vasoactive-intestinal-peptide and Nervous-System-Diseases

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two widely expressed neuropeptides with important immunomodulatory and neuroprotective properties in the central nervous system (CNS). Both VIP and PACAP have been implicated in several neurological diseases and have shown favourable effects in different animal models of multiple sclerosis (MS). MS is a chronic inflammatory and neurodegenerative disease of the CNS affecting over 2.5 million people worldwide. The disease is characterised by extensive neuroinflammation, demyelination and axonal loss. Currently, there is no cure for MS, with treatment options only displaying partial efficacy. Importantly, epidemiological studies in the MS population have demonstrated that there is a high incidence of neurological and psychological comorbidities such as depression, anxiety, epilepsy and stroke among afflicted people. Hence, given the widespread protective effects of the VIP/PACAP system in the CNS, this review will aim at exploring the beneficial roles of VIP and PACAP in ameliorating some of the most common neurological comorbidities associated with MS. The final scope of the review is to put more emphasis on how targeting the VIP/PACAP system may be an effective therapeutic strategy to modify MS disease course and its associated comorbidities.

Topics: Animals; Comorbidity; Humans; Mental Disorders; Multiple Sclerosis; Nervous System Diseases; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

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

Vasoactive intestinal peptide (VIP) is a basic 28 amino acid peptide that binds to a member of the class II family of G protein-coupled receptors (GPCRs). It is widely expressed throughout the body and plays an important role in numerous biological functions. VIP acts via three different GPCRs: VPAC1, VPAC2, and PAC1, which have been identified in various tissues, including brain, lung, kidney, gastrointestinal tract, tongue, and also on immunocompetent cells such as macrophages and lymphocytes. There is mounting evidence that VIP expression and signaling is altered in numerous neurological disorders, and it is becoming apparent that VIP and its receptors could be therapeutic loci for the treatment of several pathological conditions of the central nervous system. In this review, we describe the pathology of several major neurological disorders and discuss the potential pharmacotherapeutic role of VIP and its receptors for the treatment of disorders such as Alzheimer's disease, Parkinson's disease, and Autism Spectrum Disorders.

Topics: Animals; Drug Delivery Systems; Humans; Models, Biological; Nervous System Diseases; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

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.

Topics: Animals; Central Nervous System; Central Nervous System Vascular Malformations; Humans; Mice; Nervous System Diseases; Vasoactive Intestinal Peptide

In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimer's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.

Topics: Amino Acid Sequence; Animals; Blood-Brain Barrier; Humans; Molecular Sequence Data; Nervous System Diseases; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Secretin; Vasoactive Intestinal Peptide

This review highlights that essentially all of the recently discovered putative central nervous system (CNS) peptides and other peptide substances are measurable in human cerebrospinal fluid (CSF). Preliminary evidence also suggests that peptides in CSF may have an active regulatory role in relation to CNS function and behavior. Even if this is not the case, CSF peptides may prove to be a useful indirect marker of CNS peptide function and metabolism. Alterations in peptides have been reported in neurological and psychiatric illness, pain symptoms and their treatment, symptoms such as anxiety, and following treatment with CNS active drugs such as carbamazepine. CSF methodologies provide a strategy for the study of the interaction of classical neurotransmitters and peptide substances and their relationship to neural function and behavior in man. Assessment of peptides in CSF may supplement post mortem studies of peptide levels and receptor distribution and help lead to new diagnostic and treatment approaches in neuropsychiatric disorders.

Topics: Adrenocorticotropic Hormone; Angiotensins; beta-Endorphin; Calcitonin; Endorphins; Humans; Mental Disorders; Nervous System Diseases; Oxytocin; Peptides; Somatostatin; Substance P; Vasoactive Intestinal Peptide; Vasopressins; Vasotocin

The aim of this study was to investigate the effects of vasoactive intestinal peptide (VIP) on neurogenesis and neurological function after cerebral ischemia. Rats were intracerebroventricular administered with VIP after a 2h middle cerebral artery occlusion (MCAO) and sacrificed at 7, 14 and 28 days after MCAO. Functional outcome was studied with the modified neurological severity score. The infarct volume was evaluated via histology. Neurogenesis, angiogenesis and the protein expression of vascular endothelial growth factor (VEGF) were measured by immunohistochemistry and Western blotting analysis, respectively. The treatment with VIP significantly reduced the neurological severity score and the infarc volume, and increased the numbers of bromodeoxyuridine (BrdU) immunoreactive cells and doublecortin immunoreactive area in the subventricular zone (SVZ) at 7, 14 and 28 days after ischemia. The cerebral protein levels of VEGF and VEGF expression in the SVZ were also enhanced in VIP-treated rats at 7 days after stroke. VIP treatment obviously increased the number of BrdU positive endothelial cells in the SVZ and density of cerebral microvessels in the ischemic boundary at 28 days after ischemia. Our study suggests that in the ischemic rat brain VIP reduces brain damage and promotes neurogenesis by increasing VEGF. VIP-enhanced neurogenesis is associated with angiogenesis. These changes may contribute to improvement in functional outcome.

Topics: Animals; Antigens, CD34; Bromodeoxyuridine; Cell Count; Disease Models, Animal; Doublecortin Domain Proteins; Doublecortin Protein; Endothelial Cells; Infarction, Middle Cerebral Artery; Male; Microtubule-Associated Proteins; Nervous System Diseases; Neurogenesis; Neuropeptides; Rats; Rats, Sprague-Dawley; Time Factors; Vascular Endothelial Growth Factor A; Vasoactive Intestinal Peptide

We investigated the neuropathic effects of cisplatin in two groups of mice treated with 5 or 10 mg/kg/week of cisplatin for 7 or 8 weeks. Peripheral nerve functions were evaluated by sweat imprints, and electrophysiological, rotarod, and nociceptive tests. Protein gene product 9.5 (PGP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were immunohistochemically localized in footpads. Tibial nerves were analyzed morphometrically. Functional deficits developed progressively with higher cumulative doses, more markedly in mice treated with high than in those with low doses. From cumulative doses of 10 mg/kg, significant declines in sensory nerve conduction velocity and sudomotor responses were found, whereas motor and nociceptive functions were involved later. There were no morphometrical changes in tibial nerves. A marked decrease of CGRP- and VIP-immunoreactive nerves occurred in samples from treated mice, whereas PGP-labeled profiles decreased mildly at late stages. Impairment of the content of neuropeptides with neurosecretor role was detectable earlier than functional abnormalities. Immunohistochemical analysis of skin biopsies offers a useful diagnostic tool for peripheral neuropathies.

Topics: Animals; Antineoplastic Agents; Calcitonin Gene-Related Peptide; Cisplatin; Dose-Response Relationship, Drug; Electrophysiology; Female; Immunohistochemistry; Mice; Motor Activity; Nervous System Diseases; Nociceptors; Sweating; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Autonomic dysfunction is an increasingly recognized problem in aging animals and man. The pathologic changes that produce autonomic dysfunction in human aging are largely unknown; however, in experimental animal models specific pathologic changes have been found in selected sympathetic ganglia. To address whether similar neuropathologic changes occur in aging humans, the authors have examined paravertebral and prevertebral sympathetic ganglia from a series of 56 adult autopsied nondiabetic patients. They found significant, specific, age-related neuropathologic lesions in the prevertebral sympathetic superior mesenteric ganglia of autopsied patients. Markedly swollen dystrophic preterminal axons compressed or displaced the perikarya of principal sympathetic neurons. Ultrastructurally, these swollen presynaptic axons contained abundant disoriented neurofilaments surrounded by peripherally marginated dense core vesicles. Immunohistochemical studies demonstrated that dystrophic axons contained tyrosine hydroxylase and neuropeptide tyrosine (NPY)-like immunoreactivity but not other neuropeptides (VIP, substance P, gastrin-releasing peptide [GRP]/bombesin, met-enkephalin). Similar to the animal models of aging, lesions were much more frequent in the prevertebral superior mesenteric ganglia than in the paravertebral superior cervical ganglia. These studies demonstrate anatomic, peptidergic, and pathologic specificity in the aging human nervous system similar in many respects to that which the authors have described in experimental animal models. Neuroaxonal dystrophy in the sympathetic nervous system may underlie poorly understood alterations in clinical autonomic nervous system function that develop with age.

Topics: Adult; Aged; Aging; Autopsy; Axons; Enkephalin, Methionine; Ganglia, Sympathetic; Gastrin-Releasing Peptide; Humans; Immunohistochemistry; Microscopy, Electron; Middle Aged; Nervous System Diseases; Neurons; Neuropeptide Y; Peptides; Substance P; Synapses; Time Factors; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Nervous System Diseases; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

The effects of capsaicin, the major pungent ingredient of hot peppers, were assessed on sensory neuron neuropeptide levels and on sensory function in the adult guinea pig. Systemic doses of capsaicin as low as 2.5 mg/kg depleted substance P (SP) in dorsal roots plus ganglia (DRG) whereas a 10-mg/kg dose depleted the peptide maximally in DRG and in the dorsal spinal cord. High doses of capsaicin had no consistent effects on levels of cholecystokinin (CCK), vasoactive intestinal polypeptide, or somatostatin, although a transient decrease in CCK levels was observed 4 days after dosing. A single 5-mg/kg dose of capsaicin rendered animals completely insensitive to chemical irritation of the cornea without affecting sensitivity to noxious heat. Higher doses of capsaicin produced a marked insensitivity to nociceptive and non-nociceptive heat as well as to chemical irritation without affecting other sensory modalities. The SP depletion and sensory deficits produced by a single 50-mg/kg dose of capsaicin were still evident 10 weeks later. The pattern of selectivity of the sensory deficits produced by capsaicin differed from that produced by morphine which was active against all forms of nociceptive stimuli. The results indicate that in the guinea pig capsaicin is potent at producing a unique, long-lasting syndrome of peripheral sensory deficits that may result from an effect of the agent on SP-containing primary afferent neurons.

Topics: Animals; Capsaicin; Cholecystokinin; Dose-Response Relationship, Drug; Ganglia, Spinal; Guinea Pigs; Morphine; Nerve Tissue Proteins; Nervous System Diseases; Neurons, Afferent; Nociceptors; Peripheral Nerves; Somatostatin; Spinal Cord; Substance P; Vasoactive Intestinal Peptide

The neural and hormonal peptide content of rectal biopsy specimens from 10 patients with chronic autonomic failure, 10 patients with chronic gastrointestinal Chagas' disease, and 13 controls was studied with radioimmunoassay and immunocytochemistry. In the patients with Chagas' disease the mean concentrations of rectal vasoactive intestinal polypeptide, enteroglucagon, substance P, and somatostatin were all less than half of those in controls and in patients with chronic autonomic failure. Immunocytochemistry revealed a considerable reduction in the number and immunostaining of the peptide-containing cells and nerves. Concentrations of regulatory peptides in the rectum are thus reduced in association with intrinsic but not extrinsic autonomic neuropathy.

Topics: Autonomic Nervous System; Biopsy; Chagas Disease; Chronic Disease; Gastrointestinal Hormones; Humans; Intestinal Diseases, Parasitic; Nervous System Diseases; Rectum; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Cell Line; Cells, Cultured; Drug Resistance; Floxuridine; Glioma; Humans; Mercaptopurine; Morphine Dependence; Neoplasms, Experimental; Nervous System Diseases; Neuroblastoma; Neurophysiology; Thioguanine; Vasoactive Intestinal Peptide