Topical FK962 Facilitates Axonal Regeneration and Recovery of Corneal Sensitivity After Flap Surgery in Rabbits

Abstract

To test if the drug FK962 (N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide) facilitates axonal elongation and recovery of corneal sensitivity after creation of a corneal flap in rabbits. Animal study. Primary cultures of rabbit trigeminal ganglion cells were used to test if FK962 promoted nerve elongation in vitro. A 130 μm-thick×8.6 mm-diameter flap was created in rabbit corneas where topical 10(-6) M FK962 was administered 4 times daily. After treatment of 7 days, corneal mechanical sensitivity was measured using a Cochet-Bonnet esthesiometer. Whole-mount corneal sections were prepared, sensory nerve axons were stained with antibody for neurofilament, and axonal elongation from transected nerve termini were scored using standardized criteria. Ocular pharmacokinetics modeling was used to predict permeation of topical FK962 into cornea. FK962 accelerated sprouting and elongation of neurites in cultured neuronal cells from rabbit trigeminal ganglia. In the in vivo rabbit model, distal axons from transected nerve termini in corneas disappeared soon after flap surgery; but with time, axons regenerated and elongated. Topical application of 10(-6) M FK962 for 7 days significantly enhanced axonal elongation and increased corneal sensitivity. Increased corneal sensitivity was directly and significantly correlated with axonal elongation, suggesting functional enhancement of re-innervation by FK962. Results from a rabbit model of laser in situ keratomileusis (LASIK) surgery showed that topical FK962 facilitated corneal re-innervation leading to recovery of sensitivity. Results suggested that topical application of FK962 might decrease complications in patients after LASIK surgery.