Growth Factors and cytokines released by vasoactive intestinal peptide (VIP) were studied as mediators of neuron-glia interactions that regulate the survival of developing neurons and growth of mammalia embryos. Primary cell cultures derived from murine central nervous system were utilized to further characterize the molecular mechanism of VIP neurotrophism. The newly discovered growth factor, Activity Dependent Neurotrophic Factor (ADNF) was shown to potently increase the survival of neurons from cerebral cortex and hippocampus and to prevent the cell death associated with the envelope protein from the human immunodeficiency virus. Interleukin-1-alpha was shown to be released from astroglial cells by low concentrations of VIP. Treatment with higher concentrations of VIP also elevated IL-1 alpha mRNA. Studies on the developmental role of VIP were extended to growth regulation of whole embryo cultures. After four hours incubation, VIP increased somite number, embryonic volume, DNA and protein content, and the number of cells in S-phase. The VIP antagonist developed in our laboratory inhibited the VIP-mediated increments in growth in the CNS, but only attenuated the increases in growth in non-neural tissue. In vitro autoradiography revealed GTP-sensitive and GTP-insensitive VIP receptors which were differentially regulated in VIP-antagonist-treated embryos. The growth promoting effects elicited by VIP were not observed with Pituitary Adenylate Cyclase Activating Peptide. The distribution of both VIP and its receptors were investigated in the developing embryo. VIP mRNA was not observed in embryonic mice or rats whereas VIP receptors were abundant and dynamic with development. The role of maternal VIP in mediating embryonic growth was investigated. Radiolabeled VIP injected into uterine vessels was recovered in fetal brain.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Romano, Jacob; Beni-Adani, Liana; Nissenbaum, Orlev Levy et al. (2002) A single administration of the peptide NAP induces long-term protective changes against the consequences of head injury: gene Atlas array analysis. J Mol Neurosci 18:37-45
Steingart, Ruth A; Heldenberg, Eitan; Pinhasov, Albert et al. (2002) A vasoactive intestinal peptide receptor analog alters the expression of homeobox genes. Life Sci 71:2543-52
Leker, Ronen R; Teichner, Angella; Grigoriadis, Nikolas et al. (2002) NAP, a femtomolar-acting peptide, protects the brain against ischemic injury by reducing apoptotic death. Stroke 33:1085-92
Spong, C Y; Abebe, D T; Gozes, I et al. (2001) Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome. J Pharmacol Exp Ther 297:774-9
Servoss, S J; Lee, S J; Gibney, G et al. (2001) IGF-I as a mediator of VIP/activity-dependent neurotrophic factor-stimulated embryonic growth. Endocrinology 142:3348-53
Porter, A E; Auth, J; Prince, M et al. (2001) Optimization of cytokine stability in stored amniotic fluid. Am J Obstet Gynecol 185:459-62
Beni-Adani, L; Gozes, I; Cohen, Y et al. (2001) A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther 296:57-63
Ashur-Fabian, O; Giladi, E; Furman, S et al. (2001) Vasoactive intestinal peptide and related molecules induce nitrite accumulation in the extracellular milieu of rat cerebral cortical cultures. Neurosci Lett 307:167-70
Zamostiano, R; Pinhasov, A; Gelber, E et al. (2001) Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem 276:708-14
Zia, H; Leyton, J; Casibang, M et al. (2000) (N-stearyl, norleucine17) VIP hybrid inhibits the growth of pancreatic cancer cell lines. Life Sci 66:379-87

Showing the most recent 10 out of 19 publications