A novel TRPM8 agonist relieves dry eye discomfort

Jee Myung Yang,Hyo Seok Lee,Edward Tak Wei,Qin Liu,Fengxian Li,Michael Lentsman,Kyung Chul Yoon,Seong Jin Kim,Won Choi,Marco Rüedi

doi:10.1186/s12886-017-0495-2

Abstract

BackgroundPhysical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied. Here, we synthesized a water-soluble TRPM8 receptor agonist called cryosim-3 (C3, 1-diisopropylphosphorylnonane) which selectively activates TRPM8 (linked to cooling) but not TRPV1 or TRPA1 (linked to nociception) and tested C3 in subjects with mild forms of dry eye disease.MethodsA set of 1-dialkylphosphoryalkanes were tested for activation of TRPM8, TRPV1 and TRPA1 receptors in transfected cells. The bioactivity profiles were compared by perioral, topical, and intravenous delivery to anesthetized rats. The selected lead candidate C3 or vehicle (water) was applied with a cotton gauze pad to upper eyelids of patients with dry eye disease (n = 30). Cooling sensation, tear film break-up time (TBUT), basal tear secretion, and corneal staining were evaluated. C3 was then applied four times daily for 2 weeks to patients using a pre-loaded single unit applicator containing 2 mg/mL of C3 in water (n = 20) or water only. TBUT, basal tear secretion, and corneal staining, and three questionnaires surveys of ocular discomfort (VAS scale, OSDI, and CVS symptoms) were analyzed before and at 1 and 2 weeks thereafter.ResultsC3 was a selective and potent TRPM8 agonist without TRPV1 or TRPA1 activity. In test animals, the absence of shaking behavior after C3 perioral administration made it the first choice for further study. C3 increased tear secretion in an animal model of dry eye disease and did not irritate when wiped on eyes of volunteers. C3 singly applied (2 mg/ml) produced significant cooling in <5 min, an effecting lasting 46 min with an increase in tear secretion for 60 min. C3 applied for 2 weeks also significantly increased basal tear secretion with questionnaire surveys of ocular discomfort indices clearly showing improvement of symptoms at 1 and 2 weeks. No complaints of irritation or pain were reported by any subject.ConclusionsC3 is a promising candidate for study of TRPM8 function on the eye surface and for relief of dry eye discomfort.Trial registrationISRCTN24802609 and ISRCTN13359367. Registered 23 March 2015 and 2 September 2015.

Highlights

Physical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied
The distributions of transient receptor potential vanilloid 1 (TRPV1), and transient receptor potential melastatin 8 (TRPM8) ion channels on the cornea have been mapped, and it is likely that TRPV1 transduces the signals of heat, irritation, and pain from the ocular surface [15, 17]
TRPM8 may be associated with the detection of “dryness” on the eye surface because it is activated by evaporative cooling and by hyperosmolar solutions [18, 19]

Summary

Introduction

Physical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied. The dense neural network of the ocular surface, especially of the cornea, generates the signs and symptoms of DED, namely, redness and tearing, and irritation, itch, pain and dysesthesia such as feelings of grittiness, soreness, the presence of a foreign object, dryness, and eye fatigue [10,11,12]. Translation of these research findings to therapy of dry eye has not been clearly defined for TRP drug targets, or for studies of lead candidates, animal models of disease, mechanisms of action, or clinical observations [11, 21]

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Conclusion