VIP — Neuropeptide / immunomodulatory hormone — class B GPCR agonist (VPAC1/VPAC2 receptors)
Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide expressed in the central and peripheral nervous systems, lungs, gut, and immune cells. It acts via VPAC1 and VPAC2 (class B GPCRs) coupled to Gs/cAMP. Key mechanisms: (1) Potent bronchodilation and pulmonary vasodilation (VPAC1/VPAC2 in smooth muscle); (2) Anti-inflammatory — suppresses pro-inflammatory cytokines (TNF-α, IL-6, IL-12), promotes anti-inflammatory IL-10; shifts macrophage polarization from M1 to M2; suppresses Th1/Th17 responses; (3) Neuroprotection — reduces glutamate excitotoxicity, promotes BDNF and PACAP; (4) Gut motility regulation — relaxes intestinal smooth muscle; (5) Immunomodulation — expressed on NK cells, T cells, and B cells; modulates regulatory T cell activity. Potential in autoimmunity, post-COVID immune dysregulation, and SIBO.
Overview
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Compound Class
Neuropeptide / immunomodulatory hormone — class B GPCR agonist (VPAC1/VPAC2 receptors)
Mechanism of Action
Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide expressed in the central and peripheral nervous systems, lungs, gut, and immune cells. It acts via VPAC1 and VPAC2 (class B GPCRs) coupled to Gs/cAMP. Key mechanisms: (1) Potent bronchodilation and pulmonary vasodilation (VPAC1/VPAC2 in smooth muscle); (2) Anti-inflammatory — suppresses pro-inflammatory cytokines (TNF-α, IL-6, IL-12), promotes anti-inflammatory IL-10; shifts macrophage polarization from M1 to M2; suppresses Th1/Th17 responses; (3) Neuroprotection — reduces glutamate excitotoxicity, promotes BDNF and PACAP; (4) Gut motility regulation — relaxes intestinal smooth muscle; (5) Immunomodulation — expressed on NK cells, T cells, and B cells; modulates regulatory T cell activity. Potential in autoimmunity, post-COVID immune dysregulation, and SIBO.
Regulatory Status
NOT FDA approved for any indication. Aviptadil (synthetic VIP, NeuroRx) received FDA Fast Track designation for COVID-19 ARDS but Phase 3 did not meet primary endpoint in 2022.
Evidence Level
C — Phase 2 RCT for rheumatoid arthritis (Delgado et al., 2008, n=24) showed significant improvement in DAS28 score vs placebo. Phase 2 data for COVID-19/ARDS (NeuroRx, 2021). No Phase 3 data for any indication in the US as of 2024.