Editorial [Hot Topic:Toward Translational Research on VIP AND PACAP (Executive Editor: A. Arimura)]

Vasoactive intestinal polypeptide, VIP, was discovered from the intestinal tissues based on its vasodilatory activity in 1974 [1], and its paralog, pituitary adenylate cyclase activating polypeptide or PACAP, was isolated from the ovine hypothalamic tissues based on the activity to stimulate adenylate cyclase in pituitary cell cultures [2]. Both peptides are active in the central nervous system as well as in the peripheral tissues. Both interact at the type 1 and type 2 VIP receptors, also temed VPAC1 and VPAC2, respectively. PACAP also binds to its specific receptor PAC1-R, which has at least 10 splice variants linked with distinct signalings. Thus, both VIP and PACAP are pleiotropic peptides and share similar activities [3]. PACAP is one of the oldest peptides in the body as suggested by a conserving of structure between human and prochordate PACAP. VIP, GHRH, secretin, and other paralogs are considered to have been generated by gene duplication [4]. Numerous studies on VIP and PACAP have shown that both peptides are pleiotropic peptides and act as neurotransmitters, neuromodulators, neurotrophic factors, hypophysiotrophic hormones, vasodepressants, smooth muscle relaxants, immunosuppressants, and share other functions as well [5]. These various actions may be mediated through their three types of receptors and subtype receptors that are coupled with distinct signalings and functions. Numerous studies on VIP/PACAP and their receptors in a variety of aspects have been published, enriching our knowledge on their actions, mechanisms, and cellular and molecular pathways. Despite such remarkable advances in our knowledge in their basic study, translational research for bringing these peptides to clinical application has been frustratingly delayed. These five articles in this special chapter have been written in an attempt to present possible clinical applications of these peptides for the treatment of human diseases. Hill [6] discusses the role of VIP in development of the brain of the early stage of the fetus. She presents possible relationships between lack of VIP during the early embryonic stage and defects of brain development, autism, fetal alcoholic intoxication, and Down’s syndrome. Gozes and her [7] associates discuss the neuroprotective activity of the 8-9 amino acid peptides, NAP and ADNF9, derived from glia driven neuroprotective protein. They report that death in cultured human cortical neurons caused by oxidative insult is significantly prevented by femotomolar concentrations of NAP or ADNF9. Cultured neurons from Down’s syndrome patients treated with these small peptides had an increased survival and a suppression of degenerative change. It is hoped that they will confirm these neuroprotective effect of NAP or ADNP9 in in vivo models of these diseases. Moody [8] describes the stimulatory role of VIP in tumor growth of breast cancers and its molecular mechanism involved. A significant portion of breast cancers overexpress Her2/Neu, a tyrosine kinase, and estrogen receptor, a major molecular target. Many breast cancer as well as lung cancer also overexpress VPAC1 receptors. He suggests that the VPAC1 receptor is an additional molecular target. Radiolabeled VIP analog can be used for diagnosis of breast and lung cancer. Use of a VIP antagonist suppresses tumor growth and facilitates the efficacy of chemotherapy. The use of VIP conjugated with a toxic chemical, such as ellipticine, destroys the tumor cells. Although the application of PACAP for the treatment of cancer has not been developed, a similar approach to the use of VIP may be used for the treatment of tumors which overexpress PACAP receptors. However, it may have to be kept in mind that some tumor growth may be suppressed by PACAP, and some others stimulated, depending on the type and subtypes of receptors expressed on tumor cells. Nakata and Yada [9] presents the data on the effect of PACAP in the regulation of glucose metabolism, insulin release and utilization, and on the central effects of the peptide on appetite control center in the brain. But the development of PACAP as a practical treatment of diabetes may require additional studies. Administration of PACAP to any diabetic patient, disregarding the individual condition and their metabolic stages, may not yield favorable outcomes. Delgado and his [10] associates present the studies on the effect of VIP and PACAP on the immune system....