Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 13, Number 11, 2007

Contents


Toward Translational Research on VIP AND PACAP
Executive Editor: A. Arimura


Editorial: Pp. 1077-1078


Vasoactive Intestinal Peptide in Neurodevelopmental Disorders: Therapeutic Potential Pp. 1079-1089
J.M. Hill
[Abstract]


NAP and ADNF-9 Protect Normal and Down's Syndrome Cortical Neurons from Oxidative Damage and Apoptosis Pp. 1091-1098
J. Busciglio, A. Pelsman, P. Helguera, O. Ashur-Fabian, A. Pinhasov, D.E. Brenneman and I. Gozes
[Abstract]


Vasoactive Intestinal Peptide Receptors: A Molecular Target in Breast and Lung Cancer Pp. 1099-1104
T.W. Moody and I. Gozes
[Abstract]


PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential Pp. 1105-1112
M. Nakata and T. Yada
[Abstract]


Therapeutical Approaches of Vasoactive Intestinal Peptide as a Pleiotropic Immunomodulator Pp. 1113-1139
E. Gonzalez-Rey, A. Fernandez-Martin, A. Chorny and M. Delgado
[Abstract]


General Articles


Carotid Artery Atherosclerosis: What is the Evidence for Drug Action? Pp. 1141-1159
S.S. Daskalopoulou, M.E. Daskalopoulos, D. Perrea, A.N. Nicolaides and C.D. Liapis
[Abstract]


Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5- Phosphate Reductoisomerase (DXR) Enzyme Pp. 1161-1177
N. Singh, G. Chevé, M.A. Avery and C.R. McCurdy
[Abstract]


Magnetic Carriers: A Promising Device for Targeting Drugs Into the Human Body Pp. 1179-1185
A.K.A. Silva, É.L. Silva, A.S. Carriço and E.S.T. Egito
[Abstract]




Abstracts


[Back to top]
Editorial: Toward Translational Research on VIP AND PACAP

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. These peptides exhibit immunosuppression, and the studies suggest its use in various pathological events such as arthritis, asthma, shock, and infection to control overreaction of the tissue. Although toxicity studies of VIP or PACAP during a prolonged application in humans have not been reported, these peptides are relatively nontoxic. No clear adverse side effects of high doses of these peptides in animal experiments have been reported, except for a transient hypotension.

Since different tissues or organs express various types of receptors or subtypes of these receptors and the biological effects mediated by these different receptors and subtypes may be provoked by different concentrations of the peptide, the dose of VIP or PACAP may have to be carefully calculated before administration for the treatment of respective ailments. It is hoped that these articles would be of help for clinical researchers who attempt to use VIP or PACAP and their analogs for the treatment of human diseases.

References
[1] Mutt V, Said SI. Structure of the porcine vasoactive intestinal octacosapeptide. Determination of the amino acid sequence. Eur J Biochem 1974; 42: 581-189.

[2] Miyata A, Arimura A, Dahl RR, et al. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 1989; 164: 567-74.

[3] Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H. Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 2000; 52: 269-324.

[4] McRory J, Sherwood NM. Two protochordate genes encode pituitary adenylate cyclase-activating polypeptide and related family members. Endocrinology 1997; 138: 2380-90.

[5] Arimura A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn J Physiol 1998; 48: 301-31.

[6] Hill JM.Vasoactive Intestinal Peptide in Neurodevelopmental Disorders: Therapeutic Potential. Curr Pharm Des 2007; 13(11): 1079-1089.

[7] Busciglio J, Pelsman A, Helguera P, Ashur-Fabian O, Pinhasov A, Brenneman DE, Gozes I. NAP and ADNF-9 Protect Normal and Down's Syndrome Cortical Neurons from Oxidative Damage and Apoptosis. Curr Pharm Des 2007; 13(11): 1091-1098.

[8] Moody TW, Gozes I. Vasoactive Intestinal Peptide Receptors: A Molecular Target in Breast and Lung Cancer. Curr Pharm Des 2007; 13(11): 1099-1104.

[9] Nakata M, Yada T. PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential. Curr Pharm Des 2007; 13(11): 1105-1112.

[10] Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Delgado M. Therapeutical Approaches of Vasoactive Intestinal Peptide as a Pleiotropic Immunomodulator. Curr Pharm Des 2007; 13(11): 1113-1139.


A. Arimura
E-mail: arimura@tulane.edu


[Back to top]
Vasoactive Intestinal Peptide in Neurodevelopmental Disorders: Therapeutic Potential
J.M. Hill

Vasoactive intestinal peptide (VIP) mediates important events during the development of the nervous system. VIP can stimulate neuronogenesis as well as differentiation and neurite outgrowth; it can promote the survival of neurons and assist in neuronal repair; it is also anti-inflammatory and can modulate immune responses. In addition, VIP is necessary for the normal growth and development of the early postimplantation mouse embryo during the period when the major embryonic events are neural tube formation, neuronogenesis and expansion of the vascular system. Receptors for VIP appear during early postimplantation embryogenesis in the rodent and exhibit changing localization patterns throughout the development of the brain. During embryogenesis, unregulated VIP may have major and permanent consequences on the formation of the brain and may be a participating factor in disorders of neurodevelopment. VIP has been linked to autism, Down syndrome and fetal alcohol syndrome. This paper will review the role of VIP in neurodevelopment, its known involvement in neurodevelopmental disorders and propose ways in which VIP might be of therapeutic value.


[Back to top]
NAP and ADNF-9 Protect Normal and Down's Syndrome Cortical Neurons from Oxidative Damage and Apoptosis
J. Busciglio, A. Pelsman, P. Helguera, O. Ashur-Fabian, A. Pinhasov, D.E. Brenneman and I. Gozes

NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single letter code: NAPVSIPQ) and ADNF-9 (activity-dependent neurotrophic factor-9; Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala; single letter code: SALLRSIPA) are peptides derived from naturally occurring glial proteins that have shown neuroprotection in rodent model systems. Here, the neuroprotective activity of ADNF-9 and NAP was tested in two human models of neuronal degeneration in culture mediated by oxidative stress: normal human cortical neurons treated with H₂O₂ and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 μM H₂O₂ for 1 hour resulted in morphological and structural changes consistent with neuronal degeneration and loss of viability of more than 60% of the neurons present in the culture. Addition of ADNF-9 or NAP at femtomolar concentrations resulted in significant increases in survival of normal neurons treated with H₂O₂. Femtomolar concentrations of ADNF-9 or NAP exhibited a similar neuroprotective efficacy, comparable to the antioxidant N-tert-butyl-2-sulpho-phenylnitrone at 100 μM (s-PBN). Treatment of DS cortical neurons with ADNF-9 or NAP resulted in a significant increase in neuronal survival as well as reduction of degenerative morphological changes. The results suggest that ADNF-9 and NAP possess potent neuroprotective properties against oxidative damage in human neurons that may be useful to preserve neuronal function and prevent neuronal death associated with chronic neurodegenerative disorders.


[Back to top]
Vasoactive Intestinal Peptide Receptors: A Molecular Target in Breast and Lung Cancer
T.W. Moody and I. Gozes

Vasoactive intestinal peptide (VIP) receptors are present in the normal brain as well as periphery, and cancer cells. Three major types of VIP receptors include the VPAC₁, VPAC₂ and PAC₁ receptors. VPAC₁ receptors are present in high densities on human lung and breast cancer cells lines and biopsy specimens. Radiolabeled VIP analogues have been developed for imaging of lung and breast cancer. Synthetic VIP receptor antagonists inhibit the proliferation and potentiate the ability of chemotherapeutic agents to cause apoptosis of lung and breast cancer cells. VIP-chemotherapeutic conjugates have been synthesized which bind to VPAC₁ receptors and are internalized, resulting in the killing of lung and breast cancer cells. These results suggest that VPAC₁ receptors may be molecular targets for diagnosis, prevention and treatment of breast cancer as well as lung cancer.


[Back to top]
PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential
M. Nakata and T. Yada

Pituitary adenylate cyclase activating polypeptide (PACAP) is a ubiquitous neuropeptide in the central and peripheral nervous systems. PACAP is also produced by pancreatic islet cells. PACAP regulates the glucose and energy metabolism at multiple processes in several tissues. At postprandial states, PACAP potentiates both insulin release from pancreatic β-cells and insulin action in adipocytes, contributing to energy storage. At fasting states, PACAP on the one hand promotes feeding behavior by activating neuropeptide Y neurons in the hypothalamic feeding center, arcuate nucleus, and on the other hand stimulates secretion of catecholamine and glucagon and thereby induces lipolysis in adipocytes and glucose output from liver. Thus, PACAP plays an integrative role in the glucose and energy homeostasis. Dysfunction of expression, secretion and/or action of PACAP might be involved in the type 2 diabetes and metabolic syndrome. PACAP receptor subtype-specific agonists and/or antagonists are hopeful therapeutic agents.


[Back to top]
Therapeutical Approaches of Vasoactive Intestinal Peptide as a Pleiotropic Immunomodulator
E. Gonzalez-Rey, A. Fernandez-Martin, A. Chorny and M. Delgado

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides belonging to the VIP/secretin/glucagon family of peptides. VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and exert a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4⁺ T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors, are perfectly known. Therefore, VIP/PACAP and analogues have been recently proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson’s disease, Crohn disease, or autoimmune diabetes. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system; and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this “very important peptide” as an exciting new candidate for therapeutic intervention and drug development.


[Back to top]
Carotid Artery Atherosclerosis: What is the Evidence for Drug Action?
S.S. Daskalopoulou, M.E. Daskalopoulos, D. Perrea, A.N. Nicolaides and C.D. Liapis

Carotid artery disease is a well-established cause of cerebrovascular events. This risk is predicted by the severity of stenosis and other plaque characteristics that can be documented using imaging techniques. Among these techniques, ultrasound is the most widely available. Increased carotid intima-media thickness (IMT) measured ultrasonically is associated with a higher risk for cerebrovascular as well as coronary heart disease. Furthermore, it is increasingly recognized that echolucent and heterogeneous carotid plaques in patients with high-grade carotid stenosis are associated with a greater risk for cerebrovascular events.

Several local and systemic factors can influence plaque stability. Identifying the high-risk carotid plaque could improve selection for vascular intervention (surgery/angioplasty) and increase cost-effectiveness. Aggressive medical treatment should always be provided for these high-risk patients. For example, lipid-lowering, anthihypertensive and antiplatelet drugs decrease the carotid IMT, stabilize carotid plaques or reduce the risk of cerebrovascular and systemic events.

Continuously evolving technology will lead to more accurate identification of high-risk carotid plaques. A combination of comprehensive non- or minimally-invasive imaging techniques together with measuring clinical and systemic biochemical markers of risk may facilitate the identification of the vulnerable plaque in the vulnerable patient, and help select the best treatment options.


[Back to top]
Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5- Phosphate Reductoisomerase (DXR) Enzyme
N. Singh, G. Chevé, M.A. Avery and C.R. McCurdy

The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.


[Back to top]
Magnetic Carriers: A Promising Device for Targeting Drugs Into the Human Body
A.K.A. Silva, É.L. Silva, A.S. Carriço and E.S.T. Egito

Suboptimal disposition behavior of drugs requires innovative delivery approaches. Magnetic drug targeting seems to be a promising one. Magnetic particles develop magnetic polarization and magnetophoretic mobility, and because of such unique properties, these carriers may be eligible candidates for delivering drugs to specific locations within the body. Their special properties also allow other uses, such as those in magnetic separation, hyperthermia, and magnetic resonance imaging. This review focuses on a brief discussion of magnetic drug targeting, the properties and fate of magnetic carriers, the methods used to produce and characterize them, and their other uses in biotechnology.