Diabetes affects 451 million people worldwide, approximately 70% of whom suffer from corneal complications known collectively as diabetic keratopathy. The most frequent clinical signs of diabetic keratopathy include punctate keratitis, recurrent epithelial erosions, and ulcers that are refractory to conventional treatments and which often fail to heal completely.1
Previous controlled studies with corneal epithelial cell cultures in medium with high glucose levels have revealed that hyperglycemia over a period of 48 hours is able to delay corneal reepithelialization to levels of only 29% of normal and to greatly increase the production of reactive oxygen species.2 The pathogenesis of diabetic keratopathy is multifactorial; prior studies have pointed to the impairment of the phosphatidylinositol 3-kinase (PI3K/AKT) transduction pathway, which responds to cell proliferation and migration in various systems and which also affects corneal healing.2 In addition, oxidative stress and inflammatory cytokine production generated by hyperglycemia greatly contribute to the induction of cellular injury.2,3
In a previous study, rats with streptozotocin-induced diabetes exhibited a significant reduction in subepithelial basal nerve plexus density, as well as delayed closure of corneal epithelial ulcers 8 weeks after diabetes induction relative to controls.4
Certain growth factors, cytokines, and neurotrophins are fundamental to corneal wound healing and act as regulators of cellular behavior and corneal epithelial regeneration. These include epidermal growth factor (EGF), fibroblast growth factor (FGF), substance P (SP), nerve growth factor (NGF), insulin-like growth factor-1 (IGF-1), and acetylcholine.5,6 New drugs targeting such factors have been investigated to treat diabetic keratopathy, since diabetes is associated with a significant decrease in the levels of these molecules.7,8,9,10,11,12
Nicergoline (10a-methoxy-1,6-dimethylergoline-8β-methanol-5- bromonicotinate, Sermion, Biogenesis AntiAging, Fish Hoek, South Africa) is an ergoline derivative indicated for cerebrovascular dementias with a broad mechanism of action. It acts as an a-1 adrenergic antagonist, acetylcholinesterase inhibitor, dopaminergic agonist and PI3K/AKT pathway activator; it also increases SP and NGF levels and exhibits antioxidant properties. Such properties have inspired research into its use in corneal wound healing.13,14,15,16,17,18
In a previous study, nicergoline contributed to the corneal reepithelialization of 110 eyes from 100 rats, and corneal NGF protein was higher in the nicergoline-treated group than in the control group.16 In another experimental study that assessed 10 eyes from 5 healthy dogs without a control group, the effect of nicergoline on the ocular surface was assessed using corneal esthesiometry, Schirmer’s test 1, and tear film break-up time, but the drug did not significantly alter canine ocular surface parameters.19
In a prospective, noncomparative interventional study that included 27 eyes from 24 patients with neurotrophic keratopathy of multiple causes who had been unresponsive to conventional therapy, treatment with nicergoline contributed to the healing of neurotrophic corneal ulcers in 83% of eyes and improved Cochet–Bonnet corneal sensitivity and best-corrected visual acuity. In addition, tear NGF levels were significantly higher after nicergoline treatment.20