Nerve growth factor in dogs: Assessment of two immunoassays and selected ocular parameters following a nicergoline challenge per os

Abstract

Impairment of corneal nerves can result in the development of ocular surface diseases such as aqueous tear deficiency and neurotrophic keratopathy. This study investigates oral nicergoline, an α-adrenoceptor antagonist shown to enhance endogenous secretion of nerve growth factor (NGF) by the lacrimal gland, as a potential therapy for these conditions. Five female spayed Beagle dogs received a 2-week course of oral nicergoline (10 mg twice daily). Drug safety was evaluated with ophthalmic and physical examinations, blood pressure monitoring, bloodwork and urinalysis. The effect of nicergoline on the ocular surface was assessed with corneal esthesiometry, Schirmer tear test-1 and tear film breakup time.Drug effect on NGF levels was assessed by collecting tears and blood at baseline and completion of therapy using a bead-based immunoassay and an enzyme-linked immunosorbent assay. Although nicergoline was well tolerated in all dogs, it did not have a significant impact on corneal sensitivity, tear production or tear stability. Of note, NGF was below the limit of quantification in all tear samples, and was only detected in 8/20 serum samples with no significant difference between levels at baseline (189.4 ± 145.1 pg/ml) and completion of therapy (149.4 ± 79.4 pg/ml). Further validation of NGF analytical assays is warranted before nicergoline is investigated in clinical patients.

An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

“…41 cellulose filter paper and possess specific characteristics to promote tolerance (5-mm width × 35-mm length, 0.22-mm thick, 20-25 µm porosity, foldable extremity for ease of insertion). 249,257 In addition to their conventional use for aqueous tear assessment, Schirmer strips can retrieve tear fluid for bioanalytical purposes in humans, 182,216,219,220,228,231,258 dogs, 190,209,211,214,215,240,259 and small laboratory species. 244,260,261 For instance, Schirmer strips were used for indepth characterization of proteomics in human 173 and canine tears, 190 and can also successfully recover specific analytes such as cytokines, 200,258 clusterin, 182 and xenobiotics.…”

“…273 The distal end of the Schirmer strips should remain in position (ventrolateral conjunctival fornix) until 20, 25, or 30 mm wetness is reached. 215,240,259,270,273 Strip wetness <20 mm is discouraged given the potential "concentrating effect" of the absorbent filter with low tear volumes, 209 irritation ensued by the prolonged test duration. Importantly, investigators should be consistent with the selected mm-mark (strip wetness) within and between patients to standardize the volume of tears collected among subjects.…”

“…For consistency purposes, the authors recommend the use of dye‐free Schirmer tear strips, being consistent with the manufacturer and lot number (given the reported variability in absorptive and adsorptive properties among Schirmer strips), 274,275 as well as the time of collection (e.g., morning), 231 because of known diurnal variability in lacrimal protein composition in humans 226,249 and dogs 273 . The distal end of the Schirmer strips should remain in position (ventrolateral conjunctival fornix) until 20, 25, or 30 mm wetness is reached 215,240,259,270,273 . Strip wetness <20 mm is discouraged given the potential “ concentrating effect ” of the absorbent filter with low tear volumes, 209 while complete wetness of the strip (35 mm) should be avoided as the total protein content is significantly greater with 35 mm compared to 20–30 mm mark, 270 likely due to vascular fragility and excessive irritation ensued by the prolonged test duration.…”

Role of Nicergoline in Corneal Wound Healing in Diabetic Rats

“…To date, this is the rst experimental, controlled, and double-blind study to investigate the potential of nicergoline to improve the rate of corneal reepithelization and to treat corneal ulcers in a clinical context of diabetes, since the other studies in the literature evaluated this drug only in healthy animals. 13,14,19 The current study exhibits some limitations. It is important to mention the lack of proof of diabetic neuropathy by an objective test, such as the corneal sensitivity test with the Cochet-Bonnet esthesiometer.…”

“…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 lm break-up time, but the drug did not signi cantly 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 signi cantly higher after nicergoline treatment.…”