The Role of Dopamine in Emmetropization Modulated by Wavelength and Temporal Frequency in Guinea Pigs.

Purpose: Wavelength and temporal frequency have been found to influence refractive development. This study investigated whether retinal dopamine (DA) plays a role in these processes. Methods: Guinea pigs were randomly divided into nine groups that received different lighting conditions for 4 weeks, as follows: white, green, or blue light at 0, 0.5, or 20.0 Hz. Refractions and axial lengths were measured using streak retinoscopy and A-scan ultrasound imaging. DA and its metabolites were measured by high-pressure liquid chromatography-electrochemical detection. Results: At 0 Hz, green and blue light produced myopic and hyperopic shifts compared with that of white light. At 0.5 Hz, no significant changes were observed compared with those of green or blue light at 0 Hz, whereas white light at 0.5 Hz induced a myopic shift compared with white light at 0 or 20 Hz. At 20 Hz, green and blue light acted like white light. Among all levels of DA and its metabolites, only vitreous 3, 4-dihydroxyphenylacetic acid (DOPAC) levels and retinal DOPAC/DA ratios were dependent on wavelength, frequency, and their interaction. Specifically, retinal DOPAC/DA ratios were positively correlated with refractions in white and green light conditions. However, blue light (0, 0.5, and 20.0 Hz) produced hyperopic shifts but decreased vitreous DOPAC levels and retinal DOPAC/DA ratios. Conclusions: The retinal DOPAC/DA ratio, indicating the metabolic efficiency of DA, is correlated with ocular growth. It may underlie myopic shifts from light exposure with a long wavelength and low temporal frequency. However, different biochemical pathways may contribute to the hyperopic shifts from short wavelength light.

The Development of Ocular Biometric Parameters in Premature Infants without Retinopathy of Prematurity.

PURPOSE: The aim of this study was to investigate the developmental tendencies and distribution of ocular biometric parameters in premature infants without retinopathy of prematurity (ROP). Axial length (AL), anterior chamber depth (ACD), lens thickness (LT) and vitreous length (VL) were measured, and their relationships with birth weight (BW) and postmenstrual age (PMA) were analyzed during their earliest weeks of life. METHODS: This cross-sectional cohort study included 633 premature infants. They were divided into nine groups according to their PMA: 32 weeks, 33 weeks, 34 weeks, and onward to 40 weeks. All participants underwent portable slit-lamp examination, RetCam3 and A-scan ultrasound biometry. The following ocular biometric parameters were recorded: AL, ACD, LT and VL. The t-test, one-way analysis of variance, and the multiple regression analysis model were used to analyze the data. RESULTS: The increases in AL, ACD, LT and VL were 0.14 mm, 0.028 mm, 0.0025 mm and 0.11 mm per week, respectively. AL, ACD, LT and VL were positively correlated with BW (ß = 0.000337, 4.234E-5, 2.697E-5, 0.000278, respectively) and PMA (ß = 0.142, 0.026, 0.011, 0.103, respectively). CONCLUSIONS: With maturation, AL and VL increased and ACD deepened, but there was no significant change in LT. The ocular growth parameters were positively correlated with BW and PMA however the correlations were not strong.

Blockade of epidermal growth factor and its receptor and axial elongation in experimental myopia.

To examine the influence of epidermal growth factor (EGF) and its receptor (EGFR) on axial ocular elongation, we intraocularly injected an EGF antibody and an EGFR antibody into young guinea pigs with lens-induced axial elongation (myopization). Mean axial elongation was reduced in the eyes injected with the EGF/EGFR-antibody compared with the contralateral control eyes injected with PBS (phosphate-buffered solution) (0.43 ± 0.13 mm vs 0.53 ± 0.13 mm; P < .001). The intereye difference in axial length increased (P = .005) as the doses of the EGF antibody and EGFR antibody increased. As a corollary, the thickness of the retina at the posterior pole was dose-dependently increased in the injected eyes compared to the contralateral control eyes. Immunohistochemical staining for EGF and the relative mRNA expression of EGF and EGFR were the highest in eyes not injected with the EGF antibody or EGFR antibody and decreased (P < .05) as the dose of EGF antibody or EGFR antibody increased. In an in vitro study, EGF had a stimulating effect and the EGF antibody had an inhibitory effect on the proliferation and migration of RPE cells. The findings showed that the intravitreal application of an EGF antibody and EGFR antibody is associated with a dose-dependent reduction in lens-induced axial elongation in young guinea pigs. The EGFR family may play a role in axial elongation of the eye and in the development of myopia.

Gene Therapy Restores Mfrp and Corrects Axial Eye Length.

Hyperopia (farsightedness) is a common and significant cause of visual impairment, and extreme hyperopia (nanophthalmos) is a consequence of loss-of-function MFRP mutations. MFRP deficiency causes abnormal eye growth along the visual axis and significant visual comorbidities, such as angle closure glaucoma, cystic macular edema, and exudative retinal detachment. The Mfrp rd6 /Mfrp rd6 mouse is used as a pre-clinical animal model of retinal degeneration, and we found it was also hyperopic. To test the effect of restoring Mfrp expression, we delivered a wild-type Mfrp to the retinal pigmented epithelium (RPE) of Mfrp rd6 /Mfrp rd6 mice via adeno-associated viral (AAV) gene therapy. Phenotypic rescue was evaluated using non-invasive, human clinical testing, including fundus auto-fluorescence, optical coherence tomography, electroretinography, and ultrasound. These analyses showed gene therapy restored retinal function and normalized axial length. Proteomic analysis of RPE tissue revealed rescue of specific proteins associated with eye growth and normal retinal and RPE function. The favorable response to gene therapy in Mfrp rd6 /Mfrp rd6 mice suggests hyperopia and associated refractive errors may be amenable to AAV gene therapy.

Alterations of Glutamate and γ-Aminobutyric Acid Expressions in Normal and Myopic Eye Development in Guinea Pigs.

Purpose: The retina has an important role in the signal transmission related to eye development and myopia. Glutamate (Glu) and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters in the retina, which can affect the development of both the eye and myopia. Nevertheless, change in the balance between the excitatory and inhibitory neurotransmitters still is unclear during development of eyes and myopia. The purpose of this study was to explore the alterations of the ratio of Glu to GABA (RGG), which mediates the balance between the excitatory and inhibitory neurotransmitters in retina in the development of the eyes and lens-induced myopia (LIM) in a guinea pig model. Method: An LIM guinea pig model was established using a -10 diopter (D) negative lens. The levels of Glu, GABA, and the dynamic change of RGG were measured in the retina in normal and myopia guinea pigs at four time points (i.e., 0, 2, 4, and 6 weeks after onset of LIM). Considering that Glu and GABA are related closely to the occurrence of myopia, we further studied the changes of RGG in the retina in LIM guinea pigs. Result: Our results showed that the RGG was upregulated and was well correlated with diopter and axial length than either Glu or GABA during the development of normal eyes. Besides, we observed that the content of the RGG in the retina in myopia eyes was higher than that of Glu and GABA in normal subjects and was an obviously positive correlation. Conclusions: Taken together, our findings suggest that the RGG has a pivotal role in eye development and myopia. The abnormal retina signal induced by the unbalanced ratio between Glu and GABA is related closely to the occurrence of myopia.

Human aqueous humor levels of TGF- ß2: relationship with axial length.

PURPOSE: To analyze the relationship between transforming growth factor-beta 2 (TGF- ß 2) levels in the anterior chamber aqueous humor and axial length of patients with myopia. METHODS: TGF- ß 2 was measured with the Luminex xMAP Technology by using commercially available Milliplex xMAP Kits. Sixty-five aqueous humor samples were collected during cataract or clear lens extraction surgery and TGF- ß 2 levels in these specimens were analyzed. According to the axial length, the samples were divided into three groups: A (AL ≤ 24 mm), B (24 ~ 29 mm), and C (AL ≥ 29 mm). RESULTS: Aqueous humor samples were analyzed from subjects with an average age of 67.0 ± 11.7 years. Mean TGF- ß 2 concentration of all aqueous samples was 422.2 ± 258.8 pg/mL. TGF- ß 2 concentration in group C (543 ± 317 pg/mL) was significantly greater than that in group A (390 ± 212 pg/mL) and group B (337 ± 217 pg/mL). The concentration of TGF- ß 2 was positively correlated with axial length (r = 0.308, P = 0.013). CONCLUSIONS: TGF- ß 2 is likely to be acting as a critical factor in axial elongation and development of myopia.

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Influence of macular pigment on retinal straylight in healthy eyes.

PURPOSE: To study the influence of macular pigment on retinal straylight in healthy eyes. METHODS: This prospective study included 150 eyes of 75 healthy subjects between 12 and 81 years of age (mean, 46.1 years) without a history of ocular surgery or ocular disease known to influence straylight (e.g., cataract). Retinal straylight was measured with the compensation comparison technique, and the known influence of age and axial length was compensated by calculating the base, age, and axial length-corrected (BALC) straylight. Macular pigment optical density (MPOD) was measured using light-emitting diode (LED) heterochromatic flicker photometry. Axial length was determined with a partial coherence biometer and iris color by visual inspection. Data analysis consisted of studying the predictive values between these parameters, after correction for the symmetry between left and right eyes, using linear mixed models. RESULTS: Mean retinal straylight was 1.05 ± 0.18 log units, and the mean MPOD was 0.37 ± 0.19. Age and axial length were found to be important predictors of retinal straylight (P < 0.001 and P = 0.010, respectively) but not of MPOD (P > 0.05). The mean BALC straylight was -0.07 ± 0.13 log units. No significant relationship was found between retinal straylight and MPOD (P > 0.05), even after correction for age and axial length. Also, no significant correlation was found between iris color and BALC straylight or MPOD. CONCLUSIONS: In healthy human eyes, retinal straylight values measured with the compensation comparison technique are not significantly correlated with macular pigment optical density.

Regulation of scleral metabolism in myopia and the role of transforming growth factor-beta.

Myopia is one of the most prevalent ocular conditions and is the result of a mismatch between the power of the eye and axial length of the eye. In the vast majority of cases the structural cause of myopia is an excessive axial length of the eye, or more specifically the vitreous chamber depth. In about 3% of the general population in Europe, USA and Australia, the degree of myopia is above 6 dioptres and is termed high myopia. In South East Asia the figure is closer to 20% of the general population with high myopia. The prevalence of sight threatening ocular pathology is markedly increased in eyes with high degrees of myopia (>-6 D). This results from the excessive axial elongation of the eye which, by necessity, must involve the outer coat of the eye, the sclera. Current theories of refractive development acknowledge the pivotal role of the sclera in the control of eye size and the development of myopia. This review details the major structural, biochemical and biomechanical changes that underlie abnormal development of the mammalian sclera in myopia. In describing the changes in regulation of sclera metabolism in myopia, the pivotal role of transforming growth factor-ß signalling is highlighted as the responsible factor for certain critical events in myopia development that ultimately result in the scleral pathology observed in high myopia.

An updated view on the role of dopamine in myopia.

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers ("deprivation myopia", DM) or negative lenses ("lens induced myopia", LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose-response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies.

Inverse relationship between macular pigment optical density and axial length in Chinese subjects with myopia.

BACKGROUND: Macular pigment (MP) has been the focus of much attention in recent years, due to its protective effect against macular degenerations. In this study, we investigated the association between macular pigment optical density (MPOD) and axial length (AL) in Chinese subjects with myopia. METHODS: In total, 173 myopes (mean spherical equivalent [MSE] ≤-1.00D) were recruited for this prospective observational study. MPOD was measured in both eyes of each subject using a macular metrics densitometer. AL was measured in eyes using an IOL-Master. A raw coefficient of correlation analysis and a partial correlation analysis were used to investigate the relationship between MPOD and AL. RESULTS: The age of the subjects ranged from 18 to 67 years. The overall mean MPOD for the cohort was 0.412 ± 0.119 (range, 0.105-0.812). The mean AL was 25.18 ± 1.08 mm (range, 23.14-28.19 mm). Using a raw coefficient of correlation, a significant inverse correlation was found between MPOD and AL (r= -0.134, p=0.012). When using a partial correlation analysis to eliminate the impact of covariant, a significant inverse correlation was also found between MPOD and AL (r= -0.142, p=0.008). Furthermore, when AL was divided into two groups: AL>26 mm and AL ≤ 26 mm, a significant inverse correlation was observed between MPOD and AL in the former (r= -0.253, p=0.029), but no significant relationship was observed between these in the latter (r=0.104, p=0.067). CONCLUSIONS: MPOD correlated inversely with AL in this sample of Chinese subjects with myopia.