Vasoactive Intestinal Peptide In Brain Research Articles

The Changes of Brain-gut SP and VIP Levels in the Rats with Functional Dyspepsia and the Intervention of Pingwei Capsule

AIM : To explore the levels of substance P (SP) and vasoactive intestinal peptide (VIP) in the brain–gut axis of rats with functional dyspepsia (FD) and the intervention of Pingwei capsule. METHODS : FD model rats were established by stimulating semi-starved rats via tail damping, provocation, and forced exercise fatigue. Then, the rats were treated with domperidone and Traditional Chinese Medicine, Pingwei capsule, for 3 weeks.The rates of the rat intestinal propulsion and gastric emptying were observed and the levels of SP and VIP were detected in serum by the enzyme-linked immunosorbent assay（ELISA）, and in antrum, duodenum and hypothalamus by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS : FD rats were less active, nervous, anxious and dysphoria, loose stool was observed, the bodyweight and food intake decreased obviously, and their intestinal propulsion and gastric emptying slowed down markedly. Molecular biological experiments showed that the mRNA and protein expressions of SP and VIP increased significantly in antrum, duodenum, and hypothalamus of FD rats, but the SP level markedly decreased in serum compared with that in the control group. Domperidone and Pingwei capsule could improve the behavioral performances and intestinal propulsion and gastric emptying , and decrease the expressions of SP and VIP in brain–gut axis of FD rats. CONCLUSION : There appear abnormal behaviors, dysmotility gastrointestinal disorders and parasecretion of brain-gut SP and VIP in FD rats. Similarity to domperidone, Pingwei capsule has a degree of therapeutic effects in rats with FD.

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.

Central administration of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide differentially regulates energy metabolism in chicks

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are the members of the glucagon superfamily and bind to common receptors while PACAP also acts via the PACAP-specific receptor, PAC1. The aim of the present study was to investigate whether intracerebroventricular (i.c.v.) injection of VIP and PACAP acts in a similar or different manner to affect body temperature and energy expenditure in the domestic chick. I.c.v. injection of VIP did not significantly affect rectal temperature, but decreased energy expenditure. On the other hand, i.c.v. injection of PACAP significantly increased both body temperature and energy expenditure. These specific actions of PACAP could be explained by an interaction with the PAC1 receptor, since they were partly, but not entirely, attenuated by PACAP (6-38), a PAC1 receptor antagonist. In addition, it was observed that central administration of both VIP and PACAP induced a reduction in respiratory quotient and increased plasma non-esterified fatty acid concentrations. This suggests that both peptides act centrally to regulate a catabolic response. In summary, brain VIP and PACAP both appear to exert generally catabolic effects on energy metabolism in the chick, but their influence on body temperature and glucose metabolism differs and their central effects do not appear to be mediated by the same receptors.

Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP‐ and PACAP‐deficient mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are closely related neurotrophic peptides of the secretin/glucagon family. The two peptides are derived from a common ancestral gene and share many functional attributes in neuronal development/regeneration which occur not only from overlapping receptor subtype signaling but also through common mechanisms regulating their expression. Although PACAP or VIP null mice have been generated for study, it is unclear whether the expression of the complementary peptide or their receptor systems are altered in a compensatory manner during nervous system development. By radioimmunoassay and quantitative PCR measurements, we first show that PACAP and VIP have very different temporal patterns of expression in developing postnatal mouse brain. In wild-type animals, PACAP transcript and peptide levels increased rapidly 2- and 5-fold, respectively, within 1 week of age. These levels at 1 week of age were maintained through adulthood. VIP transcript and peptide levels, by contrast, increased 25- and 50-fold, respectively, over a later time course. In parallel studies of development, there were no apparent compensatory increases in brain VIP expression in the PACAP knockout animals, PACAP expression in the VIP-deficient animals, or receptor mRNA levels in either genotype. To the contrary, there was evidence for developmental delays in the expression of peptide and receptor transcripts in the knockout animals. A series of behavioral and neurological tests demonstrated differences between the knockout genotypes, revealing some functional distinctions between the two genes. These results suggest that the PACAP and VIP have evolved to possess distinct biological activities and intimate that the respective knockout phenotypes represent deficits unmitigated by the actions of the complementary related peptide.

Glucose-targeted niosomes deliver vasoactive intestinal peptide (VIP) to the brain

The aim of this study was to evaluate glucose-bearing niosomes as a brain targeted delivery system for the vasoactive intestinal peptide (VIP). To this end, VIP/ 125I-VIP-loaded glucose-bearing niosomes were intravenously injected to mice. Brain uptake was determined by measuring the radioactivity of 125I-labeled VIP using γ-counting, after intravenous administration of VIP in solution or encapsulated in glucose-bearing niosomes or in control niosomes. VIP integrity was assessed by reversed-phase HPLC analysis of brain extracts. Distribution of 125I-VIP derived radioactivity was examined from serial brain slices. HPLC analysis confirmed the presence of intact VIP in brain after administration of VIP-loaded niosomes, but not after administration of VIP solution. Encapsulation within glucose-bearing niosomes mainly allowed a significantly higher VIP brain uptake compared to control niosomes (up to 86%, 5 min after treatment). Brain distribution of intact VIP after injection of glucose-bearing niosomes, indicated that radioactivity was preferentially located in the posterior and the anterior parts of the brain, whereas it was homogeneously distributed in the whole brain after the administration of control vesicles. In conclusion, this novel vesicular formulation of VIP delivers intact VIP to particular brain regions in mice. Glucose-bearing vesicles might be therefore a novel tool to deliver drugs across the blood–brain barrier (BBB).

Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats

The aim of this work was to study in rats the nasal route for the brain delivery of the vasoactive intestinal peptide (VIP) neuropeptide. After evaluating VIP stability in solutions obtained from nasal washes, the effect of formulation parameters (pH 4–9, 0–1% (w/v) lauroylcarnitine (LC), hypo- or isoosmolality) on the brain uptake of intranasally administered VIP (10 −8 M)/ 125 I -VIP (300,000 cpm/ml) was studied, using an in situ perfusion technique. Brain radioactivity distribution was assessed by quantitative autoradiographic analysis. Results were compared to intravenously administered VIP. With a hypotonic formulation at pH 4 containing 0.1% LC and 1% bovine serum albumin, VIP stability was satisfactory and loss by adsorption was minimal. Using this formulation, around 0.11% of initial radioactivity was found in the brain after 30 min perfusion and was located in the olfactory bulbs, the midbrain and the cerebellum. HPLC analysis of brain and blood extracts demonstrated the presence of intact VIP in brain and its complete degradation in the blood compartment. By intravenous administration, no intact VIP was found either in brain or in blood. In conclusion, intact VIP could be delivered successfully to the brain using the intranasal route for administration.

Learning and sexual deficiencies in transgenic mice carrying a chimeric vasoactive intestinal peptide gene.

The molecular mechanisms responsible for behavior are largely unknown. A state of the art model, paving the path from genes to behavior, is offered by transgenic animals. Candidate molecules are classic neuropeptides, such as vasoactive intestinal peptide (VIP). Transgenic mice harboring a chimeric VIP gene driven by the polyoma promoter were produced. Behavioral studies revealed learning impairment and prolonged retardation in memory acquisition in the genetically altered animals. Furthermore, reduced performance was observed when the male transgenic mice were tested for sexual activity in the presence of receptive females. Surprisingly, radioimmunoassays showed an approx 20% decrease in the VIP content of the transgenic mice brains. To directly assess genetically reduced VIP content as a cause for learning impairment, transgenic mice carrying diphtheria toxin-encoding sequences driven by the rat VIP promoter were created. These animals had reduced brain VIP and exhibited deficiencies in learning abilities, strongly supporting an important neurobiological function for VIP in vivo.

Synthesis and Secretion of Vasoactive Intestinal Peptide by Rat Fetal Cerebral Cortical and Hypothalamic Cells in Culture*

To establish the neurosecretory activity of brain vasoactive intestinal peptide (VIP)ergic neurons and to characterize the molecular forms of secretion of these cells, fetal cerebrocortical and hypothalamic cells were grown in primary cultures for periods up to 4 weeks, their regulation by depolarization and calcium and sodium channel active agents was studied, and the chromatographic patterns of cell and medium VIP were determined. Mechanically dispersed cultured fetal telencephalic and diencephalic cells showed a progressive increase in immunoreactive VIP in both cells and media, reaching maximum values between 110-290 pg/mg protein.culture plate on days 15-20. Immunoreactive VIP in both cells and media corresponded almost exclusively to VIP-28 on exclusion chromatography and HPLC, and was identical to the form extracted from whole fetal brain. This indicates that both the stored and secreted forms of VIP are the mature 28-amino acid-containing peptide. To determine the influence of membrane depolarization on VIP release, the potassium concentration in the medium was increased to 30 and 56 mM, inducing a marked increase in medium VIP concentrations. The effects of K+ were dependent on Ca2+ transport, since release was blocked by the addition of verapamil, a Ca2+ channel blocker (20 microM). VIP release was stimulated by Na+ channel activation using the drug veratridine (100 microM); this effect was blocked by tetrodoxin. The influence of GH-releasing factor (GRF) on VIP release was studied by adding GRF (10(-9)-10(-7) M), alone or in the presence of anti-rGRF immunoglobulins (antirat GRF immunoglobulin G) to the incubation medium. Rat GRF stimulated VIP release and the simultaneous addition of antirat GRF immunoglobulin G blocked this effect. These findings confirm that VIP regulation by brain cells corresponds to the well defined patterns of membrane activation observed in other neuronal systems. They, furthermore, demonstrate that VIP release is under GRF influence.

Cholecystokinin and vasoactive intestinal peptide in brain and gut of the hypothyroid neonatal rat.

The rat has been a useful model for studying neuronal and metabolic abnormalities associated with fetal and neonatal hypothyroidism produced by treatment of the mother with antithyroid medication. The neonates are then maintained on this medication via the mother's milk until weaning and subsequently through the drinking water. We have determined the concentrations and contents of immunoreactive cholecystokinin (CCK) and vasoactive intestinal peptide (VIP) in the brain and gut of groups of rats exposed to antithyroid medication from day 16 of gestation. The neonates were sacrificed at 2, 4, 8 and 12 weeks. Compared to controls total body weight was greatly reduced in methimazole (MMI)-treated rats, all of whom were hypothyroid as evidenced by marked reduction of T4 and increase in TSH. Discontinuation of MMI-treatment after 8 weeks resulted in normalization of T4 and TSH and a dramatic weight gain but at 12 weeks the brain weights of the MMI-treated rats were reduced by 17% and the brain contents, of CCK and VIP were similarly reduced. Tissue weights throughout the gut were 1/2 or less than those of control rats. Since VIP but not CCK concentrations in the gut of MMI-treated animals were significantly greater than those of the control animals, it would appear that there was greater loss of mucosal tissue with its endocrine content of CCK than of neuronal tissue with its greater content of VIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional distribution of vasoactive intestinal peptide in brains from normal and parkinsonian subjects

The distribution of vasoactive intestinal peptide (VIP) in the post-mortem human brain was determined by radioimmunoassay using a highly specific antiserum. The detection limit of the assay was 4 fmol/tube. The highest concentrations of VIP were found in the cerebral cortex, amygdala, hypothalamus and hippocampus. The lowest levels of peptide were detected in basal ganglia including caudate nucleus, external pallidum, putamen and substantia nigra. All dilution curves of acetic acid extracts from different brain areas were strictly parallel to the standard curve. Sephadex G-50 gel filtration of frontal cortex extract showed that VIP-like immunoreactivity (VIP-LI) eluted as a major peak comigrating with synthetic hVIP. Detailed mapping of VIP in the human cerebral cortex showed the existence of a rostro-caudal gradient of VIP-LI concentrations: the frontal cortex exhibited the highest VIP levels, the parietal and temporal cortex contained medium values and the occipital cortex contained the lowest VIP levels. The concentrations of VIP-LI were compared in various regions of the human brain from normal and parkinsonian subjects. No significant changes in VIP-LI levels occurred in the brains of patients dying with Parkinson's disease. No difference in VIP levels could be found either when the parkinsonian group was subdivided into nondemented and demented patients. These data indicate that VIP-containing neurons are not affected in parkinsonian patients. Our results also suggest that VIP neuronal systems are not involved in the course of dementing process in Parkinson's disease.

Brain vasoactive intestinal peptide: a potent stimulant of gastric acid secretion

Vasoactive intestinal peptide (VIP) belongs to a rapidly expanding family of cerebrogastrointestinal oligopeptides. This report describes a potent dose-, time- and vagus-dependent stimulation of gastric acid secretion by brain VIP. Physiologic evidence favoring a role of VIP on acid secretion was provided by the finding that immunoneutraization of endogenous brain VIP produced a significant decrease of acid secretion. These and other data contained herein suggest that the mechanism by which central VIP stimulates acid secretion appears to involve peripheral cholinergic pathways.

STARVATION IN THE RAT: EFFECT ON PEPTIDES OF THE GUT AND BRAIN

The effects of starvation on the tissue concentrations of some peptides common to the gastrointestinal tract and the central nervous system have been examined. Groups of 6 rats were either fed ad libitum or starved for up to 4 days and killed by decapitation. Antrum, fundus, duodenum, jejunum, ileum, colon, pancreas and brain were dissected, weighed and then frozen on dry ice. The tissues were extracted sequentially in boiling water and 3% acetic acid, centrifuged and the supernatants radioimmunoassayed for gastrin, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP) and somatostatin. Each peptide was not assayed in each tissue. Starvation had no effect on the concentrations of peptides measured in the fundus (somatostatin and VIP), ileum (somatostatin, GIP, VIP) and colon (somatostatin, GIP, VIP). VIP concentration was increased in the jejunum and GIP was increased in both the duodenum and jejunum. Antral gastrin was the only peptide in the gastrointestinal tract to be decreased by food deprivation. Somatostatin concentration was approximately doubled in the antrum, duodenum, jejunum and pancreas. Brain VIP was unchanged. Brain somatostatin and CCK were significantly reduced by starvation. We conclude that starvation results in organ-specific and hormone-specific alterations in tissue concentrations of peptides of the gastrointestinal tract and the central nervous system.