induced apoptosis. However, little is known about the effect ofexogenous administration of VIP on corneal transplant outcomes. We found that VIP significantlyaccelerates endothelial wound closure and suppresses interferon-γ- and tumor necrosis factor-α-induced CEnC apoptosis invitro in a dose-dependent manner. In addition, we found that intracameral administration of VIP to mice undergoing syngeneic corneal transplantation with endothelial injury increases CEnC density and decreases graft opacity scores. Finally, using a mouse model of allogeneic corneal transplantation, we found for the first time that treatment with VIP significantly suppresses posttransplantation CEnC loss and improves corneal allograft survival.

Effects of Vasoactive Intestinal Polypeptide and Forskolin on mRNA Expression of Prolactin and Prolactin Regulatory Element-Binding Protein in the Anterior Pituitary Gland of Chicken Embryo and Laying Hens.

Vasoactive intestinal peptide (VIP) treatment induced mRNA expression of Prolactin (PRL) in the chicken anterior pituitary gland. VIP responsive element (VRE) of the PRL promoter was identified in the various bird species. However, transcription factor, which binds to VRE, has not yet been identified. Prolactin regulatory element-binding protein (PREB) gene cloned as a candidate transcription factor binds to VRE. Increases of mRNA levels of PRL and PREB during embryogenesis were identified. However, whether VIP affects levels of PRL and PREB mRNA during embryogenesis remains unknown. The effects of VIP and forskolin on mRNA expression of PRL and PREB in the embryonic anterior pituitary gland were assessed. Furthermore, administration of VIP to laying hens was conducted to examine the relationship between VIP and PREB mRNA expression. At day 14 of the embryonic growth stage, VIP treatment did not affect mRNA levels of either PRL or PREB, whereas forskolin treatment induced the increase of these mRNA levels. At day 20, both VIP and forskolin induced an increase of PRL and PREB mRNA levels. The administration of VIP significantly increased mRNA levels of PRL and PREB in the anterior pituitary gland of White Leghorn and Nagoya. These results indicate that the effects of VIP on PRL and PREB mRNA expression levels of VIP receptor may in turn affect PRL and PREB mRNA levels in the chicken anterior pituitary gland.

Vasoactive intestinal peptide administration after stroke in rats enhances neurogenesis and improves neurological function

The aim of this study was to investigate the effects of vasoactive intestinal peptide (VIP) on neurogenesis and neurological function after cerebral ischemia. Rats were intracerebroventricular administered with VIP after a 2h middle cerebral artery occlusion (MCAO) and sacrificed at 7, 14 and 28 days after MCAO. Functional outcome was studied with the modified neurological severity score. The infarct volume was evaluated via histology. Neurogenesis, angiogenesis and the protein expression of vascular endothelial growth factor (VEGF) were measured by immunohistochemistry and Western blotting analysis, respectively. The treatment with VIP significantly reduced the neurological severity score and the infarc volume, and increased the numbers of bromodeoxyuridine (BrdU) immunoreactive cells and doublecortin immunoreactive area in the subventricular zone (SVZ) at 7, 14 and 28 days after ischemia. The cerebral protein levels of VEGF and VEGF expression in the SVZ were also enhanced in VIP-treated rats at 7 days after stroke. VIP treatment obviously increased the number of BrdU positive endothelial cells in the SVZ and density of cerebral microvessels in the ischemic boundary at 28 days after ischemia. Our study suggests that in the ischemic rat brain VIP reduces brain damage and promotes neurogenesis by increasing VEGF. VIP-enhanced neurogenesis is associated with angiogenesis. These changes may contribute to improvement in functional outcome.