Engineered CGRP Eye Drops Restore Tear Secretion via TRPM8-SSN Circuitry in a Postrefractive Surgery Mouse Model.

Abstract

PURPOSE: This study aimed to investigate the role of sensory neuropeptide calcitonin gene-related peptide (CGRP) in postrefractive surgery dry eye caused by corneal nerve severing in mice. METHODS: A mouse model was established in adult C57BL/6J mice by surgical corneal severing. Additional validation was performed using a photorefractive keratectomy (PRK) model. Postoperative evaluations included corneal sensitivity, corneal nerve density, tear secretion, corneal fluorescein staining, immunofluorescence staining, and corneal RNA sequencing. Transient receptor potential melastatin 8 (TRPM8) of the trigeminal ganglia (TG), c-FOS, and in vivo electrophysiologic recording of the brain superior salivatory nucleus (SSN) were determined. The therapeutic efficacy of CGRP and an engineered CGRP (eCGRP) was assessed in treating postrefractive surgery dry eye. RESULTS: Corneal nerve severing led to a significant reduction of corneal CGRP contents, accompanied by the development of dry eye symptoms, including tear secretion reduction, epithelial barrier dysfunction, and subbasal nerve degeneration. These pathologic alterations were effectively rescued by prophylactic CGRP and significantly attenuated by therapeutic CGRP via enhancing the intact neural circuit of tear secretion. Compared with native CGRP, topical application of eCGRP exhibited superior efficacy of increasing tear secretion, restoring epithelial homeostasis, and reducing corneal inflammation, without pain-related side effects. In the laser-based PRK model, eCGRP similarly alleviated dry eye, confirming its therapeutic efficacy in a more clinically relevant surgery. CONCLUSIONS: Our data demonstrate that CGRP expression in the cornea is downregulated in postrefractive surgery dry eye through decreasing TRPM8-SSN activity. eCGRP may provide an effective therapeutic approach for its prevention and treatment.