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.
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
- Headaches, often leading to agitation and irritability
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.
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.
1. VIPoma. https://rarediseases.info.nih.gov/diseases/5493/vipoma
2. 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/
3. 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/
4. 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/
5. 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/
6. 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/
7. 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/
8. 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/
9. 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/
10. 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/
11. 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/
12. 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/
13. 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
14. 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/
15. This might be the breakthrough coronavirus cure we’ve been waiting for. https://bgr.com/science/coronavirus-cure-rlf-100-aviptadil-phase-3-trial/
16. 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/
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