Topical Recombinant Human Nerve Growth Factor Improves Outcomes in Murine Model of Neuropathic Corneal Pain

Abstract

Purpose : Since its discovery, nerve growth factor (NGF) has sparked widespread interest in possible therapeutic utility across neurologic diseases. NGF and other neurotrophic factors are upregulated in neuropathic pain, although their precise role remains to be fully understood. Herein, we assess the possible therapeutic benefit of recombinant human NGF (rhNGF) in the ciliary nerve ligation model of neuropathic corneal pain.

Methods : Adult 7- to 8-week-old male C57BL/6J mice underwent ciliary nerve ligation for the induction of NCP and were treated with six 10 μL drops/day of 0.02mg/mL rhNGF or vehicle (n=6/group). Clinical outcomes were assessed at 7-, 10-, and 14-days post-ligations. Outcomes included corneal fluorescein staining (CFS), Cochet-Bonnet esthesiometry, and challenge with 10 μL of [5M] saline, cold saline, and L-menthol for assessment of pain by the paw wipe response. At day 14, trigeminal ganglia (TG) were excised for qRT-PCR analysis of neurotrophic factors and cytokines.

Results : Ligation did not significantly alter CFS or corneal sensitivity between groups at any time point (p>0.05). Animals did not differ in their baseline or post-ligation responses to [5M] saline prior to treatment initiation (16.0 vs 13.0, p>0.05; 31.0 vs 31.6, p>0.05). There was a persistent decrease in response to [5M] saline in the rhNGF-treated group (Day 7: 21.7 vs 30.2, p<0.001; Day 10: 18.0 vs 27.4, p<0.001; Day 14: 16.2 vs 28.3, p<0.0001). Responses to cold saline were slightly, although not significantly, reduced in the NGF group (Day 7: 5 vs 8.6, Day 10: 5.2 vs 7.8, Day 14: 4.4 vs 7.2; all p>0.05). Similar results were obtained with responses to L-menthol (Day 7: 5.0 vs 9.0, p <0.05; Day 10: 5.2 vs 7.4, p >0.05; Day 14: 2.8 vs 5.8, p >0.05). rhNGF treatment reduced levels of several neurotrophic factors in the TG compared to vehicle treatment (BDNF: 0.78 vs 1.00, p<0.05; NT-3: 0.25 vs 1.00, p<0.01; NT-4/5: 0.11 vs 1.00, p<0.05), but did not show increase in pro-inflammatory cytokines (IL-1b: 0.50 vs 1.00, IL-6: 0.92 vs 1.00, TNF-a: 0.69 vs 1.00; all p>0.05).

Conclusions : These findings suggest that topical rhNGF treatment improves pain outcomes in our neuropathic corneal pain and warrant future studies in the clinic. Furthermore, qRT-PCR results indicate that topical rhNGF treatment alters expression of neurotrophic factors, but not pro-inflammatory cytokines within the TG.

This is a 2021 ARVO Annual Meeting abstract.