The retinal dopamine system – a target for the pharmacological prevention of myopia

    Student thesis: Doctoral Thesis

    Abstract

    Myopia, a chronic progressive condition arising from excessive elongation of the eye during development, is the leading cause of visual impairment and low vision world-wide. Over the past 50 years, myopia rates have increased dramatically, with estimates predicting that half of the world’s population may be affected by 2050. Consequently, understanding both the aetiology and the biochemical processes underlying myopia is critical to facilitate the continual development of novel treatments. Through work in animal models, the retinal neuromodulator dopamine has been heavily implicated in the regulation of ocular growth, and therefore myopia development. This thesis builds on this knowledge by addressing several questions regarding dopamine’s role in the prevention of experimental myopia, with a view towards developing dopaminergic interventions for human treatment. Specifically, using the chick model, this thesis investigates: whether the two major forms of experimental myopia are similarly inhibited by dopaminergic stimulation; if topically applied levodopa can form a potential treatment for myopia based on pre-clinical safety and efficacy data; whether or not topically applied dopamine can penetrate the cornea and inhibit experimental myopia; and, if modulation of the dopaminergic system underlies the anti-myopic effects of the muscarinic cholinergic antagonist atropine. This thesis reports several major findings: 1. Both form-deprivation myopia (FDM) and lens-induced myopia (LIM) are similarly inhibited by pharmacological stimulation of the dopaminergic D2-like receptor family, suggesting that dopamine’s role is indeed universal across these paradigms. 2. The dopamine precursor levodopa significantly inhibits the development of FDM and LIM in a dose dependent manner when applied as a reformulated topical eye drop solution. Therefore, levodopa may represent a novel pharmacological intervention for human myopia. 3. The protective effects of topically applied levodopa can be significantly enhanced by co-administration with carbidopa, which increases levodopa’s bioavailability within the retina. In this formulation, topical levodopa becomes approximately 30% more effective than atropine or levodopa alone at inhibiting both forms of experimental myopia. 4. Neither topically formulated levodopa, nor levodopa/carbidopa alters normal ocular development or ocular health when administered for chronic treatment periods in chicks or mice. Furthermore, no significant systemic distribution of levodopa is observed following topical application, reducing the potential for known off-target effects. Therefore, topically applied levodopa appears to be both safe and effective at inhibiting experimental myopia. 5. Unexpectedly, topical administration of dopamine and deuterium labelled dopamine can inhibit the development of FDM in a dose-dependent manner, with a similar efficacy to that of atropine and levodopa alone. This is surprising as due to its polar nature, dopamine would be assumed not to cross the corneal epithelium when applied as eye drops. Thus, topical administration of the natural ligand dopamine may be a clinically effective treatment for myopia. 6. Although high doses of atropine can increase retinal dopamine release, stimulation of the dopamine system is not required for atropine to elicit its growth inhibitory effects. 7. While investigating the role of dopamine in the anti-myopic effects of atropine, muscarinic and nicotinic cholinergic agonists, which were assumed to enhance myopia, were unexpectedly found to inhibit the development of FDM. This would suggest that cholinergic hyperactivity does not underly myopic growth and questions whether atropine inhibits myopia via cholinergic antagonism. This finding also indicates a novel drug family for the pharmacological treatment of myopia, that of nicotinic agonists, which are unlikely to suffer from the anterior segment side-effects associated with muscarinic treatment. 8. Unlike atropine or nicotinic cholinergic agonists, muscarinic cholinergic agonists elicit their anti-myopic effects through increasing retinal dopamine release.
    Date of Award2022
    Original languageEnglish
    SupervisorRegan Ashby (Supervisor) & Reena Ghildyal (Supervisor)

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