VIP
Guide on VIP for Anti-Inflammatory, Anti-Fibrotic, and Neuroprotective Therapy
VIP Peptide Structure
Amino Acid Sequence: HSDAVFTDNYXRLRKQMAVKKYLNSXLN
Molecular Formula: C147H237N43O43S
Molecular Weight: Human Gene: VIP; 6q25.2
PubChem CID: 44567960
CAS Number: 37221-79-7
Synonyms: VIP, PHM27, Vasoactive intestinal polypeptide
VIP Research
Bowel Inflammation
As it turns out, one of the primary producers of VIP is the immune nerve fibers in blood vessels of the central and peripheral nervous systems and heart. Additionally, VIP is produced directly by cells of the immune system where it helps to promote Th2-type responses which can reduce inflammation and quiet the immune system. VIP and analogues derived from it have been heavily investigated as potential inflammatory mediators in intestinal disease, heart disease, and neuroinflammatory conditions[1], [2].
The various roles of VIP in immunomodulation:
In the setting of inflammatory bowel diseases (IBDs) like Crohn’s and ulcerative colitis, VIP has been found to improve intestinal barrier homeostasis and reduce inflammation driven by Th1 cell actions[3]. This latter approach, in particular, appears to generate T cells capable of producing the inflammation suppressing peptide interleukin-10[4]. In recent years it has become apparent that Th1 inflammation is one of several important pathways in IBD.
The benefit of improved intestinal barrier function should not be understated as it is hypothesized to be a contributing cause in the pathogenesis of inflammatory bowel disease. In particular, it is thought that compromised barrier function leads to increased antigenic material in the space between cells where it is more likely to interact with immune cells and set off an inflammatory response. Mitigating antigen presentation to immune cells via improved barrier function secondary to VIP would thus reduce what is believed to be one of the first steps in the cascade of events leading to colitis and severe inflammatory bowel disease[3].
Vasoactive Intestinal Peptide in Lung Function
There are at least two ways in which VIP impacts lung function. In the first mechanism, VIP modulates pulmonary vascular remodeling in response to inflammation. It appears to have this effect though suppression of a peptide call NF fect though suppression of a peptide call NFAT, which activates , which activates T cells and leads to increased cells and leads to increased inflammation[5]. Consistent with its roll in modulating inflammation in other tissues, VIP appears to control T-cell mediate inflammation in the lungs, a process that heretofore has been difficult to address in models of inflammation. In particular, NFAT suppression may play a very important role in preventing pulmonary fibrosis, the end stage of a number of inflammatory conditions such as COPD, sarcoidosis, etc[6]. Thus, VIP may provide a very useful mechanism for preventing the kind of end stage lung disease that can only be cured by transplant and which often results in serious morbidity and even death.
VIP also appears to inhibit the proliferation of smooth muscles in pulmonary tissue. Smooth muscle cell proliferation is one of the long-term consequences of lung inflammation and is a particular problem in bronchial asthma that has been uncontrolled for extended periods[7]. There is hope that VIP will provide a mechanism by which to mitigate the effects of long-term inflammation secondary to asthma.
There is also exceptional evidence that the vasodilatory effects of VIP, which are known to help control blood pressure, may have a highly potent effect in pulmonary vasculature. Preliminary research shows that VIP lowers blood pressure significantly in the pulmonary artery, leading to increased cardiac output and improved venous oxygen saturation[8]. While more work remains to be done, there is significant hope that VIP will offer a new modality for improving lung function in the setting of primary vascular conditions.
VIP in Transplants
One of the primary problems with organ transplants is rejection by the body’s immune system. No matter how good the match between donor and recipient, the body mounts a response against transplanted organs that eventually leads to their destruction and failure. Currently, the only solution to this problem is the use of broad-spectrum anti-inflammatory medications. Unfortunately, these drugs can lead to susceptibility to serious infections and have side effects of their own, such as scarring and organ fibrosis, that can limit their use.
Research on VIP has revealed that the peptide affects dendritic cells (DCs). DCs are important in the immune response because they help the body to recognize antigens and mount appropriate countermeasures. By reducing DC proliferation and activation, VIP helps to thwart immune responses before they are even mounted. Interestingly, this function seems to favor DCs attached to antigens that are tolerogenic. In other words, VIP selectively inhibits the proliferation of DCs that might cause an autoimmune reaction. This is an area of active research as VIP could potentially reduce transplant rejection with fewer infection-promoting side effects[9]. This could make VIP or an analogue of it the foundation of transplant anti-rejection medicine in the future.
VIP as a Neuroprotectant
The role of VIP in the central nervous system is threefold: neurotransmitter, neurotrophic/neurogenic, and anti-inflammatory/neuroprotectant. As with the intestine, VIP’s role in the CNS begins with maintaining barriers. In this case, the peptide helps to maintain the very critical function of the blood-brain barrier (BBB)[10]. The BBB is a layer of cellular protection between blood vessels and the tissue of the central nervous system. It regulates what enters neurological tissue and thus controls everything from nutrition and oxygenation to immune function. Compromise of the BBB has been implicated in the pathophysiology of multiple sclerosis, encephalomyelitis, and even stroke.
VIP has also been shown to regulate the accumulation of beta amyloid in mouse models of Alzheimer Alzheimer’s disease and is known to of s disease and is known to offer neuroprotective ef fer neuroprotective effects in Parkinson’ fects in Parkinson’s disease[1 s disease[11], [12]. 1], [12]. There is also evidence that VIP is an important neuroprotectant in the developing brain where it helps to ward of excitotoxic white matter damage and improve neuron fatty acid myelination[13]. In the case of Parkinson’s disease, VIP appears to offer a similar benefit as in other inflammatory settings by shifting the immune balance away from inflammatory Th1 responses toward antiinflammatory Th2 responses[14].
The exact role of VIP The exact role of VIP in Alzheimer Alzheimer’s disease (AD) is less clear s disease (AD) is less clear. Research shows that processing of . Research shows that processing of VIP is inhibited in AD with levels of the peptide as well as amino acid byproducts being lower in the brains of people affected by AD[15], [16]. Again, the research is unclear at this point, but infusion of VIP into the brains of mice shows a substantial reduction in beta amyloid levels, proving that the peptide plays an important role in the pathophysiology of the disease.
The effects of VIP in protecting the CNS appear to be mediated through VPAC1 and VPAC2 receptors. In both cases, stimulation appears to result in increased secretion of neurotrophic factors like ADNP (activity-dependent neurotrophic factor) and BDNF (brain-derived neurotrophic factor). Both of these peptides help to protect synapses and astrocytes.
Cardiac Fibrosis
As with lung disease, fibrosis is the end stage of a number of different heart conditions. Cardiac fibrosis leads to a number of serious problems including valve dysfunction, decreases in contractility, changes in cardiac filling, and electrical problems. As in lung disease, cardiac fibrosis is the common end stage of many heart conditions and generally necessitates transplant in order to avoid mortality.
To date, most cardiac research has focused on preventing scar formation from occurring. A number of commonly used drugs can, at least to some extent, help to slow the process of cardiac remodeling that leads to scarring. Unfortunately, very few cases are 100% successful and most people experience progressive fibrosis and decline in cardiac function. Recent research in rats, however, indicates that VIP may not only slow fibrosis down, but can reverse scarring. It appears that at least part of this effect is mediated through a massive reduction in angiotensinogen and angiotensin receptor type 1a expression. This makes sense as angiotensin receptor blockers and ACE inhibitors have long been known to slow down cardiac modeling/fibrosis and are in fact the first line of prevention for fibrosis[17].
Guide to Multifunctional VIP Peptide
There are several hormones found in the multicellular organisms which help regulate the various physiological functions and behavior. Hormones, or signaling molecules, are transported to distant organs in the body and gradually, over time, these molecules influence the growth and development mechanisms of the body. One such hormonal peptide found naturally in the body is called Vasoactive Intestinal Peptide, or simply, VIP.
VIP has a vast spectrum of activities, including but not limited to neuromodulation and neurotransmission functions – which are all discussed in detail here.
As with all biological chemicals, it is crucial to maintain optimal levels of VIP peptide in our body. Adverse medical conditions, such as VIPoma (rare endocrine tumor)(1), and increased age may lead to imbalance in the VIP peptide levels. During such times, it is vital to regulate the peptide levels through exogenous administration, as needed.
VIP Peptide Basics
VIP is a short peptide hormone composed of 28 amino acid residues and found naturally in both peripheral and central nervous systems (including pancreas, gut, and brain)(2).
The wide distribution of the peptide throughout the body reflects its pleiotropic effects not only as a neurotransmitter and vasodilator, but also as immune regulator and secretagogue (2).
Given the wide range of uses, VIP has been of immense interest amongst researchers to cover all the facets and fully explore its functionalities. Below is a summary of some of the key aspects of the peptide.
Historical Background
VIP peptide was first discovered in the 1970s where it was isolated from the porcine small intestine and classified as a vasodilator (3).
A few years later, VIP was identified in the nervous systems in the human body, along with cardiac, gastrointestinal, and reproductive systems. Given the vast distribution, VIP was linked with a wide range of biological events, including immunological functions, growth and development, and cellular functions.
Working of VIP Peptide
Via SCN Pathway
The suprachiasmatic nucleus (SCN) is a small part of the brain, located above the optic chiasm. It is primarily responsible for the circadian cycle, a natural process which helps regulate the sleep – wake cycle almost every 24 hours. This activity is said to be higher during daylight while lower at night (4).
VIP peptide plays an important role in maintaining the communications between brain cells. VIP and associated neurons are found in the lateral part of the SCN, also located the optic chiasm. These neurons obtain the retinal information from this optic chiasm and transcribe the information to the SCN. This helps in maintaining the circadian cycle in the body.
Via Binding with G Protein Coupled Receptors
VIP peptide is known to bind with three types of G protein coupled receptors, namely VPAC1, VPAC2 and PAC1. Upon binding with these receptors, it activates the pathway associated with adenylate cyclase (key regulatory enzyme), resulting in biological activity (5).
The primary difference amongst the three receptors is their localization. VPAC1 is mainly expressed in the brain and peripheral area, such as liver, lungs, intestine and immune cells; whereas VPAC2 is expressed in the central nervous system and other peripheral area such as pancreas, heart, kidney, skeletal muscles, gastrointestinal and reproductive tract, and PAC1 is predominant in the brain and adrenal region (5).
Owing to the wide distribution of the receptors, it is evident that VIP and receptor binding can affect different targets in the central and peripheral system (depending on receptor location).
Biological Effects of VIP Peptide
As previously mentioned, VIP peptide has a wide variety of clinical effects, including but not limited to:
- Lower blood pressure
- Stimulate dilation of smooth muscles in the GI tract
- Stimulate water and electrolyte secretion in intestine
- Potential use in the treatment of heart failure
- Stimulate contraction of the heart muscle, increasing heart rate
- Elevate glycogen metabolism in liver
- Regulate vaginal lubrication
- Regulate prolactin secretion
- Regulate circadian rhythm (sleep – wake cycle)
- Neuroprotective function against oxidative stress
- Reduce inflammation
- Alter cardiac fibrosis
- Modulate lung function
- Studies showing promising results in preliminary studies against Covid-19
Research and Clinical Studies
Studies with Anti-inflammatory Properties
Research (6) has shown that VIP, produced directly by immune cells themselves, exhibits various immunological functions to maintain an equilibrium of the immune system. Several studies have shown that VIP possesses anti-inflammatory properties, in both innate (hereditary) immunity and adaptive (acquired) immunity.
In innate immunity, VIP inhibits the synthesis of inflammatory chemicals such as cytokines and chemokines; while in adaptive immunity, VIP inhibits responses of the inflammatory Th1-type cells and promotes Th2-type cell responses.
Due to its ability to reduce Th1-type inflammatory cell actions, VIP has been identified to improve intestinal immunity and decrease inflammation in diseases such as Inflammatory Bowel disease, ulcerative colitis and Crohn’s disease (7).
Studies with Transplants
One of the major causes of transplant failures is rejection by one’s own immune system. No matter how perfect the match is between the donor and recipient’s organs, there are high chances the recipient’s body generates a series of anti-immune responses towards the transplanted organ leading to failure. The only current medications to counteract this reaction are anti-inflammatory drugs. Sadly enough, these drugs may also potentially lead to other serious fatal infections, such as fibrosis, which limits their use.
Research (8,9) has shown that the VIP may potentially be useful in treating several autoimmune disorders and transplant rejection due to its ability to regulate the differentiation of dendritic cells.
Dendritic cells are vital for the body to generate immune responses as they help identify antigens and mount corresponding immune reactions to ‘fight’ the antigen. By lowering the proliferation of these cells, VIP peptide helps prevent any autoimmune response before it even gets initiated. Interestingly, the VIP peptide exhibits selective property towards dendritic cell inhibition and only exerts their inhibition if the cells are likely to generate autoimmune responses.
While efforts are still ongoing to fully understand this aspect of VIP, research so far has shown promising results for the peptide in counteracting transplant rejection.
Studies Exhibiting Neuroprotective Properties
Maintaining Blood Brain Barrier
The blood brain barrier (BBB) is a crucial part of the nervous system as it provides cellular protection to the tissues and blood vessels of the central nervous system. BBB filters everything from oxygen to nutrition factors that may potentially enter these neurological vessels and affect the immune function.
Compromise of the BBB may lead to severe ailments such as multiple sclerosis and even stroke. Research has shown that VIP has the potential to protect the functioning of the BBB due to its neuroprotective properties (10).
Counteracting Parkinson’s Disease
Studies (11) have shown that VIP possesses a crucial neuroprotective function whereby it helps wash away any excitotoxic damaged white matter in the developing brain and improve the neuron fatty acid maturation. Analogous to before, the peptide reduces Th1-type inflammatory responses and shifts to Th2-type responses. Owing to this phenomenon, it helps counteract Parkinson’s disease.
Role in Alzheimer’s disease
While the role of VIP in Alzheimer’s disease is not clear, it is noted that the peptide levels and associated neuronal levels drop significantly in the patients suffering from this cognitive impairment. A study (12) has shown that when the mice model, suffering from induced cognitive impairment and were treated with VIP peptide, it led to reduction in the concentration of beta amyloid cells. This event demonstrates the ability of the peptide to counteract with the Alzheimer’s disease progression.
Studies with Cardiac Fibrosis
Cardiac Fibrosis is considered an end stage of several different cardiac ailments, as it leads to various serious cardiac dysfunctions including decreased contraction, improper valve function and abnormal changes in cardiac pumping. This condition usually necessitates a heart transplant in order to improve chances of survival.
The pathophysiology of cardiac fibrosis shows high association with the angiotensinogen receptors and angiotensinogen converting enzymes (ACE), both of which lead to vascular inflammation. Research (13) has shown that VIP peptide administration promotes significant reduction in these angiotensinogen expressions – similar to medications classified as ACE inhibitors. As a result, VIP can help counteract cardiac fibrosis and also reverse scarring of the heart muscles.
VIP and Social Behavioral Responses
As mentioned earlier, VIP neurons are found in the hypothalamus region which are associated with social behavior of certain multicellular organisms.
Studies (14) have shown that the VIP neurons are activated based on the social circumstances that trigger certain regions of the brain known to regulate behavioral responses. The activation of the VIP neurons in the hypothalamus region also triggers the secretion of prolactin hormones in the body. This secretion of the prolactin hormone is known to trigger behaviors such as aggression and parental care.
Studies Demonstrating Use in Covid-19 Treatment
Covid-19 is an infectious disease caused by the SARS-CoV-2 virus, mainly affecting the lung tissues and leading to severe fatal reactions in the body. Research is ongoing to date on how to prevent and combat this ailment as the world continues to fight the pandemic.
One recent development (15) in the research of Covid-19 treatment was the use of Aviptadil (RLF-100), a synthetic version of the VIP peptide. This medication, similar to endogenous VIP peptide, prevents inflammatory cytokine synthesis. This in turn leads to protecting and promoting the alveolar cell function in the lungs that is responsible for the oxygen exchange that occurs in the lung tissues. This study has demonstrated that the medication can help prevent SARS-CoV-2 penetration and infection in the lung cells.
Owing to the positive results of the study, FDA has fast-tracked the phase 2 and 3 clinical trials of the synthetic VIP administration for Covid-19 treatment. While preliminary results have been promising so far, more clinical data is awaited.
Side Effects of VIP
Based on the scientific studies conducted so far, VIP has demonstrated to possess an outstanding safety profile with small, low risk side effects.
Below listed are the potential side effects, which are also common with other peptides, that may occur with exogenous VIP administration:
- Redness and temporary pain at the site of administration
- Low blood pressure
- Skin rashes
- Lightheadedness
- Headaches, often leading to agitation and irritability
Pharmacokinetic Profile
A study (16) was conducted where four healthy volunteers were administered with incremental doses of 0.6, 1.3, and 3.3 pmol/kg/min of VIP over 30 minute intervals via intravenous route of administration.
It was noted that even the smallest dose of the VIP peptide led to significantly elevated plasma levels of VIP. After the study, once the administrations were ceased, the plasma levels fell strikingly, with an average clearance half time of 1 minute. Based on the calculations, it was determined that the clearance rate of the VIP peptide is 9ml/kg body weight per minute, while the distribution volume is 14ml/kg body weight.
Summary
Vasoactive Intestinal Peptide, aka VIP, is an endogenous hormonal peptide composed of 28 amino acid residues. It is found in several areas of the body, mainly the peripheral and central nervous system.
The peptide primarily functions by binding with the G protein coupled receptors, which include VPAC1, VPAC2 and PAC1. Since the receptors and peptides are vastly spread throughout the body, VIP is identified to affect a wide range of biological functions.
Extensive medical research has demonstrated that VIP has potent anti-inflammatory responses that can be used to counteract major ailments such as Crohn’s disease, inflammatory bowel disease, cardiac fibrosis and transplant rejection. Preliminary clinical trials have also demonstrated the promising effects of the peptide in treating Covid-19 pandemic.
While the peptide discovery occurred almost 50 years ago, research continues to date to fully explore the functionalities of the peptide and establish its use as a potent therapeutic agent.
References:
- VIPoma. https://rarediseases.info.nih.gov/diseases/5493/vipoma
- Delgado, M., & Ganea, D. (2013). Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino acids, 45(1), 25–39. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883350/
- Iwasaki, M., Akiba, Y., & Kaunitz, J. D. (2019). Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Research, 8, F1000 Faculty Rev-1629. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743256/
- Welsh, D. K., Takahashi, J. S., & Kay, S. A. (2010). Suprachiasmatic nucleus: cell autonomy and network properties. Annual review of physiology, 72, 551–577. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758475/
- Vosko, A. M., Schroeder, A., Loh, D. H., & Colwell, C. S. (2007). Vasoactive intestinal peptide and the mammalian circadian system. General and comparative endocrinology, 152(2-3), 165–175. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994114/
- Gonzalez-Rey E, Delgado M. Role of vasoactive intestinal peptide in inflammation and autoimmunity. Curr Opin Investig Drugs. 2005 Nov;6(11):1116-23. https://pubmed.ncbi.nlm.nih.gov/16312132/
- Seo S, Miyake H, Alganabi M, Janssen Lok M, O’Connell JS, Lee C, Li B, Pierro A. Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis. https://pubmed.ncbi.nlm.nih.gov/31668399/
- Chorny A, Gonzalez-Rey E, Delgado M. Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation. Ann N Y Acad Sci. 2006 Nov;1088:187-94. https://pubmed.ncbi.nlm.nih.gov/17192565/
- Chorny, A., Gonzalez-Rey, E., Fernandez-Martin, A., Pozo, D., Ganea, D., & Delgado, M. (2005). Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders. Proceedings of the National Academy of Sciences of the United States of America, 102(38), 13562–13567. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1224633/
- Staines DR, Brenu EW, Marshall-Gradisnik S. Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment? Neuropsychiatr Dis Treat. 2009;5:81-9. Epub 2009 Apr 8. PMID: 19557103; PMCID: PMC2695238. https://pubmed.ncbi.nlm.nih.gov/19557103/
- Mosley RL, Lu Y, Olson KE, Machhi J, Yan W, Namminga KL, Smith JR, Shandler SJ, Gendelman HE. A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson’s Disease. Front Cell Neurosci. 2019 Sep 18;13:421. https://pubmed.ncbi.nlm.nih.gov/31619964/
- Solés-Tarrés, I., Cabezas-Llobet, N., Vaudry, D., & Xifró, X. (2020). Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Peptide Against Cognitive Decline in Neurodegenerative Diseases. Frontiers in cellular neuroscience, 14, 221. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380167/
- Karen A. Duggan, George Hodge, Juchuan Chen, Tegan Hunter, Vasoactive intestinal peptide infusion reverses existing myocardial fibrosis in the rat, European Journal of Pharmacology, Volume 862, 2019, 172629, ISSN 0014-2999. https://www.sciencedirect.com/science/article/pii/S0014299919305813
- Kingsbury MA. New perspectives on vasoactive intestinal polypeptide as a widespread modulator of social behavior. Curr Opin Behav Sci. 2015 Dec 1;6:139-147. https://pubmed.ncbi.nlm.nih.gov/26858968/
- This might be the breakthrough coronavirus cure we’ve been waiting for. https://bgr.com/science/coronavirus-cure-rlf-100-aviptadil-phase-3-trial/
- Domschke, S., Domschke, W., Bloom, S. R., Mitznegg, P., Mitchell, S. J., Lux, G., & Strunz, U. (1978). Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut, 19(11), 1049–1053. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1412244/
Summary
VIP Nasal Spray (Vasoactive intestinal peptide – Aviptadil)
Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain.
VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gallbladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.
VIP has a half-life (t½) in the blood of about two minutes.
Proven gut repair, increases glycogenolysis, contractility in the heart, lowers arterial blood pressure, relaxes the smooth muscle of trachea, stomach and gallbladder.
Regulates prolactin secretion, full balancing of circadian rhythm, can assist with osteoarthritis.
1 Spray p/nostril, up to 4 times p/day, or as prescribed by your healthcare practitioner.
Store in freezer until 1st use, then expiry starts 60 days in fridge at 2°C - 8°C.