Recovery of Corneal Sensitivity, Calcitonin Gene-Related Peptide–Positive Nerves, and Increased Wound Healing Induced by Pigment Epithelial–Derived Factor Plus Docosahexaenoic Acid After Experimental Surgery

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Abstract

Objective

To assess function of regenerated corneal nerves in correlation with epithelial wound healing after experimental nerve damage in rabbits treated with pigment epithelial–derived factor (PEDF) plus docosahexaenoic acid (DHA).

Methods

An 8-mm stromal dissection was performed in the right eyes of adult New Zealand rabbits. Treatment with PEDF+DHA was for 6 weeks. Corneal sensation was measured weekly by Cochet-Bonnet esthesiometer. After 8 weeks, immunofluorescence with βIII-tubulin, calcitonin gene-related peptide, and substance P antibodies was performed to quantify nerves. Also, rabbits were treated with PEDF+DHA for 4 weeks after lamellar keratectomy, followed by 8-mm epithelial debridement and epithelial defect assessment. One week after surgery, corneas were stained with anti-Ki67 antibody to assess cell proliferation.

Results

Eight weeks after surgery, calcitonin gene-related peptide–positive nerve fibers in the PEDF+DHA group were similar to normal rabbit corneas but were decreased in the vehicle. Substance P was localized in the subepithelial plexus but appeared in epithelial cells after nerve injury regardless of treatment. Five weeks after surgery, an increase in corneal sensitivity occurred in the PEDF+DHA group and reached normal values by 8 weeks. Pigment epithelial–derived factor plus DHA increased epithelial wound healing after lamellar keratectomy. One week after epithelial injury, Ki67-positive cells increased in the limbal area.

Conclusion

Pigment epithelial–derived factor plus DHA promotes regeneration of calcitonin gene-related peptide–positive corneal nerves, accelerating wound healing and return of corneal sensitivity.

Clinical Relevance

Pigment epithelial–derived factor plus DHA represents a new approach to regenerate nerves and a potential treatment for prevention of severe dry eye after surgery or diseases of the ocular surface.

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