Role of the Neurokinin-1 Receptor in the Promotion of Corneal Epithelial Wound Healing by the Peptides FGLM-NH2 and SSSR in Neurotrophic Keratopathy

• Published in: Investigative ophthalmology & visual science 2020-07, Vol.61 (8), p.29-29
• Main Authors: Yanai, Ryoji, Nishida, Teruo, Hatano, Makoto, Uchi, Sho-Hei, Yamada, Naoyuki, Kimura, Kazuhiro
• Format: Article
• Language: English
• Subjects: Animals; Cornea; Corneal Injuries - drug therapy; Corneal Injuries - immunology; Epithelium, Corneal - drug effects; Epithelium, Corneal - injuries; Epithelium, Corneal - metabolism; Insulin-Like Growth Factor I - metabolism; Mice; Neurokinin-1 Receptor Antagonists - pharmacology; Neurotransmitter Agents - metabolism; Neurotransmitter Agents - pharmacology; Piperidines - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Neurokinin-1 - metabolism; Signal Transduction - drug effects; Substance P - metabolism; Substance P - pharmacology; Wound Healing - drug effects; Wound Healing - immunology
• ISSN: 0146-0404; 1552-5783
• DOI: 10.1167/iovs.61.8.29

Neurotrophic keratopathy is a corneal epitheliopathy induced by trigeminal denervation that can be treated with eyedrops containing the neuropeptide substance P (or the peptide FGLM-NH2 derived therefrom) and insulin-like growth factor 1 (or the peptide SSSR derived therefrom). Here, we examine the mechanism by which substance P (or FGLM-NH2) promotes corneal epithelial wound healing in a mouse model of neurotrophic keratopathy. The left eye of mice subjected to trigeminal nerve axotomy in the right eye served as a model of neurotrophic keratopathy. Corneal epithelial wound healing was monitored by fluorescein staining and slit-lamp examination. The distribution of substance P, neurokinin-1 receptor (NK-1R), and phosphorylated Akt was examined by immunohistofluorescence analysis. Cytokine and chemokine concentrations in intraocular fluid were measured with a multiplex assay. Topical administration of FGLM-NH2 and SSSR promoted corneal epithelial wound healing in the neurotrophic keratopathy model in a manner sensitive to the NK-1R antagonist L-733,060. Expression of substance P and NK-1R in the superficial layer of the corneal epithelium decreased and increased, respectively, in model mice compared with healthy mice. FGLM-NH2 and SSSR treatment suppressed the production of interleukin-1α, macrophage inflammatory protein 1α (MIP-1α) and MIP-1β induced by corneal epithelial injury in the model mice. It also increased the amount of phosphorylated Akt in the corneal epithelium during wound healing in a manner sensitive to prior L-733,060 administration. The substance P-NK-1R axis promotes corneal epithelial wound healing in a neurotrophic keratopathy model in association with upregulation of Akt signaling and attenuation of changes in the cytokine-chemokine network.