| Author: | Uddin, Mezbah |
| Title: | Effects of ocular hypotensive drugs and their mechanism of actions to control experimental induced myopia in chicken |
| Advisors: | Tse, Dennis (SO) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | School of Optometry |
| Pages: | 1 volume (various pagings) : color illustrations |
| Language: | English |
| Abstract: | Myopia is a common cause of correctable vision loss and uncorrected myopia has become one of the leading causes of blindness worldwide. The overall prevalence of myopia is increasing rapidly. It is estimated that 33.9% of the world's population is myopic and by 2050 this is predicted to reach nearly 50%. In South-East Asia, myopia affects more than 80% to 90% of young adults, of whom approximately 10-20% are high myopes. High myopia increases the risk of ocular pathological changes, including retinal degeneration, retinal detachment, cataracts, and glaucoma. Despite substantial research, the exact mechanism of myopia development remains unclear. There is also no universally accepted pharmaceutical therapy to control myopia progression. Research in this area found that atropine and only a few muscarinic acetylcholine receptors (mAChR) antagonists can effectively inhibit myopia. Currently, topical atropine 1% is the most effective pharmaceutical therapy for myopia control in humans, but adverse side effects include photophobia, glare, paralysis of accommodation, allergies and rebound effects. The underlying mechanism through which atropine inhibits myopia development also remains unclear. More recently, a few pharmacological agents, originally approved for glaucoma, have been shown to be effective in treating induced myopia in animal models. This PhD thesis describes work that aimed to unravel the signaling pathways involved in myopia development in the posterior eye by using a chicken model of myopia and a pharmacological approach. The study commenced with an experiment delineating the dose-response of atropine (Chapter 3). This extended to an investigation of non-canonical molecular targets of atropine, and examined the relations between glaucoma and myopia molecular pathways. There is significant evidence that myopia-inhibiting non-MAChR antagonist drugs, such as atropine and mamba toxin-3 (MT3), not only react with M4 mAChR, but also bind with α-adrenoceptors. The MT3 component of the mamba venom is especially selective for M4 mAChR subtypes in humans and is the most effective anti-myopia agent. Therefore, the next stage of the study was an investigation as to whether α1A (metaraminol), α2A (lofexidine), and a non-specific adrenergic receptor drug (cirazoline) may be involved in regulation of excessive eye growth (Chapter 4). The results provided novel evidence that α1 adrenergic agonists and nonspecific agonists had a similar inhibitory effect against myopia in chickens, suggesting their potential as pharmacological therapies. The data also revealed that α2-adrenoceptor agonist inhibited lens-induced myopia (LIM) as well as form-deprivation myopia (FDM) in a dose-dependent manner. Other evidence suggested that few α-adrenoceptor drugs are most effective at reducing myopia through IOP-independent mechanisms. It affects the extracellular matrix of the sclera and is a relatively new IOP-lowering drug. Further study revealed that the link between the development of myopia and axial length elongation was associated with extracellular remodeling of the sclera. Therefore, the effects of one of the most potent IOP-lowering prostaglandin analogue drugs, topical latanoprost, were investigated and were found to be very effective in slowing the progression of myopia in chicks with either FDM or LIM (Chapter 5). Although the exact underlying mechanism of topical latanoprost in FDM and LIM involved in myopia control remains unknown, the initial results demonstrated that daily topical administration of latanoprost was effective in inhibiting both experimental myopia models of FDM and LIM in chicks. Further study revealed that its effect was associated with reduced scleral thinning and relatively upregulated EGR1 protein expression in the retina. Furthermore, it was demonstrated that the chosen concentration of latanoprost also reduced IOP in chicks. Later study investigated the effects of another ocular hypertensive medication that effectively reduces IOP. Rho-kinase is a serine/threonine kinase that plays a significant role in regulating and modifying cell size and shape. Rho-kinase inhibitors increase aqueous outflow facility by altering the ultrastructure of the trabecular meshwork leading to a reduction in IOP, which is similar to effects of prostaglandin analogues. The potential myopia-controlling effects of different doses of the Rho-kinase inhibitor (Y-33075 dihydrochloride) were examined in chicken eyes using LIM and FDM models (Chapter 6). This work provided the first evidence that intravitreal injection of Rho-kinase inhibitor (Y-33075 dihydrochloride) could significantly inhibit ocular growth and myopic refractive error in both LIM and FDM models in a dose-dependent manner. The result also showed that all tested doses of Rho-kinase inhibitor (Y-33075 dihydrochloride) significantly lowered IOP compared to control groups. This evidence may open up new opportunities to explore IOP-lowering drugs as future treatment options for myopia. |
| Rights: | All rights reserved |
| Access: | open access |
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