Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms

Abstract

Despite the high prevalence and public health impact of refractive errors, the mechanisms responsible for ametropias are poorly understood. Much evidence now supports the concept that the retina is central to the mechanism(s) regulating emmetropization and underlying refractive errors. Using a variety of pharmacologic methods and well-defined experimental eye growth models in laboratory animals, many retinal neurotransmitters and neuromodulators have been implicated in this process. Nonetheless, an accepted framework for understanding the molecular and/or cellular pathways that govern postnatal eye development is lacking. Here, we review two extensively studied signaling pathways whose general roles in refractive development are supported by both experimental and clinical data: acetylcholine signaling through muscarinic and/or nicotinic acetylcholine receptors and retinal dopamine pharmacology. The muscarinic acetylcholine receptor antagonist atropine was first studied as an anti-myopia drug some two centuries ago, and much subsequent work has continued to connect muscarinic receptors to eye growth regulation. Recent research implicates a potential role of nicotinic acetylcholine receptors; and the refractive effects in population surveys of passive exposure to cigarette smoke, of which nicotine is a constituent, support clinical relevance. Reviewed here, many puzzling results inhibit formulating a mechanistic framework that explains acetylcholine's role in refractive development. How cholinergic receptor mechanisms might be used to develop acceptable approaches to normalize refractive development remains a challenge. Retinal dopamine signaling not only has a putative role in refractive development, its upregulation by light comprises an important component of the retinal clock network and contributes to the regulation of retinal circadian physiology. During postnatal development, the ocular dimensions undergo circadian and/or diurnal fluctuations in magnitude; these rhythms shift in eyes developing experimental ametropia. Long-standing clinical ideas about myopia in particular have postulated a role for ambient lighting, although molecular or cellular mechanisms for these speculations have remained obscure. Experimental myopia induced by the wearing of a concave spectacle lens alters the retinal expression of a significant proportion of intrinsic circadian clock genes, as well as genes encoding a melatonin receptor and the photopigment melanopsin. Together this evidence suggests a hypothesis that the retinal clock and intrinsic retinal circadian rhythms may be fundamental to the mechanism(s) regulating refractive development, and that disruptions in circadian signals may produce refractive errors. Here we review the potential role of biological rhythms in refractive development. While much future research is needed, this hypothesis could unify many of the disparate clinical and laboratory observations addressing the pathogenesis of refractive errors.

Keywords: acetylcholine; ametropia; circadian rhythms; clock genes; dopamine; emmetropia; myopia; retina.

Fig. 1

Dopamine, melatonin and retinal physiology. Dopamine and melatonin play opposing roles in retinal physiology. Both are diffusible neuromodulators, but dopamine promotes light adaptive retinal physiology and melatonin has dark-adaptive effects. The synthesis and release of dopamine and melatonin are modulated by circadian clocks, with dopamine released during the daytime and melatonin released at night. Light stimulates dopamine release and inhibits melatonin secretion. Both neuromodulators act on G protein-coupled receptors that are widely distributed in the retina. Melatonin inhibits dopamine release from amacrine/interplexiform cells and dopamine inhibits the release of melatonin from photoreceptor cells. Thus, the dopamine-secreting inner retinal neurons and melatonin-secreting photoreceptor cells form an intercellular feedback loop that regulates circadian retinal physiology. The dopamine neurons also interact with intrinsically photosensitive melanopsin-containing ganglion cells, providing another link to circadian physiology. Adapted from (Tosini et al., 2008) © 2008 Wiley Periodicals, Inc.

Fig. 2

Influence of nighttime lighting before age 2 years on subsequent refraction. A history of increased nighttime light exposure during the first two years of life was associated with increased prevalence of myopia and reduced prevalence of emmetropia later in childhood (P < 0.00001). Hyperopia prevalence was unaffected. Despite the high statistical significance of these findings, the positive results in subsequent studies have been less strong; and they have not been replicated in other studies, as discussed in the text. Modified from (Quinn et al., 1999).

Fig. 3

Myopia prevalence and birth month. The prevalence of moderate and severe myopia increased with increasing hours of daylight during the subjects’ birth month among over 275,000 Israeli army conscripts. The solid line shows the averaged daily period of daylight for each month. From (Mandel et al., 2008) with permission from Elsevier.

Fig. 4

The influence of light intensity on the refractive response to spectacle lens wear. Illustrating an effect of light intensity on emmetropization in the chick, the rate of refractive compensation of chicks wearing either a unilateral −7 diopter spectacle lens (in A) or a unilateral +7 diopter spectacle lens (in B) was altered by ambient daytime light intensity during a 12 hour light:dark cycle. Compared to chicks reared under 500 lux lighting (usual laboratory conditions), chicks that were exposed to 5 hours of intense 15,000 lux lighting in the middle of the day demonstrated a slowed response to minus lens wear (in A) and an accelerated response to plus lens wear (in B). The refractive development of the contralateral eyes with non-impaired visual input was not affected by light intensity in either group over this short rearing period. (Error bars: SEM; *P < 0.05; **P < 0.01.) From (Ashby and Schaeffel, 2010); the Association for Research in Vision and Ophthalmology is the copyright holder.

Fig. 5

The effect of light intensity on refractive development in normal chickens with non-impaired visual input. Chicks, reared from hatching under high (10,000 lux), medium (500 lux) or low (50 lux) illumination for 90 days, demonstrated different patterns of refractive development (P <0.0001). At 90 days, the chicks reared under low intensity lighting were mildly myopic (−2.4 diopters), and those reared under high intensity lighting were slightly hyperopic (+1.1D), with intermediate refractions for the cohort reared under medium intensity lighting. (Error bars: SD). Modified from (Cohen et al., 2011), with permission from Elsevier.

Fig. 6

A hypothetical framework for the regulation of eye growth and refractive development. Proposed here is the possibility that intrinsic retinal circadian rhythms might be central to the signaling mechanism regulating refractive development. This scheme proposes that the neurotransmitter responses to visual input interact with the intrinsic retinal circadian clock. The clock also can be influenced by light and possibly other Zeitgebers (e.g., temperature, diet). The retinal clock presumably governs the daily rhythms in eye growth and ocular dimensions and thus could modulate the overall refractive development of the eye. While consistent with the diverse clinical and laboratory data discussed in the text, much work is needed to confirm the components of this hypothetical pathway. While not necessarily required, parallel but independent pathways might also contribute to the emmetropization process.