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Biomedical subjects

I Gozes

Publications and source records attributed to I Gozes.

At least 55 records · Page 3Linked to original sources
PubMed1999

Vasoactive intestinal peptide. Link between electrical activity and glia-mediated neurotrophism.

Vasoactive intestinal peptide has neurotrophic and neuroprotective properties that influence the survival of activity-dependent neurons in the central nervous system. Investigations of the mechanism of this neurotrophic peptide indicated that these actions are contingent on interactions with astroglia. The complex mixture of neurotrophic mediators released from astroglia include cytokines, a protease inhibitor, and activity-dependent neurotrophic factor, a protein with apparent structural similarities to hsp60. Investigations of ADNF resulted in the discovery of active peptides of extraordinary potency and broad neuroprotective properties. These studies indicate that a nine-amino acid core peptide of ADNF had significantly greater neuroprotective properties in comparison to the parent growth factor and these advantages identify ADNF-9 as an attractive lead compound for drug development.

Animals↗
PubMed1999

Vasoactive intestinal peptide regulates embryonic growth through the action of activity-dependent neurotrophic factor.

Activity-dependent neurotrophic factor is a potent, neuroprotective protein released from astroglia by VIP and accounts in part for the neuroprotective properties of this neuropeptide. The growth-regulatory actions of VIP during embryogenesis may also occur indirectly through the release of activity-dependent neurotrophic factor. Whole cultured day-9 mouse embryos treated with activity-dependent neurotrophic factor (10(-13) M) for 4 hr grew 3.1 somites, compared with 1.6 somites in control embryos. Treated embryos appeared morphologically normal and exhibited significant increases in cross-sectional area, protein, and DNA content and bromodeoxyuridine incorporation. Anti-activity-dependent neurotrophic factor significantly inhibited growth. Co-treatment of embryos with anti-activity-dependent neurotrophic factor inhibited VIP-stimulated growth; however, anti-VIP did not inhibit activity-dependent neurotrophic factor-induced growth. These data indicate that an activity-dependent neurotrophic factor-like substance is an endogenous embryonic growth factor and that VIP-regulated growth occurs, at least in part, through activity-dependent neurotrophic factor.

Animals↗
PubMed1999

A novel signaling molecule for neuropeptide action: activity-dependent neuroprotective protein.

The complete coding sequence of a novel protein (828 amino acids, pI 5.99), a potential new mediator of vasoactive intestinal peptide (VIP) activity was recently revealed. The expression of this molecule, activity-dependent neuroprotective protein (ADNP), was augmented in the presence of VIP, in cerebral cortical astrocytes. The mRNA transcripts encoding ADNP were enriched in the mouse hippocampus and cerebellum. The protein deduced sequence contained the following: (1) a unique peptide, NAPVSIPQ, sharing structural and immunological homologies with the previously reported, activity-dependent neurotrophic factor (ADNF) and exhibiting neuroprotection in vitro and in vivo; (2) a glutaredoxin active site; and (3) a classical zinc binding domain. Comparative studies suggested that the peptide, NAPVSIPQ (NAP), was more efficacious than peptides derived from ADNF. ADNP, a potential mediator of VIP-associated neuronal survival, and the new peptide, a potential lead compound for drug design, are discussed below.

Amino Acid Sequence↗
PubMed1999

Neuroprotection of the developing brain by systemic administration of vasoactive intestinal peptide derivatives.

Periventricular leukomalacia (PVL), a necrotic and often cystic lesion of the cerebral white matter occurring in very premature babies, is the leading cause of cerebral palsy in this population. Increased glutamate release and the excitotoxic cascade thus triggered may be critical factors in the development of PVL. The glutamatergic analog ibotenate injected intracerebrally into newborn mice produces white matter cysts that mimic human PVL. Concomitant injection of vasoactive intestinal peptide (VIP), a trophic factor, protects the white matter against excitotoxic lesions. The goal of the present study was to assess the protective properties of systemically injected VIP analogs against ibotenate-induced excitotoxic white matter lesions in newborn mice. VIP analogs were selected on the basis of their low susceptibility to endopeptidases and their potential ability to cross biological membranes. RO-25-1553, a long-lasting cyclic VIP analog, and stearyl-norleucine-VIP, a fatty derivative of VIP, reduced ibotenate-induced white matter cysts by up to 87% and 84%, respectively, when injected i.p. immediately after ibotenate. By comparison, i.p. coadministration of VIP and ibotenate was not protective against the excitotoxic insult. Furthermore, RO-25-1553 and stearyl-norleucine-VIP still induced significant neuroprotection of the developing white matter when injected systemically 8 and 12 h, respectively, after ibotenate, establishing these peptides as therapeutic agents in this murine model. VIP analogs may have therapeutic potential in human premature babies at high risk for PVL.

Amino Acid Sequence↗
PubMed1999

Pharmaceutical VIP: prospects and problems.

Recently, multiple receptors for vasoactive intestinal peptide (VIP) have been molecularly cloned and our understanding of VIP chemistry and mechanisms of action has been broadened. The following review outlines the physiological effects of the hormone from growth regulation, reproduction, bronchodilation, vasodilation and immune interactions to neurotrophism. VIP-based drug design and non-invasive innovative delivery modes are discussed with emphasis on tumor diagnosis and treatment, impotence treatment and neuroprotection.

Amino Acid Sequence↗
PubMed1998

VIP neurotrophism in the central nervous system: multiple effectors and identification of a femtomolar-acting neuroprotective peptide.

Vasoactive intestinal peptide has neurotrophic and growth-regulating properties. As in the case of many neurotrophic molecules, VIP also has neuroprotective properties, including the prevention of cell death associated with excitotoxicity (NMDA), beta-amyloid peptide, and gp120, the neurotoxic envelope protein from the human immunodeficiency virus. The neurotrophic and neuroprotective properties are mediated in part through the action of glial-derived substances released by VIP. These substance include cytokines, protease nexin I, and ADNF, a novel neuroprotective protein with structural similarities to heat-shock protein 60. Antiserum against ADNF produced neuronal cell death and an increase in apoptotic neurons in cell culture. A 14 amino acid peptide (ADNF-14) derived from ADNF has been discovered that mimics the survival-promoting action of the parent protein. These studies support the conclusion that VIP, PACAP, and associated molecules are both important regulators of neurodevelopment and strong candidates for therapeutic development for the treatment of neurodegenerative disease.

Amino Acid Sequence↗
PubMed1998

Multiple actions of a hybrid PACAP antagonist: neuronal cell killing and inhibition of sperm motility.

Pituitary stimulating adenylate cyclase (PACAP) is a major regulatory peptide with two active molecular forms: PACAP-27 and PACAP-38. Both molecular forms promote neuronal survival and protect against neurotoxicity. Based on our previous hybrid peptide strategy in designing vasoactive intestinal peptide (VIP) antagonists, novel PACAP analogues were synthesized (neurotensin6-11 PACAP7-27 and neurotensin6-11 PACAP7-38). In addition to the hybrid modification, the methionine in position 17 was replaced by norleucine (Nle). Treatment of rat cerebral cortical cultures for five days with the putative PACAP antagonists (1 nM) resulted in a 35-45% reduction in neuronal cell counts as compared to controls. Neuronal cell death was already obtained at picomolar concentrations for the neurotensin6-11 PACAP7-27 antagonist with 70% death at 10(-8) M. Co-administration of the PACAP hybrid analogue with picomolar amounts of PACAP-27 or Nle17-PACAP-27 attenuated the reduction in neuronal cell counts. While the protective effects of both analogues exhibited a peak at 1 pM concentrations, the Nle-containing agonist displayed a broader range of active concentrations (10(-12)M-10(-9) M). The putative PACAP antagonist also inhibited sperm motility (golden hamster) in a dose-dependent manner as assessed in vitro. Complete inhibition was observed at 10 microM, suggesting a role for PACAP in sperm motility and sexual function. Thus, previous findings of a large number of PACAP and PACAP receptors in the nervous system and the reproductive system are now correlated with a function in neuronal survival and sperm motility. The structure-activity studies suggest that the methionine in position 17 and the first six amino acids are important in the determination of PACAP activity, knowledge that may facilitate PACAP-based drug design.

Amino Acid Sequence↗
PubMed1998

VIP and breast cancer.

VIP1 receptors are present in breast cancer cells. VIP elevates the cAMP and stimulates nuclear oncogene expression in MCF-7 cells. VIPhybrid is a VIP receptor antagonist that inhibits breast cancer proliferation. A VIP analog has been developed for imaging breast tumors. Therefore VIP1 receptors may be utilized for the early detection and treatment of breast cancer.

Animals↗
PubMed1998

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun.

Tumor necrosis factor alpha (TNFalpha), an early cytokine produced by activated macrophages, plays an essential role in normal and pathological inflammatory reactions. The excessive production of TNFalpha is prevented by the so-called "macrophage-deactivating factors." This study examines the role of two structurally related neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating peptide (PACAP), as inhibitors of TNFalpha. Both VIP and PACAP inhibit TNFalpha production from lipopolysaccharide-stimulated RAW 246.7 cells in a dose- and time-dependent manner. Although the activated cells express mRNA for all three VIP/PACAP receptors, agonist and antagonist studies indicate that the major receptor involved is VIP1R. VIP/PACAP inhibit TNFalpha gene expression by affecting both NF-kB binding and the composition of the cAMP responsive element binding complex (CREB/c-Jun). Two transduction pathways, a cAMP-dependent and a cAMP-independent pathway, are involved in the inhibition of TNFalpha gene expression and appear to differentially regulate the transcriptional factors involved. Because TNFalpha plays a central role in various inflammatory diseases such as endotoxic shock, multiple sclerosis, cerebral malaria, and various autoimmune conditions, the down-regulatory effect of VIP/PACAP may have a significant therapeutic potential.

Animals↗
PubMed1998

The identification of secreted heat shock 60 -like protein from rat glial cells and a human neuroblastoma cell line.

The intracellular stress-induced proteins provide protection against toxic insults. Here, a 60,000-Da heat shock 60 (hsp60)-like protein was detected, with five different antibodies, in conditioned media derived from rat cortical astrocytes and a human neuroblastoma cell line. Extracellular neuroblastoma hsp60-like immunoreactivity was increased 3-fold in the presence of the neuropeptide vasoactive intestinal peptide (VIP) and was augmented 2-fold after temperature elevation. Intracellular hsp60 immunoreactivity was reduced 2-3-fold in the presence of VIP; this reduction was attenuated in the presence of brefeldin A, an inhibitor of protein secretion. In contrast, the activity of lactate dehydrogenase (LDH), an intracellular marker, did not change in the presence of VIP. Essentially no extracellular LDH activity was detected, indicating no cellular damage. A novel aspect for stress proteins having extracellular protective roles is suggested.

Animals↗
PubMed1998

Protection against developmental deficiencies by a lipophilic VIP analogue.

Stearyl-Nle-VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100-fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, the developmental and protective effects of SNV were investigated in vivo using two models of developmental retardation, hypoxia and cholinergic blockade. In both cases chronic administration of SNV during development provided protective effects. Water maze experiments on the weaned animals have demonstrated a prophylactic action for SNV and enhancement of spatial memory in animals exposed to a cholinotoxin. SNV may act by providing neuroprotection, thereby improving cognitive functions. This work is dedicated to Prof. R.J. Wurtman whose inspiration and leadership in the field of neuroscience and cognition is beyond comparison.

Aging↗
PubMed1998

Involvement of pituitary adenylate cyclase-activating polypeptide II vasoactive intestinal peptide 2 receptor in mouse neocortical astrocytogenesis.

At the end of neuronal migration, the neopallial germinative zone produces glial cells destined to colonize the upper layers of neocortex. High densities of binding sites for vasoactive intestinal peptide (VIP) have been found in the rodent germinative zone just after completion of neuronal migration, suggesting a possible role of VIP in neocortical astrocytogenesis. In the present study, administration of a VIP antagonist at embryonic days 17 and 18 to pregnant mice was followed by a dramatic depletion of astrocytes in the upper cortical layer of the offspring. The depletion of astrocytes was dose-dependent, with a 42% reduction in the density of astrocytes observed with 50 microg of antagonist. The antagonist effect was reversed by cotreatment with VIP or pituitary adenylate cyclase-activating polypeptide (PACAP), suggesting the involvement of a receptor common to these two neuropeptides. VIP antagonist-induced inhibition of astrocytogenesis was also blocked by Ro 25-1553, a long-acting cyclic VIP analogue selective for the PACAP II VIP2 receptor subclass. Our results demonstrate that VIP and/or PACAP play a crucial physiological role in neocortical astrocytogenesis, possibly through interaction with PACAP II VIP2 receptors.

Animals↗
PubMed1998

Activity-dependent neurotrophic factor: structure-activity relationships of femtomolar-acting peptides.

Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein that is neuroprotective at femtomolar concentrations. A 14-amino acid peptide of ADNF (ADNF-14) has been reported that protects cultured neurons from multiple neurotoxins. Structure-activity relationships of peptides related to ADNF-14 now have been determined. A 9-amino acid core peptide (ADNF-9) has been identified that has greater potency and a broader effective concentration range (10(-16) to 10(-13) M) than ADNF or ADNF-14 in preventing cell death associated with tetrodotoxin treatment of cerebral cortical cultures. Deletions or conservative amino acid substitutions to ADNF-9 resulted in reduced potency, narrower effective concentration range and/or decreased efficacy. Removal of the N-terminal serine or the COOH-terminal isoleucine-proline-alanine from ADNF-9 produced a significant reduction in survival-promoting activity. Comparative studies of ADNF-9 action in mixed (glia plus neurons) vs. glia-depleted neuronal cultures indicated that ADNF-9 can act directly on neurons, although the potency of the peptide was 10,000-fold greater in mixed cultures. Kinetic studies showed that exposure to ADNF-9 for only 2 hr was sufficient to produce a 4-day protection against the cell-killing action of tetrodotoxin. Treatment with bafilomycin A1 (an inhibitor of receptor-mediated endocytosis) for 2 hr prevented the ADNF- and ADNF-9-mediated neuroprotection. ADNF-9, like ADNF-14, was neuroprotective against N-methyl-D-aspartate and the beta-amyloid peptide (amino acids 25-35), and had a much broader range of effective concentrations than ADNF-14. These studies identify ADNF-9 as an attractive lead compound for the development of therapeutic agents against neurodegenerative diseases.

Animals↗
PubMed1997

Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain.

Excitotoxic damage may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected at birth, the glutamatergic analog ibotenate induces mouse brain lesions that strikingly mimic human microgyria. When ibotenate is injected at postnatal day 5, it produces transcortical necrosis and white matter cysts that mimic human perinatal hypoxic-like lesions. Vasoactive intestinal peptide (VIP) has potent growth-related actions and neuroprotective properties that influence mitosis and neuronal survival in culture. The goal of this study was to assess the protective role of VIP against excitotoxic lesions induced by ibotenate in developing mouse brain. VIP cotreatment reduced ibotenate-induced microgyric-like cortical lesions and white matter cysts by up to 77 and 85%, respectively. VIP protective effects were reproduced by a peptide derived from activity-dependent neurotrophic factor (ADNF), a trophic factor released by VIP-stimulated astrocytes, and by stearyl norleucine VIP, a specific VIP agonist that does not activate adenylate cyclase. Neither forskolin, an adenylate cyclase activator, nor pituitary adenylate cyclase-activating peptide, provided VIP-like protection. VIP and neurotrophic analogs, acting through a cAMP-independent mechanism and inducing ADNF release, could represent new avenues in the understanding and prevention of human cerebral palsy.

Animals↗
PubMed1997

Transcription of the vasoactive intestinal peptide gene in response to glucocorticoids: differential regulation of alternative transcripts is modulated by a labile protein in rat anterior pituitary.

Expression of the vasoactive intestinal peptide (VIP) gene is controlled by glucocorticoids in a tissue- and endocrine status-specific manner. We have investigated the molecular mechanisms that determine glucocorticoid regulation of VIP gene expression in the rat pituitary. In initial experiments, using explant cultures of rat pituitary glands, we have demonstrated that treatment with the glucocorticoid agonist dexamethasone leads to a marked increase in VIP mRNA levels. This effect was found to be selective for the larger of two alternatively polyadenylated VIP transcripts, and in addition, protein synthesis inhibitors markedly enhanced the magnitude of this response indicating that a labile pituitary protein acts to attenuate the transcript-selective response to glucocorticoids. Nuclear run-on analysis of transcription demonstrated that the effects of dexamethasone in vitro are mediated largely, if not completely, at the level of transcription. In order to investigate the role of VIP promoter sequence in the glucocorticoid response, we then demonstrated that the activity of rat VIP gene promoter/reporter constructs in GH3 pituitary cells are up-regulated by dexamethasone. This up-regulation is virtually abolished following removal of promoter sequence between -162 and -89 of the start of transcription. Using an in vitro electrophoretic mobility shift assay, we have also demonstrated that this region of the promoter binds recombinant glucocorticoid receptor protein. The results of our study therefore indicate a direct mechanism of action for the modulation of VIP gene expression by glucocorticoids, and furthermore provide evidence of a mechanism that permits selective glucocorticoid regulation of alternative VIP transcripts.

Animals↗