Blocking Substance P's Receptor Reduces Abnormal Blood Vessel Growth in the Cornea | Research

The takeaway

NK1 receptor antagonists that block Substance P activity reduced both blood and lymphatic vessel growth in injured mouse corneas, offering a potential new approach to treating corneal neovascularization.

Dual vessel reduction
Lanepitant reduced both hemangiogenesis (blood vessel) and lymphangiogenesis (lymphatic vessel) growth in the cornea by blocking Substance P's NK1 receptor

What the researchers found

Substance P levels increased in injured corneas in both the alkali burn and suture models. The NK1R antagonist Lanepitant, applied topically as eye drops, was nontoxic and reduced both blood vessel (hemangiogenesis) and lymphatic vessel (lymphangiogenesis) growth, corneal SP levels, and inflammatory cell (leukocyte) infiltration within 4 days in the alkali burn model.

Subconjunctival injection of Lanepitant was effective in the suture model (where topical drops were insufficient), reducing lymphatic vessels, leukocyte infiltration, and SP levels after 10 days. In the alkali burn model, subconjunctival Lanepitant additionally reduced corneal perforation rates, opacity, and improved tear secretion. Befetupitant also showed efficacy but its vehicle (DMSO) was toxic to the eye surface.

Why it matters

Corneal neovascularization is a leading cause of vision loss worldwide, occurring after infections, chemical burns, contact lens complications, and transplant rejection. Current treatments (steroids, anti-VEGF agents) have significant limitations. Targeting Substance P through NK1R antagonists represents a completely different approach — addressing the neurogenic inflammation that drives vessel growth rather than blocking the growth factors directly. Since Lanepitant was already developed for other indications, repurposing it as an eye drop could accelerate clinical translation.

How the study worked

Researchers used two mouse models of corneal neovascularization (alkali burn and suture) in C57BL/6 mice. They tested Lanepitant and Befetupitant at different concentrations via topical eye drops or subconjunctival injection. Outcomes included clinical examination, Substance P levels, corneal neovascularization index, and leukocyte infiltration measurements.

What this study cannot tell us

This is a mouse study, and corneal biology differs between mice and humans. The topical formulation was ineffective in the suture model (requiring injection), which may limit practical application. Specific quantitative outcome data (percentage reductions, p-values for each comparison) are partially described but not fully detailed in the abstract. Befetupitant's vehicle toxicity prevented complete evaluation. Long-term safety and efficacy of repeated NK1R antagonist use on the eye surface were not assessed.

How to read the evidence

This is a preclinical animal study using two validated mouse models of corneal neovascularization. The use of multiple models, routes, and concentrations strengthens the findings, but no human data exists yet.

When this study was published

Published in 2014, this study introduced NK1R antagonists as a potential corneal neovascularization treatment. The concept has been explored further since, though clinical translation to ophthalmology is still in progress.

The bigger picture

Substance P is a neuropeptide involved in pain and inflammation throughout the body. This study reveals its specific role in driving abnormal blood vessel growth in the cornea — linking the nervous system to vascular pathology. The finding that NK1R blockade reduces both blood and lymphatic vessel growth is noteworthy because lymphatic vessels are important for transplant rejection. This could make NK1R antagonists valuable as adjunctive therapy after corneal transplantation.

Questions still open

Would NK1R antagonist eye drops be effective in human corneal neovascularization, and could they complement existing anti-VEGF treatments?
Could NK1R blockade reduce corneal transplant rejection by inhibiting lymphatic vessel growth in the cornea?

Common questions

What is corneal neovascularization and why is it dangerous?

The cornea is normally the only transparent tissue in the body without blood vessels — this clarity is what lets light pass through to your retina. When the cornea is injured or inflamed, new blood vessels can grow into it (neovascularization), blocking light and causing vision loss. It's a leading cause of blindness worldwide, occurring after infections, chemical injuries, and contact lens problems.

What is Substance P's role in eye disease?

Substance P is a neuropeptide released by nerve endings when tissue is injured. In the cornea, which has one of the densest nerve supplies in the body, Substance P increases after injury and drives both inflammation and new blood vessel growth. By blocking its receptor (NK1R), researchers can potentially interrupt this chain of events before the vessel growth begins, preserving corneal clarity.

Read the original research

NK1 receptor antagonists as a new treatment for corneal neovascularization.

Investigative ophthalmology & visual science, 55(10), 6783-94

View on PubMed ↗Publisher’s paper ↗

Citation

Bignami, Fabio; Giacomini, Chiara; Lorusso, Anna; Aramini, Andrea; Rama, Paolo; Ferrari, Giulio. (2014). NK1 receptor antagonists as a new treatment for corneal neovascularization.. Investigative ophthalmology & visual science, 55(10), 6783-94. https://doi.org/10.1167/iovs.14-14553