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Biomedical subjects

I Gozes

Publications and source records attributed to I Gozes.

At least 19 recordsLinked to original sources
PubMed1992

Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist.

The external envelope glycoprotein (gp120) of the human immunodeficiency virus (HIV) has been shown to be toxic to neurons in culture. To further investigate the neurological effects of gp120, the involvement of this protein with the acquisition of spatial discrimination was assessed. Both native and recombinant gp120 were administered into the cerebral ventricles of adult rats and performance was evaluated in the Morris swim maze. Gp120 treatment retarded acquisition after daily administration of 12 ng. The specificity of this impairment was demonstrated in that the performance of animals given the same amount of gp160 from recombinant baculovirus was not different from animals given saline. Vasoactive intestinal peptide (VIP) has been shown to block gp120-induced neurotoxicity in culture and a VIP receptor antagonist has displayed toxic properties to neurons in culture. We show here that this antagonist, which competitively inhibits VIP binding and blocks VIP-mediated functions in cell cultures from the CNS, also produced an impairment of performance. This retardation was attenuated by cotreatment with VIP, supporting the specificity of the observed impairment. Thus, gp120 and the VIP antagonist produced similar retardation of spatial discrimination, suggesting that both may impair memory for spatially related stimulus control.

Animals↗
PubMed1992

Distribution of cells expressing vasoactive intestinal peptide/peptide histidine isoleucine-amide precursor messenger RNA in the rat brain.

The distribution of cells expressing vasoactive intestinal peptide/peptide histidine isoleucine-amide precursor messenger RNA was investigated in the rat brain and pituitary by in situ hybridization using a synthetic 35S-labeled oligonucleotide probe. Detection of labeled neurons by light-microscopic radioautography revealed a selective repartition of the messenger RNA-expressing cells. Several major vasoactive intestinal peptide/peptide histidine isoleucine-amide messenger RNA-containing cell groups were demonstrated including layers II-VI of the cerebral cortex, the suprachiasmatic nucleus and various thalamic structures such as the ventrolateral, posterior, lateral reticular, paracentralis and gelatinosus nuclei. Positive cells, to a lesser extent, were also found in the limbic system, medial preoptic area, superior and inferior colliculi as well as in the central gray matter. They were totally absent in the pituitary and the pineal gland of normal rats. The results of the present study provide a detailed mapping of neurons expressing vasoactive intestinal peptide/peptide histidine isoleucine-amide messenger RNA in the adult rat brain. The predominance of vasoactive intestinal peptide/peptide histidine isoleucine-amide messenger RNA-containing neurons in the cerebral cortex, suprachiasmatic nucleus and thalamus suggest that vasoactive intestinal peptide is mainly involved in the control of cortical informations, circadian rhythms and sensory perception in agreement with several physiological data.

Animals↗
PubMed1992

Cytokine regulation of neuronal survival.

Interleukin-1 is a cytokine involved in the immune response to infection and inflammation as well as a growth promotor for several cell types. Interleukin-1-like immunoreactive material has been found in the nervous system. We now show that antisera, which blocked the T-cell proliferative effects of interleukin-1 alpha, decreased neuronal cell counts (to 40% of control) in dissociated spinal cord cultures derived from fetal mice. This neuronal loss was prevented by addition of interleukin-1 alpha, and to a lesser extent by interleukin-1 beta. Exogenous interleukin-1 alpha increased the survival of neurons when added to cultures in which the electrical activity was blocked with tetrodotoxin, whereas no such cytokine-related increase in neuronal survival was observed in electrically active cultures. The antiserum-induced death could also be prevented by cotreatment of the cultures with 0.1 nM vasoactive intestinal peptide, a substance that induces the secretion of neuronal trophic factors from nonneuronal spinal cord cells and thereby increases neuronal survival in electrically inactive cultures. These studies indicate that the cytokine interleukin-1, or an immunologically cross-reactive protein, can increase neuronal survival.

Animals↗
PubMed1992

A fatty neuropeptide. Potential drug for noninvasive impotence treatment in a rat model.

Vasoactive intestinal peptide (VIP), a key penile neurotransmitter, induces erection after local injection in man. To augment the therapeutic potential of VIP for impotence treatment and circumvent difficulties of direct penile injections, a strategy was designed to increase peptide hydrophobicity. This was accomplished by the synthesis of a conjugate of VIP and stearic acid (stearyl-VIP). Upon penile topical application, stearyl-VIP, in contrast to native VIP, significantly increased sexual function as measured by copulatory activity and penile reflexes (erections) in testosterone-treated, castrated rats. In addition, stearyl-VIP penetrated the body in amounts severalfold greater than VIP. Pharmacokinetic studies demonstrated 10-fold higher penile concentrations of stearyl-VIP, as compared with that measured in the blood 15 min after application, with a gradual decrease thereafter. The peak of incorporation into peripheral tissues that was observed 30 min after administration was 1,000-fold less than that found in the penile tissue. Tissue extraction and chromatographic analysis revealed that stearyl-VIP remained essentially intact for greater than or equal to 15 min and was cleared after 1 h. Thus, topically administered stearyl-VIP had increased bioavailability in comparison with VIP without apparent toxicity, suggesting significant therapeutic potential.

Animals↗
PubMed1991

A VIP antagonist distinguishes VIP receptors on spinal cord cells and lymphocytes.

Vasoactive intestinal peptide (VIP) is a neuropeptide which also interacts with cells of the immune system. The paucity of specific VIP receptor antagonists has hampered studies of possible receptor heterogeneity and of VIP function. To aid in achieving these goals, a new VIP antagonist, a hybrid between neurotensin and VIP, has been synthesized. This peptide interacted with VIP receptors on spinal cord cells with an affinity 10-fold greater than VIP itself. In contrast, 1000-fold higher concentrations of the antagonist were required to displace labeled VIP from its receptor on lymphoid cells as compared to VIP itself, suggesting VIP receptor heterogeneity between immune and spinal cord cells.

Amino Acid Sequence↗
PubMed1991

Spontaneous electrical activity regulates vasoactive intestinal peptide expression in dissociated spinal cord cell cultures.

Activity-dependent expression of vasoactive intestinal peptide (VIP) was investigated in spinal cord/dorsal root ganglia cultures derived from embryonic mice. Since all spinal cord neurons appear to exhibit spontaneous action potentials after one week in vitro, activity-dependent regulation of VIP-transcripts (mRNAVIP) could be studied with or without electrical blockade induced by tetrodotoxin (TTX). In 10-day-old cultures, a 50% decrease in mRNAVIP was observed after 3 days of treatment with TTX. The decrease in mRNAVIP was reversed upon removal of the TTX and was dependent on the age of the cultures: no decreases from control were observed in 5-day-old cultures and much smaller decrements were produced in one month old cultures treated with TTX. A variety of neuroactive substances were tested for effects on mRNAVIP in electrically active and electrically blocked cultures. Application of 8-bromo-cAMP (cAMP), N-methyl-D-aspartate (NMDA), substance P, muscimol, A23187 and VIP to electrically active cultures resulted in a 2- to 3-fold increase in mRNAVIP, while phorbol myristate 13-acetate (PMA) and 8-bromo-cGMP (cGMP) had no effect. In contrast, electrically inactive cultures exhibited a 3 to 4-fold increase in mRNAVIP after treatment with PMA, cAMP and VIP, while NMDA, substance P, muscimol, A23187 and cGMP produced no increases. In summary, the regulation of VIP gene expression in embryonic spinal cord neurons shows a temporal sensitivity to TTX-induced electrical blockade and may be mediated by multiple neurotransmitter inputs which converge on cAMP- and calcium-related processes in an activity-dependent manner.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

An antagonist to vasoactive intestinal peptide affects cellular functions in the central nervous system.

A vasoactive intestinal peptide (VIP) antagonist was synthesized and used to investigate the interactions of VIP with its receptors present in the central nervous system (CNS). The VIP antagonist is a hybrid peptide consisting of a portion of VIP and a portion of neurotensin, designed to change the membrane permeability of the VIP portion. The hybrid antagonist displaced 80 to 90% of [125I]VIP binding to cell cultures from cerebral cortex, hippocampus or spinal cord. The displacement curve was biphasic, suggesting two binding sites. In the case of cortical astrocytes, the antagonist had a Ki of 45 pM at one site and a Ki of 74 nM at the other. At the lower affinity binding site, the antagonist was about 10-fold more potent than VIP in displacing radiolabeled VIP. The accumulation of cyclic AMP (cAMP) in VIP-stimulated cortical glia cultures was decreased by the new antagonist (EC50, 59 nM). This decrease in cAMP was greater than that achieved in the presence of other putative VIP antagonists. Finally, the addition of 1 nM hybrid antagonist to dissociated spinal cord cultures resulted in a 42% reduction in neuronal cell counts as compared with controls, and the EC50 of this effect was about 30 pM, which corresponded closely to the Ki of antagonist displacement of [125I]VIP binding at the high-affinity site. The antagonist appears to be a competitive blocker for both VIP-mediated increases in cAMP formation or VIP-associated maintenance of neuronal survival in spinal cord cultures. Thus, we describe a potent VIP antagonist which interacts with two functionally distinct VIP receptors in the CNS.

Amino Acid Sequence↗
PubMed1990

The complete structure of the rat VIP gene.

Vasoactive intestinal polypeptide (VIP) is a regulatory neuropeptide/neurotransmitter of 28 amino acids involved in a wide variety of physiological functions. Using synthetic oligodeoxynucleotide probes related to the rat VIP-cDNA, we have isolated and characterized the gene encoding the rat pre-pro VIP/PHI-27 and compared it to the human VIP gene. The rat VIP gene spanned 7400 base pairs, and contained 7 exons interrupted by 6 introns. 100% identity was found between the gene exons and the cDNA sequence. Differences in sizes of introns 2, 4 and 5 (shorter in the rat gene) are the reason for the shorter rat gene compared with the human gene of 8837 base pairs. Comparison of the genes in the two species showed a high homology in the exon sequences, 80-90% in exons 2, 4, 5, 6 and 30-50% in exons 1 and 7. In addition, the exon-intron junctions shared high identity between the genes. The rat untranslated exon 1 had little homology (30%) with human exon 1 and was 13 base pairs shorter. Interestingly, the 160 base pairs at the 5'-flanking region upstream of the cap-site share more than 75% identity between the two genes, including the exact position of TATA-boxes in positions -28, -145, -155, a cAMP-responsive element in position -80 and a CAAT sequence in position -127. The conservation of the 5'-flanking region of the VIP gene in parallel with the conservation of its coding exons emphasize the importance of these sequences during evolution.

Amino Acid Sequence↗
PubMed1977

Synthesis of tubulin and actin by neuronal and glial nuclear preparations from devloping rat brain.

A system was established in which nuclear preparations from rat brains were capable of protein synthesis under cell-free conditions. The electrophoretic pattern of the synthesized proteins was similar to that found in vivo provided that the reaction mixture contained pH 5 precipitated factors derived from the high speed supernatant fraction of brain. In the absence of the pH 5 factors, using nuclear preparations from brains of 2-day-old rats, approximately 1.5% and 2% of the newly synthesized proteins were identified as tubulin and actin, respectively. In the presence of pH 5 factors, protein synthesis was stimulated and the proportion of the newly synthesized tubulin and actin increased to 26% and 11%, respectively. In contrast to nuclear fractions from 2-day-old rats, when nuclei from brains of 1-month-old rats were tested in the presence of pH 5 factors, the proportion of tubulin and actin synthesized was lower and amounted to 10% and 4%, respectively. The age-dependent change in the relative amount of the tubulin and actin synthesized is in good agreement with the translational pattern shown by brain polyribosomes in a brain cell-free system as well as with the pattern obtained with brain mRNA translated in a wheat germ cell-free system. Nuclei enriched for either neuronal or glial populations synthesized similar proportions of tubulin and actin in vitro. We conclude that the reduction in the synthesis of tubulin and actin during the postnatal development of the rat brain occurs in both neuronal and glial cells.

Actins↗
PubMed1977

Decrease in levels and rates of synthesis of tubulin and actin in developing rat brain.

The cytoplasmic and particulate tubulin content of postnatal rat brains was determined at various stages of development. The amount of tubulin in the soluble fraction was found to increase after birth and levels off at the age of 10-15 days, while the total protein content is still increasing. Indeed, the percentage of tubulin in the soluble fraction is about 33% at birth, stays at this value until day 10, and then decreases to 20% between days 10 and 15. On the other hand, the rate of increase in the level of the particulate tubulin parallels that of the total particulate proteins, and hence there is no change in the percentage of particulate tubulin during brain development. There was close agreement between the tubulin values obtained by the [3H]-colchicine binding assay and those obtained by electrophoretic resolution in sodium dodecylsulfate-polyacrylamide gels. Polyacrylamide gel electrophoresis was also utilized to determine actin levels in developing brains. The percentage of cytoplasmic brain actin also decreased with the age of the rats, from a value of 20% at birth to 10% at day 30, while the percentage of the particulate actin remained constant. The decline in the percentage of cytoplasmic tubulin and actin during brain development can be accounted for by reduction in the proportions of the respective mRNA species. Translation of poly (A)-rich brain mRNA in a wheat-germ cell-free system showed that the percentages of tubulin and actin synthesized decreased gradually with age. Similar results were obtained by analyzing the proteins produced by isolated brain polysomes in a brain cell-free system.

Actins↗