VIP

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide that was first isolated from porcine intestine in 1970 by Sami Said and Viktor Mutt. Its initial discovery centered on its ability to cause vasodilation and influence intestinal function—hence the name. However, over five decades of research have revealed VIP to be far more than a gut hormone, establishing it as a crucial signaling molecule in the nervous system, immune system, and multiple organ systems throughout the body.

VIP belongs to the glucagon-secretin superfamily of peptides, which also includes PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide), secretin, and glucagon. It exerts its biological effects by binding to two G-protein coupled receptors: VPAC1 and VPAC2. These receptors are widely distributed throughout the body—VPAC1 predominates in lung, liver, and T lymphocytes, while VPAC2 is more abundant in smooth muscle, brain, and pancreas. This broad receptor distribution underlies VIP's remarkably diverse physiological functions.

In the nervous system, VIP acts as a neurotransmitter and neuromodulator, with particularly important roles in the enteric nervous system (the 'second brain' governing gut function) and the suprachiasmatic nucleus (the brain's master circadian clock). Neurons expressing VIP are found throughout the central and peripheral nervous systems, where the peptide influences synaptic transmission, neuronal survival, and neural stem cell differentiation.

What has driven intense research interest in VIP over recent decades is its potent anti-inflammatory and immunomodulatory activity. VIP can shift immune responses from inflammatory to tolerogenic phenotypes, suppress pro-inflammatory cytokine production, and promote regulatory T cell function. These properties have been demonstrated across numerous autoimmune disease models, positioning VIP as a promising therapeutic candidate for conditions where immune dysregulation drives pathology.

VIP's mechanisms of action are multifaceted, operating through receptor-mediated signaling cascades that ultimately influence gene expression, cellular function, and tissue homeostasis. Understanding these mechanisms helps explain VIP's broad therapeutic potential.

Receptor Binding and Signal Transduction

VIP binds with high affinity to two class B G-protein coupled receptors: VPAC1 and VPAC2. Upon binding, these receptors activate adenylyl cyclase, increasing intracellular cyclic AMP (cAMP) levels. This activates protein kinase A (PKA), which phosphorylates downstream targets affecting gene transcription, ion channel activity, and cellular metabolism. VIP can also activate additional signaling pathways including PI3K/Akt and MAPK cascades, contributing to its diverse biological effects.

Anti-Inflammatory Mechanisms

VIP's anti-inflammatory effects operate at multiple levels of the immune response:

Neuroprotective Mechanisms

In the nervous system, VIP protects neurons through several complementary pathways. It upregulates expression of brain-derived neurotrophic factor (BDNF) and other survival factors. VIP reduces oxidative stress by enhancing antioxidant enzyme activity and decreasing reactive oxygen species production. It also inhibits microglial activation, reducing neuroinflammation that can damage neurons in conditions like Parkinson's and Alzheimer's disease.

Gut and Barrier Function

In the gastrointestinal tract, VIP released from enteric neurons regulates motility, secretion, and blood flow. It relaxes smooth muscle (contributing to peristalsis coordination), stimulates fluid secretion, and dilates mesenteric blood vessels. Critically for gut health, VIP enhances intestinal barrier function by upregulating tight junction proteins like occludin and claudins, helping maintain the epithelial barrier that separates gut contents from underlying tissue.

Circadian Clock Synchronization

VIP-expressing neurons in the suprachiasmatic nucleus (SCN) play an essential role in circadian rhythm coordination. VIP release synchronizes the firing of SCN neurons, ensuring they function as a coherent biological clock. Without VIP signaling, individual neurons become desynchronized, disrupting circadian output signals that coordinate sleep-wake cycles, hormone release, and metabolism throughout the body.

VIP has been extensively studied in preclinical models for over four decades, with research demonstrating therapeutic potential across a remarkable range of conditions. More recently, clinical trials have begun evaluating VIP and its analogs in human patients.

Inflammatory Bowel Disease

Research in animal models of colitis has consistently shown VIP reduces intestinal inflammation and promotes mucosal healing. VIP administration decreased clinical disease scores, reduced pro-inflammatory cytokine levels in gut tissue, and improved histological measures of inflammation. Mechanistic studies revealed VIP acts on both immune cells infiltrating the gut and on epithelial cells directly, enhancing barrier function while dampening inflammation. Human studies remain limited, but the preclinical evidence supports VIP as a candidate for Crohn's disease and ulcerative colitis research.

Rheumatoid Arthritis

In collagen-induced arthritis models (the standard preclinical model for RA), VIP treatment reduced joint swelling, cartilage destruction, and bone erosion. Studies demonstrated VIP decreased levels of autoantibodies and shifted the cytokine profile in joints from inflammatory to regulatory. VIP also protected chondrocytes from inflammatory damage. These effects were mediated through both local anti-inflammatory action and systemic immunomodulation. A small open-label human study showed some clinical improvement in RA patients receiving intravenous VIP, though controlled trials are needed.

Multiple Sclerosis

Experimental autoimmune encephalomyelitis (EAE), the primary animal model for multiple sclerosis, has been extensively studied with VIP treatment. VIP reduced disease severity, decreased demyelination, and lowered the infiltration of inflammatory cells into the central nervous system. The mechanism involved suppression of encephalitogenic T cells and induction of regulatory T cells. VIP also directly protected oligodendrocytes (the myelin-producing cells) from inflammatory damage. While human MS trials haven't been completed, these findings position VIP as a candidate for neuroinflammatory conditions.

Parkinson's Disease

VIP has shown neuroprotective effects in multiple Parkinson's disease models. In MPTP-treated mice (a neurotoxin model that damages dopaminergic neurons), VIP protected substantia nigra neurons from death and preserved motor function. Similar protection was seen in 6-OHDA models. Mechanistic studies attributed these effects to VIP's ability to reduce oxidative stress, inhibit microglial activation, and provide direct neurotrophic support to dopaminergic neurons. These findings suggest potential for VIP in slowing Parkinson's progression, though human trials have not been conducted.

COVID-19 and Respiratory Failure

During the COVID-19 pandemic, inhaled VIP (Aviptadil) was evaluated in clinical trials for treating respiratory failure. The rationale included VIP's expression in lung tissue, its ability to protect type II pneumocytes (preferentially infected by SARS-CoV-2), and its anti-inflammatory effects against cytokine storm. While some trials reported improvements in oxygenation and respiratory outcomes, results have been inconsistent, and the FDA has not approved VIP for COVID-19 treatment. This research nevertheless highlighted VIP's potential in acute respiratory conditions.

Establishing optimal VIP dosing protocols for research applications remains an area of active investigation. The peptide's very short half-life creates unique challenges that have driven development of various administration strategies and stabilized analogs.

Preclinical Dosing Ranges

In animal studies, VIP doses have varied significantly depending on the model, route of administration, and outcome being measured. For systemic inflammation models, intraperitoneal doses typically range from 1-10 nmol per mouse, often given once or twice daily. Localized delivery approaches use lower total doses, as in intra-articular injection for arthritis models.

Administration Routes

Intravenous: Provides immediate systemic distribution but requires continuous infusion to maintain levels due to the short half-life. Used in some human studies but impractical for chronic treatment.

Intraperitoneal: Standard route for rodent studies. Achieves rapid absorption and systemic distribution.

Intranasal: Allows VIP to bypass the blood-brain barrier and access the CNS directly. Particularly relevant for neurological applications and avoids peripheral degradation.

Inhaled: Used in pulmonary research including COVID-19 trials. Delivers VIP directly to lung tissue where VPAC receptors are abundant.

Subcutaneous: Less commonly used due to rapid local degradation, though stabilized analogs may be more suitable for this route.

Stabilized VIP Analogs

To address the short half-life limitation, researchers have developed modified VIP analogs with improved stability:

• Stearyl-VIP: Fatty acid conjugation extends half-life and improves membrane interaction
• PEGylated VIP: Polyethylene glycol attachment reduces renal clearance
• D-amino acid substitutions: Replace specific residues with D-amino acids to resist enzymatic cleavage
• Cyclic VIP analogs: Constrained structures with enhanced stability

Reconstitution and Handling

VIP is typically supplied as a lyophilized powder and should be reconstituted in sterile water or saline. Due to its susceptibility to degradation, reconstituted VIP should be aliquoted immediately and stored frozen at -20°C or below. Avoid repeated freeze-thaw cycles. Working solutions should be prepared fresh and kept cold during experiments.

VIP's safety profile has been evaluated in numerous preclinical studies and limited human trials. As an endogenous peptide with physiological roles throughout the body, VIP generally demonstrates good tolerability, though its potent vasodilatory effects require careful consideration.

Cardiovascular Effects

The most commonly observed effects of VIP administration relate to its vasodilatory properties. VIP causes relaxation of vascular smooth muscle, leading to decreased blood pressure. In clinical settings, this manifests as:

Gastrointestinal Effects

Given VIP's role in gut function, gastrointestinal effects can occur:

• Diarrhea (VIP stimulates intestinal secretion)
• Abdominal discomfort
• Nausea (usually mild)

These effects are dose-related and typically resolve as VIP is rapidly cleared from circulation.

Preclinical Safety Data

Chronic administration studies in animals have not revealed significant toxicity. VIP does not appear to be carcinogenic or teratogenic in the studies conducted to date. Immunological assessments have not shown concerning immunosuppression or increased infection susceptibility, despite VIP's immunomodulatory effects—possibly because VIP promotes immune tolerance rather than broad immunosuppression.

Human Trial Experience

Clinical trials with VIP and its analogs have reported a favorable safety profile. In COVID-19 respiratory trials, inhaled VIP (Aviptadil) was generally well-tolerated. Adverse events were mostly mild and related to vasodilation. However, the total human exposure remains limited compared to approved therapeutics, and long-term safety data are not available.

Contraindications and Precautions

Based on VIP's mechanisms, theoretical contraindications would include:

• Significant hypotension or cardiovascular instability
• VIPoma (VIP-secreting tumor)—these patients already have excess VIP
• Conditions requiring intact inflammatory responses (active infections)
• Pregnancy (insufficient safety data)