Levodopa inhibits the development of lens-induced myopia in chicks

Abstract

Animal models have demonstrated a link between dysregulation of the retinal dopamine system and the development of myopia (short-sightedness). We have previously demonstrated that topical application of levodopa in chicks can inhibit the development of form-deprivation myopia (fDM) in a dose-dependent manner. Here, we examine whether this same protection is observed in lens-induced myopia (LiM), and whether levodopa's protection against fDM and LiM occurs through a dopamine D1-or D2-like receptor mechanism. To do this, levodopa was first administered daily as an intravitreal injection or topical eye drop, at one of four ascending doses, to chicks developing LiM. Levodopa's mechanism of action was then examined by co-administration of levodopa injections with D1-like (SCH-23390) or D2-like (spiperone) dopamine antagonists in chicks developing FDM or LIM. For both experiments, levodopa's effectiveness was examined by measuring axial length and refraction after 4 days of treatment. Levodopa inhibited the development of LIM in a dose-dependent manner similar to its inhibition of fDM when administered via intravitreal injections or topical eye drops. in both fDM and LiM, levodopa injections remained protective against myopia when co-administered with ScH-23390, but not spiperone, indicating that levodopa elicits its protection through a dopamine D2-like receptor mechanism in both paradigms. Abbreviations DOPAC 3,4-Dihydroxyphenylacetic acid FDM Form-deprivation myopia LC-MS-MS High performance liquid chromatography-tandem mass spectrometry LIM Lens induced myopia PBS Phosphate buffered saline Myopia, commonly known as short-sightedness, is a refractive disorder arising from a mismatch between the axial length and optical power of the eye. This is generally due to excessive elongation of the eye during development and into early adulthood. In urban East and Southeast Asia the prevalence of myopia in young adults has risen from 20-30% to 80-85% in the last five decades (For review see 1). The prevalence of high myopia (≤ − 6 diopters (D)) has increased disproportionately to that of myopia in the last five decades, rising from 1-5% to 10-20% (For review see 1). Although the refractive error associated with this condition can easily be corrected, such corrections do not address the sight-threatening pathologies associated with myopia, and especially high myopia, which include retinal detachment, myopic macular degeneration, staphyloma, glaucoma, and cataracts 2-6. Furthermore, the odds of such pathologies significantly increase with the severity of myopia 7. Through work in animal models, changes in retinal dopamine release have been heavily implicated in the development of myopia (for review see 8-10). Specifically, in chicks, rhesus monkeys, guinea pigs, tree shrews and in some cases mice, retinal levels of dopamine, and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), have been shown to be significantly down-regulated during the development of form-deprivation myopia (FDM) 11-16. Consistent with a role fo...

Coadministration With Carbidopa Enhances the Antimyopic Effects of Levodopa in Chickens

“… Data for levodopa eye drops, denoted with an asterisk (*), are from previously published work. 12 , 13 Because of solubility limits, to gain a higher dose for IP injections than that used for topical application, a larger volume was used. IV injection, intravitreal injection.…”

“…Following 4 days of drug administration, axial length and refractive measurements from levodopa:carbidopa treated chicks were compared with those from the left eyes of FDM only, LIM only, and age-matched untreated control animals. Levodopa:carbidopa dose–response curves were also retrospectively compared against levodopa only dose–response curves for both FDM (previous data 12 ) and LIM (previous data 13 ).…”

“…This experiment also examined the effects of topical application of carbidopa alone (180 nmoles) on the development of FDM and LIM. As topical application of the vehicle solution has previously been shown to have no effect on the development of FDM 12 or LIM, 13 vehicle treated groups were not included. Finally, this experiment examined the effects of levodopa:carbidopa treatment on normal ocular development by administering levodopa:carbidopa at their highest doses (720:180 nmoles) to chicks receiving no visual treatment.…”

“… 8 With respect to its potential use in the treatment of myopia, animal models have shown that systemic administration of levodopa can inhibit the development of form-deprivation myopia (FDM) in guinea pigs 9 and mice, 10 as well as the development of spontaneous myopia in albino guinea pigs. 11 In chicks, levodopa has been demonstrated to inhibit the development of FDM 12 and lens-induced myopia (LIM) 13 in a dose-dependent manner when administered as either an intravitreal injection or topical eye drops. This levodopa-induced protection appears to be driven by an increase in dopamine synthesis and release from the retina, 9 , 11 , 12 , 14 with protection lost by coadministration with the D2-like receptor antagonist spiperone.…”

“…This levodopa-induced protection appears to be driven by an increase in dopamine synthesis and release from the retina, 9 , 11 , 12 , 14 with protection lost by coadministration with the D2-like receptor antagonist spiperone. 13 …”