NK1 receptor antagonists as a new treatment for corneal neovascularization.

Abstract

PURPOSE:

To determine whether the inhibition of Substance P (SP) activity can reduce corneal neovascularization (CNV) by means of local administration of high-affinity, competitive, tachykinin 1 receptor (NK1R) antagonists Lanepitant and Befetupitant.

METHODS:

We performed a safety and efficacy study by using (1) two different C57BL/6 mouse models of CNV: alkali burn and sutures; (2) different concentrations; and (3) different routes of administration: topical or subconjunctival. Clinical examination endpoints, SP levels, CNV index, and leukocyte infiltration were measured.

RESULTS:

Substance P increased after injury in the corneal epithelium of both CNV models, and later in the suture model. Topical Lanepitant was nontoxic to the ocular surface and effective in reducing hemangiogenesis and lymphangiogenesis, corneal SP levels, and leukocyte infiltration, as soon as 4 days later in the alkali burn model. Topical Lanepitant, up to 7 days, was ineffective in the suture model. However, subconjunctival Lanepitant was effective in reducing lymphatic CNV, leukocyte infiltration, and SP levels in the suture model, after 10 days. Additionally, in the alkali burn model, subconjunctival Lanepitant significantly reduced blood CNV, corneal perforation rate, opacity, and leukocyte infiltration, and improved tear secretion. Finally, topical application of Befetupitant reduced CNV in the alkali burn model but was toxic owing to the vehicle (dimethyl sulfoxide [DMSO]); hence, Befetupitant was not tested in the suture model.

CONCLUSIONS:

The NK1R antagonist Lanepitant is safe for the ocular surface and effective in reducing both corneal hemangiogenesis and lymphangiogenesis, and leukocyte infiltration. We suggest that inhibition of NK1R may represent an adjunctive tool in the treatment of CNV.

• Authors: Fabio Bignami, Chiara Giacomini, Anna Lorusso, Andrea Aramini, Paolo Rama, Giulio Ferrari
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 55 Issue 10 Pg. 6783-94 (Sep 16 2014) ISSN: 1552-5783 [Electronic] United States
• PMID: 25228541 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Chemical References

• 1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane
• Indoles
• Neurokinin-1 Receptor Antagonists
• Ophthalmic Solutions
• Piperidines
• Pyridines
• Receptors, Neurokinin-1
• befetupitant

Topics

• Administration, Topical
• Animals
• Burns, Chemical (complications, drug therapy, metabolism)
• Conjunctiva
• Cornea (metabolism, pathology)
• Corneal Injuries (complications, metabolism, pathology)
• Corneal Neovascularization (drug therapy, etiology, metabolism)
• Disease Models, Animal
• Eye Burns (complications, drug therapy, metabolism)
• Female
• Follow-Up Studies
• Immunohistochemistry
• Indoles (administration & dosage)
• Injections
• Mice
• Mice, Inbred C57BL
• Neurokinin-1 Receptor Antagonists (administration & dosage)
• Ophthalmic Solutions (administration & dosage)
• Piperidines (administration & dosage)
• Pyridines (administration & dosage)
• Receptors, Neurokinin-1 (drug effects, metabolism)
• Sutures (adverse effects)
• Tomography, Optical Coherence
• Treatment Outcome