vasoactive-intestinal-peptide and Brain-Injuries

A hallmark in most neurological disorders is a massive neuronal cell death, in which uncontrolled immune response is usually involved, leading to neurodegeneration. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. Alterations on VIP/VIP receptors in patients with neurodenegerative diseases, together with its involvement in the development of embryonic nervous tissue, and findings found in VIP-deficient mutant mice, have showed the relevance of this endogenous peptide in normal physiology and in pathologic states of the central nervous system (CNS). In this review, we will summarize the role of VIP in normal CNS and in neurological disorders. The studies carried out with this peptide have demonstrated its therapeutic effect and render it as an attractive candidate to be considered in several neurological disorders linked to neuroinflammation or abnormal neural development.

Topics: Alzheimer Disease; Animals; Autistic Disorder; Brain; Brain Injuries; Developmental Disabilities; Down Syndrome; Encephalitis; Female; Fetal Alcohol Spectrum Disorders; Humans; Mice; Multiple Sclerosis; Nervous System Diseases; Neuroprotective Agents; Parkinson Disease; Pregnancy; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. The gene encoding ADNP is highly conserved and abundantly expressed in the brain. ADNP contains a homeobox profile and a peptide motif providing neuroprotection against a variety of cytotoxic insults. ADNP mRNA and protein expression responds to brain injury and oscillates as a function of the estrus cycle. The plastic nature of ADNP expression is correlated with brain protection and an association between neuroendocrine regulation and neuroprotection is put forth with ADNP as a focal point. Further understanding of neuroprotective molecules should pave the path to better diagnostics and therapies. In this respect, structure-activity studies have identified a short 8 amino acid peptide in ADNP/NAPVSIPQ (NAP) that provides potent neuroprotection. NAP is currently in clinical development for neuroprotection.

Topics: Animals; Brain Injuries; Disease Models, Animal; Drug Design; Gene Expression; Homeodomain Proteins; Mice; Nerve Tissue Proteins; Neuroprotective Agents; Oligopeptides; Rats; Vasoactive Intestinal Peptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally restricted PACAP-analogs in positions important for receptor-selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1-4, 14-17, 20-22, 28, 34, 38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2-R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6-78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding-affinities correlated significantly with agonist potency, the degree of receptor-spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to 103-fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half-lives (substitutions at potential sites of proteolysis and attachment of long-chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases.

Topics: Animals; Brain Injuries; Cell Line, Tumor; Humans; Mice; NIH 3T3 Cells; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Stroke; Vasoactive Intestinal Peptide

To study the alterations of brain-gut peptides following traumatic brain injury (TBI) and to explore the underlying significance of these peptides in the complicated gastrointestinal dysfunction.. Rat models of focal traumatic brain injury were established by impact insult method, and divided into 6 groups (6 rats each group) including control group with sham operation and TBI groups at postinjury 3, 12, 24, 72 h, and d 7. Blood and proximal jejunum samples were taken at time point of each group and gross observations of gastrointestinal pathology were recorded simultaneously. The levels of vasoactive intestinal peptide (VIP) in plasma, calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) in both plasma and jejunum were measured by enzyme immunoassay (EIA). Radioimmunoassay (RIA) was used to determine the levels of VIP in jejunum.. Gastric distension, delayed gastric emptying and intestinal dilatation with a large amount of yellowish effusion and thin edematous wall were found in TBI rats through 12 h and 72 h, which peaked at postinjury 72 h. As compared with that of control group (247.8+/-29.5 ng/L), plasma VIP levels were significantly decreased at postinjury 3, 12 and 24 h (106.7+/-34.1 ng/L, 148.7+/-22.8 ng/L, 132.8+/-21.6 ng/L, respectively), but significantly increased at 72 h (405.0+/-29.8 ng/L) and markedly declined on d 7 (130.7+/-19.3 ng/L). However, Plasma levels CCK and CGRP were significantly increased through 3 h and 7 d following TBI (126-691% increases), with the peak at 72 h. Compared with control (VIP, 13.6+/-1.4 ng /g; CGRP, 70.6+/-17.7 ng/g); VIP and CGRP levels in jejunum were significantly increased at 3 h after TBI (VIP, 35.4+/-5.0 ng/g; CGRP, 103.8+/-22.1 ng/g), and declined gradually at 12 h and 24 h (VIP, 16.5+/-1.8 ng/g, 5.5+/-1.4 ng/g; CGRP, 34.9+/-9.7 ng/g, 18.5+/-7.7 ng/g), but were significantly increased again at 72 h (VIP, 48.7+/-9.5 ng/g; CGRP, 142.1+/-24.3 ng/g), then declined in various degrees on d 7 (VIP, 3.8+/-1.1 ng/g; CGRP, 102.5+/-18.1 ng/g). The CCK levels in jejunum were found to change in a similar trend as that in plasma with the concentrations of CCK significantly increased following TBI (99-517% increases) and peaked at 72 h.. Traumatic brain injury can lead to significant changes of brain-gut peptides in both plasma and small intestine, which may be involved in the pathogenesis of complicated gastrointestinal dysfunction.

Topics: Animals; Brain Injuries; Calcitonin Gene-Related Peptide; Cholecystokinin; Digestive System; Jejunum; Male; Rats; Rats, Wistar; Vasoactive Intestinal Peptide

Topics: Animals; Brain Injuries; Calcitonin Gene-Related Peptide; Cholecystokinin; Jejunum; Rats; Reproducibility of Results; Vasoactive Intestinal Peptide