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PubMed2006

Pituitary adenylate cyclase-activating polypeptide regulates forebrain neural stem cells and neurogenesis in vitro and in vivo.

Recent studies suggest that adult neurogenesis can contribute significantly to recovery from brain damage. As a result, there is strong interest in the field in identifying potentially therapeutic factors capable of promoting increased expansion of endogenous neural stem cell (NSC) populations and increased neurogenesis. In the present study, we have investigated the effects of PACAP on the NSC populations of the embryonic and adult forebrain. Our results demonstrate that the PACAP receptor, PAC1-R, is expressed by both embryonic and adult NSCs. The activation of PACAP signaling in vitro enhanced NSC proliferation/survival through a protein kinase A (PKA)-independent mechanism. In contrast, PACAP promoted NSC self-renewal and neurogenesis through a mechanism dependent on PKA activation. Finally, we determined that the intracerebroventricular infusion of PACAP into the adult forebrain was sufficient to increase neurogenesis significantly in both the hippocampus and the subventricular zone. These results demonstrate PACAP is unique in that it is capable of promoting NSC proliferation/survival, self-renewal, and neurogenesis and, therefore, may be ideal for promoting the endogenous regeneration of damaged brain tissue.

Animals↗
PubMed2006

Pituitary adenylate cyclase-activating polypeptide-induced differentiation of embryonic neural stem cells into astrocytes is mediated via the beta isoform of protein kinase C.

We have found previously that pituitary adenylate cyclase-activating polypeptide (PACAP) increases the number of astrocytes generated from cultured mouse neural stem cells (NSCs) via a mechanism that is independent of the cyclic AMP/protein kinase A pathway (Ohno et al., 2005). In the present study, the signaling pathway involved in the differentiation process was further investigated. PACAP-induced differentiation was inhibited by the phospholipase C inhibitor, U73122, the protein kinase C (PKC) inhibitor, chelerythrine, and the intracellular calcium chelator, BAPTA-AM, and was mimicked by phorbol 12-myristate 13-acetate (PMA), but not by 4alpha-PMA. These results suggest that the PACAP-generated signal was mediated via the PACAP receptor, PAC1 stimulated heterotrimeric G-protein, resulting in activation of phospholipase C, followed by calcium- and phospholipid-dependent protein kinase C (cPKC). To elucidate the involvement of the different isoforms of cPKC, their gene and protein expression were examined. Embryonic NSCs expressed alpha and betaII PKC, but lacked PKCgamma. When NSCs were exposed to 2 nM PACAP, protein expression levels of the betaII isoform transiently increased two-fold before differentiation, returning to basal levels by Day 4, whereas the level of PKCalpha increased linearly up to Day 6. Overexpression of PKCbetaII with adenovirus vector synergistically enhanced differentiation in the presence of 1 nM PACAP, whereas expression of the dominant-negative mutant of PKCbetaII proved inhibitory. These results indicate that the beta isoform of PKC plays a crucial role in the PACAP-induced differentiation of mouse embryonic NSCs into astrocytes.

Adenoviridae↗
PubMedDate not supplied

Human cytomegalovirus terminase as a target for antiviral chemotherapy.

Herpesviral DNA packaging is a complex process involving binding and cleavage of DNA containing the specific DNA-packaging motifs, pac1 and pac2, and packaging of the resulting unit-length genomes into preformed procapsids. This process is believed to be mediated by two packaging proteins, the terminase subunits. In the case of human cytomegalovirus the terminase consists of the proteins pUL56 and pUL89. While pUL56 (i) mediates the specific binding to pac sequences on the concatamers, (ii) provides energy for the translocation of the DNA to the procapsids and (iii) associates itself with the capsid for enabling the entry of the DNA into the procapsid, pUL89 is mainly required to effect DNA cleavage. Based on the limited efficacy of the current drugs ganciclovir, cidofovir and foscarnet, new antiviral therapeutics appear to be in demand. Inhibitors targeting pUL56 and/or pUL89 may offer an attractive alternative since mammalian cell DNA replication does not involve cleavage of concatameric DNA. Drugs targeted to terminase-like proteins should therefore be safe and highly selective.

Antiviral Agents↗
PubMed2002

The mei3 region of the Schizosaccharomyces pombe genome.

Expression of the mei3 gene is sufficient to induce meiosis in the fission yeast Schizosaccharomyces pombe. The mei3 gene is located 0.64 Mb from the telomere of the left arm of Sz. pombe chromosome II. We have sequenced and analysed 107 kb of DNA from the mei3 genomic region. The sequence includes 14 known genes (bag1-B, csh3, dps1, gpt1, mei3, mfm3, pac1, prp31, rpl38-1, rpn3, rti1, spa1, spm1 and ubc4) and 26 other open reading frames (ORFs) longer than 100 codons: a density of one protein-coding gene per 2.7 kb. Twenty-one of the 40 ORFs (53%) have introns. In addition there is one lone Tf1 transposon long terminal repeat (LTR), tRNA(Trp) and tRNA(Ser) genes and a 5S rRNA gene. 14 of the novel ORFs show sequence similarities which suggest functions of their products, including a coatomer alpha-subunit, a catechol O-methyltransferase, protein kinase, asparagine synthetase, zinc metalloprotease, acetyltransferase, phosphatidylinositol 4-kinase, inositol polyphosphate phosphatase, GTPase-activating protein, permease, pre-mRNA splicing factor, 20S proteasome component and a thioredoxin-like protein. One predicted protein has similarity to the human Cockayne syndrome protein CSA and one with human GTPase XPA binding protein XAB1. Three ORFs are likely to code for proteins because they have sequence similarity with hypothetical proteins, three encode predicted coiled-coil proteins and four are sequence orphans.

Cosmids↗
PubMed1995

Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11.

The mitogen-induced gene, DUSP2, encodes a nuclear protein, PAC1, that acts as a dual-specific protein phosphatase with stringent substrate specificity for MAP kinase. MAP kinase phosphorylation and consequent enzymatic activation is a central and often obligatory component in signal transduction initiated by growth factor stimulation or resulting from various types of oncogenic transformation. DUSP2 downregulates intracellular signal transduction through the dephosphorylation/inactivation of MAP kinases. To facilitate assessment of the possible role of DUSP2 in growth processes, the genomic structure and chromosomal location of the gene have been determined. DUSP2 has been localized to the pericentromeric region of human chromosome 2 (2p11.2-q11) by analysis of somatic cell hybrids, in situ chromosome hybridization, and genetic linkage analysis using a single-strand conformational polymorphism (SSCP) that has been identified in the 3' UTR of the gene. No consistent translocations or deletions at this chromosomal site have been reported in hematopoietic neoplasias or other tumors.

Base Sequence↗
PubMed2002

Pituitary adenylate cyclase-activating polypeptide induces astrocyte differentiation of precursor cells from developing cerebral cortex.

Ciliary neurotrophic factor and bone morphogenetic proteins induce astrocytogenesis in the developing rat brain by stimulating STAT- and Smad-dependent signaling, respectively. We previously found that stimulation of the cAMP-dependent signaling pathway also triggers differentiation of cerebral cortical precursor cells into astrocytes, providing an additional mechanism to promote astrocyte differentiation. In this study, we show that pituitary adenylate cyclase-activating polypeptide (PACAP), but not the related vasoactive intestinal peptide, induces astrocyte differentiation of cortical precursor cells, even after a transient exposure. Cortical precursors were found to express predominantly the short isoform of the PACAP-specific PAC1 receptor, which couples to adenylate cyclase. Consistent with this notion, we determined that exposure of cortical precursors to PACAP resulted in a dose-dependent increase in cAMP production. Pretreatment of cells with the cAMP antagonist Rp-cAMPS prevented astrocyte differentiation. Thus, PACAP acts as an extracellular signal to trigger cortical precursor cell differentiation into astrocytes via stimulation of intracellular cAMP production.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Construction of shuttle vectors for cloning in Escherichia coli and Acetobacter pasteurianus.

New cloning vectors were prepared with the aid of a large plasmid isolated from Acetobacter pasteurianus and from plasmids pBR322 and pUC4-KAPA. Of the prepared cloning vectors, pACK5 contains a gene coding for kanamycin resistance, pACT7 and pACT71 contain a gene coding for tetracycline resistance and vector pACG3 with a gene coding for both kanamycin and tetracycline resistance. The vectors prepared only contained the beginning of replication from the pAC1 plasmid and possessed the ability to replicate within E. coli and A. pasteurianus. The vectors are highly stable in both strains and during the 5-d cultivation under nonselective conditions are not eliminated.

Acetobacter↗
PubMed2000

The cadmium-resistant gene, CAD2, which is a mutated putative copper-transporter gene (PCA1), controls the intracellular cadmium-level in the yeast S. cerevisiae.

Yeast cells carrying the CAD2 gene exhibit a resistance to cadmium. We cloned this gene and demonstrated that it was a mutated form derived from the gene of a putative copper-transporting ATPase (PCA1). By site-directed mutagenesis, it appeared that the mutation conferring cadmium resistance was a R970G-substitution in the C-terminal region of Pca1 protein. The intracellular cadmium level of cells carrying CAD2 was lower than that of cells carrying either PAC1 or delta cad2. Furthermore, cells with overexpression of CAD2 showed a much lower intracellular cadmium level than that of cells with a single-copy CAD2. From these results, we conclude that the Cad2 protein controls the intracellular cadmium level through an enhanced cadmium efflux system.

Adenosine Triphosphatases↗
PubMed2004

Target areas innervated by PACAP-immunoreactive retinal ganglion cells.

The retinohypothalamic tract (RHT) originates from a subset of retinal ganglion cells (RGCs). The cells of the RHT co-store the neurotransmitters PACAP and glutamate, which in a complex interplay mediate light information to the circadian clock located in the suprachiasmatic nuclei (SCN). These ganglion cells are intrinsically photosensitive probably due to expression of melanopsin, a putative photoreceptor involved in light entrainment. In the present study we examined PACAP-containing retinal projections to the brain using intravitreal injection of the anterograde tracer cholera toxin subunit B (ChB) and double immunostaining for PACAP and ChB. Our results show that the PACAP-containing nerve fibres not only constituted the major projections to the SCN and the intergeniculate leaflet of the thalamus but also had a large terminal field in the olivary pretectal nucleus. The contralateral projection dominated except for the SCN, which showed bilateral innervation. PACAP-containing retinal fibres were also found in the ventrolateral preoptic nucleus, the anterior and lateral hypothalamic area, the subparaventricular zone, the ventral part of the lateral geniculate nucleus and the nucleus of the optic tract. Retinal projections not previously described in the rat also contained PACAP. These new projections were found in the lateral posterior nucleus, the posterior limitans nucleus, the dorsal part of the anterior pretectal nucleus and the posterior and medial pretectal nuclei. Only a few PACAP-containing retinal fibres were found in the superior colliculus. Areas innervated by PACAP-immunoreactive fibres also expressed the PACAP-specific PAC1 receptor as shown by in situ hybridization histochemistry. The findings suggest that PACAP plays a role as neurotransmitter in non-imaging photoperception to target areas in the brain regulating circadian timing, masking, regulation of sleep-wake cycle and pupillary reflex.

Animals↗
PubMed1988

The cleavage recognition signal is contained within sequences surrounding an a-a junction in herpes simplex virus DNA.

Herpesvirus genome maturation involves site-specific cleavage of viral DNA concatemers and encapsidation of unit-length molecules, processes that are apparently coupled. Here, applying a transfection-infection approach, we have investigated the arrangement of the DNA sequence elements involved in cleavage and shown that specific cleavage occurs independently of DNA replication. We show that the cis-acting signal for cleavage is located within a 179-bp fragment from across an a-a junction formed as part of the genome maturation process of herpes simplex virus 1. Plasmids carrying the 179-bp fragment are cleaved at the appropriate site even though they are unable to replicate in HSV-infected cells. When linked to an origin, the same 179-bp a-a fragment will replicate and package into progeny virus as a defective genome. Two highly conserved homologies, pac1 and pac2, that have been observed in all herpesviruses examined, including cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, and herpes simplex virus 2 as well as the herpes simplex virus 1 genome, are contained within the 179-bp fragment. This suggests that a common mechanism is utilized for genome maturation in the herpesvirus group.

Animals↗
PubMed1996

Calbindin-D28K-immunoreactive cells and fibres in the human amygdaloid complex.

The distribution of calbindin-D28k-immunoreactive cells and fibres in five human amygdalae was analysed from sections that had been stained immunohistochemically with a monoclonal antibody raised against calbindin-D28k. The highest density of calbindin-D28k-positive neurons were found in the anterior cortical, medial, posterior cortical and accessory basal nuclei, in the parvicellular division of the basal nucleus and in the amygdalohippocampal area. The lowest densities of immunopositive neurons were found in the paralaminar nucleus, in the periamygdaloid cortex (PAC1 and PACo) and in some of the intercalated nuclei. The deep nuclei (lateral, basal and accessory basal nuclei) contained a high density of calbindin-D28k-immunoreactive fibres and terminals. The cortical nuclei and the central nucleus were characterized by intense neuropil labelling. Morphologically, a large majority of the calbindin-D28k-immunoreactive neurons were aspiny or sparsely spiny and resembled inhibitory local circuit neurons. A small population of lightly-stained, pyramidal-shaped neurons was also observed. In most of the amygdaloid nuclei, calbindin-D28k-immunoreactive fibres travelled close to each other and formed bundles, which suggests that some of the immunostained neurons were double-bouquet cells. In the paralaminar nucleus, the calbindin-D28k-immunoreactive axons formed tortuous plexus (100-200 microns in diameter) that surrounded several unstained somata. This study provides baseline information on the morphology and distribution of calcium-binding protein-containing inhibitory cells and fibres immunoreactive for calbindin-D28k in the human amygdaloid complex. This information can be used in future studies on the pathogenesis of diseases known to damage the amygdala, such as Alzheimer's disease and temporal lobe epilepsy.

Adult↗
PubMed2005

Long-term hormone replacement therapy does not cause increased platelet activation.

BACKGROUND: Observational studies have shown apparently lower ischemic coronary disease risk in postmenopausal women receiving hormone replacement therapy (HRT). However, several recent studies have shown an increase in ischemic cardiac events when HRT is initiated in postmenopausal women with known coronary artery disease. It is postulated that estrogen may result in increased platelet aggregation. METHODS: We evaluated platelet activation, as measured by flow cytometric analysis using P selectin and PAC1 as activation markers, and aggregation, as measured by standard platelet aggregation using platelet-rich plasma, in 27 postmenopausal women (17 HRT, 10 placebo) who were participants in 2 placebo-controlled randomized angiographic trials evaluating the effect of HRT on coronary atherosclerosis or saphenous vein graft disease. All women had received HRT or placebo for >2 years and were on aspirin therapy. The estrogen component was either conjugated equine estrogen or 17beta-estradiol. RESULTS: Patients on HRT and those on placebo had comparable degrees of platelet aggregation when measured using various doses of agonists (adenosine diphosphate and epinephrine). There were no significant differences in levels of platelet activation measured by flow cytometry. CONCLUSION: We conclude that long-term HRT does not appear to cause increased platelet activation and aggregation in women with coronary artery disease. There may be increased platelet activation in the early period after HRT initiation; however, this was not assessed in this study.

Aged↗
PubMed2006

PACAP induces neurite outgrowth in cultured trigeminal ganglion cells and recovery of corneal sensitivity after flap surgery in rabbits.

PURPOSE: To evaluate the ability of pituitary adenylate cyclase-activating polypeptide (PACAP) to induce growth of neuronal processes in cultured trigeminal ganglion cells, and to accelerate neurite outgrowth and recovery of corneal sensitivity after creation of a corneal flap in a rabbit model of laser-assisted in situ keratomileusis (LASIK) surgery. DESIGN: Animal study. METHODS: The cDNA of rabbit PACAP was sequenced, and the expression of PACAP receptors in the trigeminal ganglia from rabbits was quantified by quantitative real-time polymerase chain reaction. Trigeminal ganglion cells were isolated from rabbits and cultured for 48 hours with or without PACAP27 (bioactive N-terminal peptide from PACAP). Cells were stained with antibody against neurofilaments, and neurite outgrowth was quantified by cell counting. In the rabbit LASIK model, a corneal flap with a planned thickness of 130 microm and 8.5 mm diameter was created with a microkeratome. The rabbits then received eyedrops containing PACAP27 four times a day for eight weeks, and corneal sensitivity was measured. Neurite outgrowth was assessed by staining histologic sections of the flap area for cholinesterase. RESULTS: The deduced amino acid sequence of PACAP in rabbit was identical to that of human. PACAP receptor, PAC1, was highly expressed in trigeminal ganglia from newborn and adult rabbits. PACAP27 at 1 microM induced growth of neuronal processes in cultured primary trigeminal ganglion cells. In the LASIK model, extensions of neuronal processes from amputated nerve trunks in cornea were observed after administration of eyedrops containing 1 or 10 microM PACAP27. The 10 microM PACAP27 treatment also greatly accelerated recovery of corneal sensitivity. CONCLUSIONS: PACAP may be a candidate drug for ameliorating dry eye after LASIK surgery.

Animals↗
PubMed2004

Multiple signal pathways coupling VIP and PACAP receptors to calcium channels in hamster submandibular ganglion neurons.

The Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two novel neuropeptides which produce particular biological effects caused by interaction with G-protein-coupled receptors. We have shown in a previous study where VIP and PACAP 38 inhibit voltage-dependent calcium channel (VDCC) currents (ICa) via G-proteins in hamster submandibular ganglion (SMG) neurons. In this study, we attempt to further characterize the signal transduction pathways of VIP-and PACAP 38-induced modulation of ICa. Application of 1 microM VIP and PACAP 38 inhibited ICa by 33.0 +/- 3.1% and 36.8 +/- 2.6%, respectively (mean +/- S.E.M., n = 8). Application of strong voltage prepulse attenuated PACAP 38-induced inhibition of ICa. Pretreatment of cAMP dependent protein kinase (PKA) activator attenuated VIP-induced inhibition, but not the PACAP 38-induced inhibition. Intracellular dialysis of the PKA inhibitor attenuated the VIP-induced inhibition, but not the PACAP 38-induced inhibition. Pretreatment of protein kinase C (PKC) activator and inhibitor attenuated VIP-induced inhibition, but not the PACAP 38-induced inhibition. Pretreatment of cholera toxin (CTX) attenuated PACAP 38-induced inhibition of ICa. These findings indicate that there are multiple signaling pathways in VIP and PACAP 38-induced inhibitions of ICa: one pathway would be the VPAC1/VPAC2 receptors-induced inhibition involving both the PKA and PKC, and another one concerns the PAC1 receptor-induced inhibition via Gs-protein betagamma subunits. The VIP-and PACAP 38-induced facilitation of ICa can be observed in the SMG neurons in addition to inhibiting of ICa.

Animals↗
PubMed2005

Expression of functional receptors and transmitter enzymes in cultured Muller cells.

Glia represents the most numerous group of nervous system cells and CNS development and function depend on glial cells. We developed a purified Muller glia culture to investigate the expression of several neurotransmitter markers on these cells, such as dopaminergic, cholinergic, GABAergic and peptidergic receptors or enzymes, based on functional assays measuring second messenger levels or Western blot for specific proteins. Purified Muller cell culture was obtained from 8-day-old (E8) embryonic chick. Glial cells cultured for 15 days (E8C15) expressed D1A and D1B receptors mRNAs, but not D1D, as detected by RT-PCR. The binding of [3H]-SCH 23390 revealed an amount of expressed receptors around 40 fmol/mg protein. Dopamine (100 microM), PACAP (50 nM) and forskolin (10 microM) induced a 50-, 30- and 40-fold cAMP accumulation on glial cells, respectively, but not ip3 production. The dopamine-promoted cAMP accumulation was blocked by 2 microM SCH 23390. Carbachol stimulated a 3-fold ip3 accumulation. Western blot analysis also revealed the expression of tyrosine hydroxylase, L-dopa decarboxylase, PAC1 receptor, GAD67 and beta2-nicotinic receptor subunit by these cells. These results indicate that several components of neurotransmitter signaling and metabolism are found in cultured Muller cells.

Animals↗
PubMed2005

The neuropeptide pituitary adenylate cyclase activating protein is a physiological activator of human monocytes.

Pituitary adenylate cyclase activating protein (PACAP) and its structurally related vasointestinal peptide (VIP) bind to three G-protein-coupled receptors named VPAC1 and VPAC2 for VIP/PACAP receptors and PAC1 for PACAP preferred receptors. We report that in freshly isolated human monocytes PACAP acts as a pro-inflammatory molecule. By RT-PCR, VPAC1 mRNA was the only receptor found to be expressed; VPAC1 protein was detected by Western blotting and visualized by immunohistochemistry. Signaling pathways activated by PACAP include the extracellular regulated kinase (ERK), the stress-activated MAPK p38, the focal adhesion kinase, Pyk2 and its associated cytoskeleton protein paxillin and the phosphatidylinositol 3-kinase (PI-3K). PACAP induces a transient peak in cytoplasmic calcium associated with an increase in reactive oxygen species production and upregulation in membrane expression of the integrin CD11b as well as the complement receptor 1. Control of the different pathways and functions stimulated by PACAP were evaluated using Phospholipase C (PLC), PI-3K, ERK and p38 MAPK inhibitors and led to the conclusion that PLC and to a lesser degree PI-3K activation are upstream events occurring in VPAC1 mediated PACAP stimulation of monocytes and are in contrast to ERK and p38 mandatory for the initiation of other cellular events associated with monocytes activation.

CD11b Antigen↗
PubMed2005

Pituitary adenylate cyclase-activating polypeptide (PACAP) can act as determinant of the tyrosine hydroxylase phenotype of dopaminergic cells during retina development.

In the chick retina, dopaminergic cells are generated between embryonic days 3 and 7 (E3/E7). However, the expression of tyrosine hydroxylase (TH), the first enzyme in the catecholamine synthetic pathway, is only detected after E11/E12. During the interval comprising E7 to E12, signals conveyed by cAMP are important to determine the TH phenotype. The present study shows that pituitary adenylyl cyclase-activating polypeptide (PACAP), via cAMP, is a major endogenous component in defining the TH phenotype of retina dopaminergic cells during development. PACAP type 1 receptor and its mRNA were detected in retinas since E6. PACAP was also immunodetected in cells localized in the inner nuclear layer of retinas since E8. This peptide promoted greater than 10-fold increase in cAMP accumulation of retinas obtained from embryos since E8, an effect that was blocked by PACAP6-38 (PAC1 receptor antagonist). In cultured retina cells from E8 and E9, maintained for 6 days in vitro with 10 nM PACAP (for 5 days), the number of dopaminergic cells expressing tyrosine hydroxylase increased 2.4-fold. The cAMP analog, 8-Br-cAMP and 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor) also increased the number of tyrosine hydroxylase-positive cells by 4- to 6-fold. IBMX plus PACAP treatment resulted in 17-fold increase in the number of cells positive for tyrosine hydroxylase. Under this condition the amount of tyrosine hydroxylase expression, as detected by western blot analysis, was also increased. The protein kinase-A inhibitor, rp-cAMPS, significantly reduced the effect of PACAP. Our data show that this peptide is an important factor influencing the definition of the tyrosine hydroxylase phenotype of retina dopaminergic cells within a narrow window of development.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Novel concepts of neuropeptide-based drug therapy: vasoactive intestinal polypeptide and its receptors.

Chronic inflammatory airway diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD) are major contributors to the global burden of disease. Although inflammatory cells play the central role in the pathogenesis of the diseases, recent observations indicate that also resident respiratory cells represent important targets for pulmonary drug development. Especially targeting airway neuromediators offers a possible mechanism by which respiratory diseases may be treated in the future. Among numerous peptide mediators such as tachykinins, calcitonin gene-related peptide, neurotrophins or opioids, vasoactive intestinal polypeptide (VIP) is one of the most abundant molecules found in the respiratory tract. In human airways, it influences many respiratory functions via the receptors VPAC1, VPAC2 and PAC1. VIP-expressing nerve fibers are present in the tracheobronchial smooth muscle layer, submucosal glands and in the walls of pulmonary and bronchial arteries and veins. Next to its strong bronchodilator effects, VIP potently relaxes pulmonary vessels, and plays a pivotal role in the mediation of immune mechanisms. A therapy utilizing the respiratory effects of VIP would offer potential benefits in the treatment of obstructive and inflammatory diseases and long acting VIP-based synthetic non-peptide compounds may represent a novel target for drug development.

Animals↗