VIP: Research Applications
🫁 ARDS & COVID-19 (Aviptadil)
Aviptadil has been investigated for critical respiratory failure because it protects alveolar type II cells and blocks cytokine storm. In the Phase 2b/3 trial (NCT04311697, n=196), IV aviptadil achieved a twofold increase in 60-day survival (OR 2.0; p=0.035) and a 10-fold increase in survival among mechanically ventilated study subjects, with significant IL-6 reduction. The larger TESICO trial (n=461) was stopped for futility. [4] [20]
🧠 Neurodegenerative Disorders (Parkinson’s & Alzheimer’s)
VIP acts as a neuroprotective agent by deactivating microglia and inhibiting neurotoxin release (TNF-α, IL-1β). In Parkinson’s models, the VIPR2 agonist LBT-3627 (2.0 mg/kg) increased surviving dopaminergic neurons by 43% and reduced reactive microglia by 57–61%. In Alzheimer’s models, VIP protects against β-amyloid toxicity via ADNP induction. [19] [21]
See also: BPC-157 for related neuroprotective research.
🔬 Inflammatory Bowel Disease (IBD)
VIP maintains intestinal barrier homeostasis. VIP-loaded sterically stabilized micelles (VIP-SSM) reversed severe colitis in DSS mouse models with a single experimental dose, restoring tight junction protein occludin and chloride transporter DRA expression. Free VIP required alternate-day dosing for comparable effects. [22]
🎯 Oncology Imaging (VPAC1 PET)
VPAC1 receptors are overexpressed in breast, prostate, colon, and lung cancers. Radiolabeled VIP analogues (⁶⁴Cu-VIP, ¹²³I-VIP, Tc-99m-TP3654) enable PET imaging of tumors — achieving 87% primary detection in colorectal cancer and 100% lymph node metastasis detection. ⁶⁴Cu-VIP also detected grade IV prostate neoplasia undetectable by standard ¹⁸F-FDG PET or CT. [23] [24]
❤️ Pulmonary Hypertension
Inhaled VIP (100–200 µg) caused potent pulmonary vasodilation in 20 study subjects — decreased pulmonary artery pressure and vascular resistance, improved mixed venous oxygen saturation, and increased cardiac output — without significant systemic reported observations in study populations. VIP is 50-fold more potent than prostacyclin at relaxing pulmonary arteries. [7]
🫁 Sarcoidosis
In a Phase II trial (n=20), nebulized VIP (50 µg, 4x daily for 4 weeks) exerted immunoregulatory effects in study subjects with active sarcoidosis — significantly reducing TNF-α production in bronchoalveolar lavage (BAL) fluid and increasing regulatory T-cell counts. No systemic immunosuppression or obvious reported observations in study populations. [25]
⏰ Circadian Rhythm Regulation
The suprachiasmatic nucleus (SCN) relies on VIP signaling to synchronize cellular circadian clocks to environmental light cycles. VIP application phase-shifts circadian rhythms, with pulsing rapidly resetting rhythm via swift reduction of PER2 protein. VIP is necessary for synchronization of SCN neurons, influencing sleep and hormonal cycles. [16]
🦠 Sepsis
In a Phase I trial (n=8), IV aviptadil (50–100 pmol/kg/hr for 12 hours) achieved 75% survival (6/8) in sepsis-induced ARDS. VIP inhibits high levels of inflammatory cytokines and is viewed as a potential adjunctive experimental protocol to antibiotics for septic shock management. [26]
References
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- Said SI, Rosenberg RN. Vasoactive intestinal polypeptide: abundant immunoreactivity in neuronal cell lines and normal nervous tissues. Science, 192(4242), 907–908, 1976.
- Langer I, Jeandriens J, Couvineau A, et al. Signal transduction by VIP and PACAP receptors. Biochem Soc Trans, 50(1), 2022.
- Youssef JG, Lavin P, Schoenfeld DA, et al. The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in study subjects With Critical COVID-19 Respiratory Failure. Crit Care Med, 50(11), 1545–1554, 2022.
- Domschke S, Domschke W, Bloom SR, et al. Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut, 19(11), 1049–1053, 1978.
- Harmar AJ, Arimura A, Gozes I, et al. International union of pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev, 50(2), 265–270, 1998.
- Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J, 32(5), 1289–1294, 2008.
- Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev, 56(2), 249–290, 2004.
- Couvineau A, Laburthe M. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol, 166(1), 42–50, 2012.
- Hou X, Yang H, Bhatt VR, et al. VIP/VPAC signaling in pancreatic islet β-cells and glucose homeostasis. J Mol Endocrinol, 68(3), R65–R75, 2022.
- Smalley SG, Barrow PA, Foster N. Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its experimental potential in inflammatory disease. Clin Exp Immunol, 157(2), 225–234, 2009.
- Constantin S, Bhattarai JP, Bhatt R, et al. VIP signaling in GnRH neurons involves dual Gs/AC and Gq/PLC pathways. J Neuroendocrinol, 36(4), e13392, 2024.
- Hou X, et al. VIP/VPAC signaling in pancreatic islet β-cells: PKA and Epac pathways drive glucose-dependent insulin secretion. J Mol Endocrinol, 2022.
- Moody TW, Nuche-Berenguer B, Jensen RT. Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes, 23(1), 38–47, 2016.
- Mathioudakis AG, Chatzimavridou-Grigoriadou V, Evangelopoulou E, Mathioudakis GA. Vasoactive Intestinal Peptide Inhaled Agonists: Potential Role in Respiratory Therapeutics. Hippokratia, 17(1), 12–16, 2013.
- Kudo T, Tahara Y, Gamble KL, et al. Vasoactive intestinal peptide produces long-lasting changes in neural activity in the suprachiasmatic nucleus. J Neurophysiol, 110(5), 1097–1106, 2013.
- Said SI. Vasoactive intestinal peptide in the lung. Ann N Y Acad Sci, 527, 450–464, 1988.
- An S, Tsai C, Bhatt R, et al. Vasoactive intestinal polypeptide phase-shifts the circadian clock via cAMP/PKA dependent pathway. J Biol Rhythms, 26(4), 313–326, 2011.
- Mosley RL, Lu Y, Olson KE, et al. A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson’s Disease. Front Cell Neurosci, 13, 421, 2019.
- Brown SM, Barkauskas CE, Grund B, et al. Intravenous aviptadil and remdesivir for investigation of COVID-19-associated hypoxaemic respiratory failure (TESICO). Lancet Respir Med, 11(9), 791–803, 2023.
- Delgado M, Ganea D. Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. FASEB J, 17(8), 944–946, 2003.
- Jayawardena D, Guzman G, Gill RK, et al. Expression and localization of VPAC1, the major receptor of vasoactive intestinal peptide along the length of the intestine. Am J Physiol Gastrointest Liver Physiol, 313(1), G16–G25, 2017.
- Virgolini I, Raderer M, Kurtaran A, et al. Vasoactive intestinal peptide-receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors. N Engl J Med, 331, 1116–1121, 1994.
- Zhang K, Aruva MR, Shanthly N, et al. PET imaging of VPAC1 expression in experimental and spontaneous prostate cancer. J Nucl Med, 49(1), 112–121, 2008.
- Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med, 182(4), 540–548, 2010.
- Youssef JG, Said SI, et al. Rapid clinical recovery from critical COVID-19 with respiratory failure in a lung transplant patient treated with intravenous vasoactive intestinal peptide. Preprints, 2020.
- Esendagli D, Sarı N, Akhan S, et al. Inhaled Aviptadil Is a New Hope for Recovery of Lung Damage due to COVID-19. Med Princ Pract, 34(2), 191–200, 2025.
- Dewan B, Shinde S. Aviptadil in acute respiratory distress syndrome associated with covid-19 infection. Eur J Pharm Med Res, 9(6), 243–253, 2022.
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