The PEDF Neuroprotective Domain Plus DHA Induces Corneal Nerve Regeneration After Experimental Surgery

Invest Ophthalmol Vis Sci. 2015 Jun;56(6):3505-13. doi: 10.1167/iovs.15-16755.


Purpose: To compare a 44-mer pigment epithelial-derived factor (PEDF) peptide with neurotrophic activity, and a 34-mer PEDF with antiangiogenic properties in association with docosahexaenoic acid (DHA) in corneal nerve regeneration after experimental surgery.

Methods: A corneal stromal dissection was performed in rabbits. Treatment groups received topical 44-mer, 34-mer, or full PEDF plus DHA. Corneal sensitivity and Schirmer's test were performed weekly. Rabbits were euthanized at 2 and 4 days and 8 weeks. Two- and 4-day samples were stained for neutrophils and CD11b+ cells. Corneal nerves were stained with βIII tubulin and calcitonin gene-related peptide (CGRP) antibodies in specimens collected at 8 weeks. Subepithelial nerve plexus density was calculated. A PEDF-receptor (PEDF-R) was analyzed in rabbit corneal epithelial cells (RCEC) by Western blot and immunofluorescence.

Results: Infiltration of CD11b+cells and neutrophils was reduced by treatment with 44-mer PEDF+DHA. A 3-fold increase in subepithelial corneal nerves and CGRP-positive nerves was found in the 44-mer PEDF+DHA-treated group compared with the 34-mer PEDF+DHA- and vehicle-treated groups. There was a 75% recovery of corneal sensitivity by week 7, and Schirmer's test reached control values in the 44-mer PEDF+DHA-treated corneas at 7 weeks. A PEDF-R protein with homology to calcium-independent phospholipase A2ς was expressed in RCEC.

Conclusions: The 44-mer PEDF+DHA, but not the 34-mer PEDF+DHA, promotes functional regeneration of damaged corneal nerves. Forty four-mer PEDF, by activating a corneal epithelial receptor, in conjunction with DHA could be a novel therapeutic agent for the treatment of neurotrophic keratitis and dry eye that develops as a result of corneal nerve damage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cornea / innervation
  • Cornea / physiology*
  • Corneal Stroma / surgery*
  • Disease Models, Animal
  • Docosahexaenoic Acids / pharmacology*
  • Drug Therapy, Combination
  • Epithelial Cells / metabolism
  • Epithelium, Corneal / metabolism
  • Eye Proteins / pharmacology*
  • Nerve Growth Factors / pharmacology*
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / physiology
  • Ophthalmic Nerve / injuries
  • Ophthalmic Nerve / physiology*
  • Rabbits
  • Receptors, Neuropeptide / metabolism
  • Serpins / pharmacology*


  • Eye Proteins
  • Nerve Growth Factors
  • Receptors, Neuropeptide
  • Serpins
  • pigment epithelium-derived factor
  • pigment epithelium-derived factor receptor
  • Docosahexaenoic Acids