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Inhibition of experimental myopia by a dopamine agonist: Different effectiveness between form deprivation and hyperopic defocus in guinea pigs

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The dopamine (DA) system in the retina is critical to normal visual development as lack of retinal DA signaling may contribute to myopic development. The involvement of DA in myopic development is complex and may be different between form deprivation and hyperopic defocus. This study evaluated effects of a non-selective DA receptor agonist, apomorphine (APO) on refractive development in guinea pigs treated with form deprivation or hyperopic defocus. APO was subconjunctivally injected daily for 11 days in form-deprived (0.025 to 2.5 ng/µl) and defocused (0.025 to 250 ng/µl) eyes. Changes in ocular biometry and retinal concentration of DA and its metabolites (DOPAC) were measured in the 2 animal models to assess the level of DA involvement in each of the models (the less the change, the lower the involvement). Similar myopic degree was induced in both the deprived and defocused eyes (-4.06 D versus -3.64 D) at 11 days of the experiment. DA and DOPAC levels were reduced in the deprived eyes but did not change significantly in the defocused eyes compared to the fellow and normal control eyes. A subconjunctival injection of APO daily for 11 days at concentrations ranged from 0.025 to 2.5 ng/µl inhibited form deprivation myopia in a concentration-dependent manner. By contrast, the APO treatment ranged from 0.025 to 250 ng/µl did not effectively inhibit the defocus-induced myopia and the associated axial elongation. DA signaling may play a more critical role in form deprivation myopia than in defocus-induced myopia, raising a question whether the mechanisms of DA signaling are different under these two types of experimental myopia.
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... A currently favored hypothesis is that a reduction in retinal dopamine levels, or inhibition of the dopamine pathway, results in myopia. 6,7 Consistent with this, treatments with exogenous dopamine, dopamine precursor Ldihydroxyphenylalanine, or the non-selective dopamine agonist apomorphine have a protective effect against myopia development in various animal models, including chicks, [8][9][10][11][12][13][14][15][16][17][18] guinea pigs, 19,20 rabbits, 21 tree shrews, 22 nonhuman primates, 23 and mice. 24,25 However, the underlying mechanism-including the specific type(s) of dopamine receptors, and the tissues and cells that express themis largely undefined in these animal models. ...
... Thus the dopaminergic mechanisms controlling refractive development appear to be localized chiefly in the retina, the major site of dopamine release in the eye. In the chick, dopamine content is far higher in the retina than in any other ocular tissue, 54 and during the development of FDM, retinal and vitreal levels of dopamine or its metabolite 3,4dihydroxyphenylacetic acid become reduced, 9,19,55 whereas choroidal and scleral dopamine levels remain unaltered. 54 In much the same way, with partial-field FD, the decrease of retinal 3,4-dihydroxyphenylacetic acid is restricted to the specific retinal areas in which myopia is induced. ...
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Purpose: To learn more about the locations of dopamine D2 receptors (D2Rs) that regulate form-deprivation myopia (FDM), using different transgenic mouse models. Methods: One eye of D2R-knockout (KO) mice and wild-type littermates was subjected to four weeks of monocular FDM, whereas the fellow eye served as control. Mice in both groups received daily intraperitoneal injections of either the D2R antagonist sulpiride (8 µg/g) or vehicle alone. FDM was also induced in retina- (Six3creD2Rfl/fl) or fibroblast-specific (S100a4creD2Rfl/fl) D2R-KO mice. A subset of retina-specific D2R-KO mice and D2Rfl/fl littermates were also given sulpiride or vehicle injections. Refraction was measured with an eccentric infrared photorefractor, and other biometric parameters were measured by optical coherence tomography (n ≈ 20 for each group). Results: FDM development was attenuated in wild-type littermates treated with sulpiride. However, this inhibitory effect disappeared in the D2R-KO mice, suggesting that antagonizing D2Rs suppressed myopia development. Similarly, the development of myopia was partially inhibited by retina-specific (deletion efficiency: 94.7%) but not fibroblast-specific (66.9%) D2R-KO. The sulpiride-mediated inhibitory effects on FDM also disappeared with retinal D2R-KO, suggesting that antagonizing D2Rs outside the retina may not attenuate myopia. Changes in axial length were less marked than changes in refraction, but in general the two were correlated. Conclusions: This study demonstrates that D2Rs located in the retina participate in dopaminergic regulation of FDM in mice. These findings provide an important and fundamental basis for further exploring the retinal mechanism(s) involved in dopamine signaling and myopia development.
... Alternatively, it could be that dopamine receptors in the myopic retina have an increased affinity to dopamine 61 . This is supported by the fact that apomorphine slows ocular growth and myopia development in form-deprived guinea pigs, which have significantly reduced retinal dopamine levels, but not control guinea pigs, which have normal dopamine levels 62 . Mutti et al. 63 recently reported that repeated exposure to blue light (λ = 448 nm) resulted in greater, more sustained pupillary constriction in young non-myopic adults than in myopic adults. ...
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Altered retinal dopamine and ON-pathway activity may underlie myopia development. It has been shown that the stimulation of the blind spot with short-wavelength light increases the electroretinogram (ERG) b-wave amplitude of myopic eyes and may engage the retinal dopaminergic system. This study evaluated the impact of various durations of blind spot stimulation on the electrophysiological response of the myopic retina and their relationship to axial length. Six myopic individuals underwent three short-wavelength blue light blind spot stimulation protocols (10 s, 1 min, 10 min) using a virtual reality headset. As a control condition, no stimulation was shown for 1 min. The b-wave amplitude of the photopic full-field ERG was measured at baseline and 10, 20, 30, 40, 50, and 60 min after each condition. A significant increase in b-wave amplitude was observed for all stimulation protocols compared to the control. The peak b-wave amplitude was observed 20 min after the 1-min stimulation protocol and 60 min after the 10-min stimulation protocol. A significant positive correlation was found between axial length of the eye and percent change in b-wave amplitude for the 10-min stimulation protocol. A rapid and a delayed b-wave time course responses were observed following 1 min and 10 min of blind spot stimulation, respectively. Overall, these results indicate that light stimulation of the blind spot for various durations elevates ON-bipolar cell activity in the retina and as such is assumed to reduce the myopic response. These findings could have implications for future myopia treatment.
... 163,164 Correspondingly, pharmacological stimulation of dopamine signaling (via e.g. nonspecific dopamine receptor agonist apomorphine) protects against FDM in a wide range of species including mice, [165][166][167] primates, 168 chicks, 169,170 guinea pigs, 171,172 and rabbits. 173 Conversely, dopamine receptor antagonists facilitate myopia development induced by FDM. ...
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Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to severe ocular complications later in life. Genomewide association studies (GWAS) have made considerable contributions to the understanding of the genetic architecture of refractive errors. Among the hundreds of genetic variants identified, common variants near the gap junction delta-2 (GJD2) gene have consistently been reported as one of the top hits. GJD2 encodes the connexin 36 (Cx36) protein, which forms gap junction channels and is highly expressed in the neural retina. In this review, we provide current evidence that links GJD2(Cx36) to the development of myopia. We summarize the gap junctional communication in the eye and the specific role of GJD2(Cx36) in retinal processing of visual signals. Finally, we discuss the pathways involving dopamine and gap junction phosphorylation and coupling as potential mechanisms that may explain the role of GJD2(Cx36) in refractive error development.
... A reduced retinal DA level was also found in LIM chicks (Guo et al., 1995). Furthermore, an increasing DA level was reported to prevent FDM in guinea pigs (Mao et al., 2010;Dong et al., 2011), mice (Yan et al., 2015), rabbits (Gao et al., 2006), and monkeys (Iuvone et al., 1991). In addition, a previous study suggested that an intravitreal injection of atropine increased dopamine release and the concentration of its metabolite DOPAC in the chick retina (Schwahn et al., 2000). ...
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Purpose: Atropine, a non-selective muscarinic antagonist, effectively slows down myopia progression in human adolescents and several animal models. However, the underlying molecular mechanism is unclear. The current study investigated retinal protein changes of form-deprived myopic (FDM) guinea pigs in response to topical administration of 1% atropine gel (10 g/L). Methods: At the first stage, the differentially expressed proteins were screened using fractionated isobaric tags for a relative and absolute quantification (iTRAQ) approach, coupled with nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) ( n = 24, 48 eyes) using a sample pooling technique. At the second stage, retinal tissues from another cohort with the same treatment ( n = 12, 24 eyes) with significant ocular changes were subjected to label-free sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics for orthogonal protein target confirmation. The localization of Alpha-synuclein was verified using immunohistochemistry and confocal imaging. Results: A total of 1,695 proteins (8,875 peptides) were identified with 479 regulated proteins (FC ≥ 1.5 or ≤0.67) found from FDM eyes and atropine-treated eyes receiving 4-weeks drug treatment using iTRAQ-MS proteomics. Combining the iTRAQ-MS and SWATH-MS datasets, a total of 29 confident proteins at 1% FDR were consistently quantified and matched, comprising 12 up-regulated and 17 down-regulated proteins which differed between FDM eyes and atropine treated eyes (iTRAQ: FC ≥ 1.5 or ≤0.67, SWATH: FC ≥ 1.4 or ≤0.71, p -value of ≤0.05). Bioinformatics analysis using IPA and STRING databases of these commonly regulated proteins revealed the involvement of the three commonly significant pathways: EIF2 signaling; glycolysis; and dopamine secretion. Additionally, the most significantly regulated proteins were closely connected to Alpha-synuclein (SNCA). Using immunostaining ( n = 3), SNCA was further confirmed in the inner margin of the inner nuclear layer (INL) and spread throughout the inner plexiform layer (IPL) of the retina of guinea pigs. Conclusion: The molecular evidence using next-generation proteomics (NGP) revealed that retinal EIF2 signaling, glycolysis, and dopamine secretion through SNCA are implicated in atropine treatment of myopia in the FDM-induced guinea pig model.
... Ainsi la sécrétion de dopamine dans l'oeil préviendrait l'apparition d'une myopie en agissant tel un signal « stop » sur la croissance oculaire. En effet, il a été mis en évidence que le taux de dopamine et de DOPAC diminuait dans les yeux d'animaux soumis à des modèles d'induction de myopie [264][265][266][267]. L'augmentation de dopamine par injection de la molécule directement dans l'oeil ou par l'administration systémique de L-DOPA préviendrait l'apparition de myopie dans des modèles animaux [268][269][270]. ...
Thesis
La dégénérescence liée à l’âge (DMLA) néovasculaire est l’une des causes majeures de perte de vision, malgré une thérapie répétée par injection intravitréenne d’anti-VEGF qui constitue un fardeau considérable pour les patients, les ophtalmologistes et le système de santé. Une étude de cohorte rétrospective sur plusieurs millions de patients aux États-Unis a retrouvé que les patients parkinsoniens, traités par la L-DOPA avaient un âge de diagnostic de DMLA néovasculaire significativement plus tardif que les patients non traités. Grâce à l’utilisation d’un modèle murin de Parkinson par intoxication au MPTP, et d’un modèle murin de DMLA néovasculaire induite par phototraumatisme laser, en association avec le traitement standard de la maladie de Parkinson, nous avons montré qu’un traitement par L-DOPA induit une augmentation de la signalisation du récepteur à la dopamine D2, responsable d’une inhibition de la néovascularisation choroïdienne. Ces résultats apportent une explication à une épidémiologie intrigante. Poursuivant les travaux sur les récepteurs de la dopamine dans nos modèles murins, nous avons montré que des agonistes systémiques du récepteur D2 provoquaient une diminution de la néovascularisation. Ce comportement pourrait constituer une thérapie efficace pour réduire le besoin d’injections d’anti-VEGF chez les patients atteints de DMLA néovasculaire.
... R etinal dopamine (DA) plays a pivotal role in modulating refractive development. [1][2][3][4][5][6] As a chemical signal of retinal photoadaptation, retinal DA release and turnover have been shown to be regulated by light in several vertebrates. [7][8][9][10][11] Bright light and flickering light can stimulate the ON pathway and intrinsically photosensitive retinal ganglion cells, as well as alter DA synthesis and release. ...
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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.
Article
The global prevalence of myopia, or nearsightedness, has increased at an alarming rate over the last few decades. An eye is myopic if incoming light focuses prior to reaching the retinal photoreceptors, which indicates a mismatch in its shape and optical power. This mismatch commonly results from excessive axial elongation. Important drivers of the myopia epidemic include environmental factors, genetic factors, and their interactions, e.g., genetic factors influencing the effects of environmental factors. One factor often hypothesized to be a driver of the myopia epidemic is environmental light, which has changed drastically and rapidly on a global scale. In support of this, it is well established that eye size is regulated by a homeostatic process that incorporates visual cues (emmetropization). This process allows the eye to detect and minimize refractive errors quite accurately and locally over time by modulating the rate of elongation of the eye via remodeling its outermost coat, the sclera. Critically, emmetropization is not dependent on post-retinal processing. Thus, visual cues appear to influence axial elongation through a retina-to-sclera, or retinoscleral, signaling cascade, capable of transmitting information from the innermost layer of the eye to the outermost layer. Despite significant global research interest, the specifics of retinoscleral signaling pathways remain elusive. While a few pharmacological treatments have proven to be effective in slowing axial elongation (most notably topical atropine), the mechanisms behind these treatments are still not fully understood. Additionally, several retinal neuromodulators, neurotransmitters, and other small molecules have been found to influence axial length and/or refractive error or be influenced by myopigenic cues, yet little progress has been made explaining how the signal that originates in the retina crosses the highly vascular choroid to affect the sclera. Here, we compile and synthesize the evidence surrounding three of the major candidate pathways receiving significant research attention — dopamine, retinoic acid, and adenosine. All three candidates have both correlational and causal evidence backing their involvement in axial elongation and have been implicated by multiple independent research groups across diverse species. Two hypothesized mechanisms are presented for how a retina-originating signal crosses the choroid — via 1) all-trans retinoic acid or 2) choroidal blood flow influencing scleral oxygenation. Evidence of crosstalk between the pathways is discussed in the context of these two mechanisms.
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Myopia has become one of the most critical health problems in the world with the increasing time spent indoors and increasing close work. Pathological myopia may have multiple complications, such as myopic macular degeneration, retinal detachment, cataracts, open-angle glaucoma, and severe cases that can cause blindness. Mounting evidence suggests that the cause of myopia can be attributed to the complex interaction of environmental exposure and genetic susceptibility. An increasing number of researchers have focused on the genetic pathogenesis of myopia in recent years. Scleral remodeling and excessive axial elongating induced retina thinning and even retinal detachment are myopia's most important pathological manifestations. The related signaling pathways are indispensable in myopia occurrence and development, such as dopamine, nitric oxide, TGF-β, HIF-1α, etc. We review the current major and recent progress of biomedicine on myopia-related signaling pathways and mechanisms.
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Myopia, or nearsightedness, is the most common form of refractive abnormality and is characterized by excessive ocular elongation in relation to ocular power. Retinal neurotransmitter signaling, including dopamine, is implicated in myopic ocular growth, but the visual pathways that initiate and sustain myopia remain unclear. Melanopsin-expressing retinal ganglion cells (mRGCs), which detect light, are important for visual function, and have connections with retinal dopamine cells. Here, we investigated how mRGCs influence normal and myopic refractive development using two mutant mouse models: Opn4−/− mice that lack functional melanopsin photopigments and intrinsic mRGC responses but still receive other photoreceptor-mediated input to these cells; and Opn4DTA/DTA mice that lack intrinsic and photoreceptor-mediated mRGC responses due to mRGC cell death. In mice with intact vision or form-deprivation, we measured refractive error, ocular properties including axial length and corneal curvature, and the levels of retinal dopamine and its primary metabolite, L-3,4-dihydroxyphenylalanine (DOPAC). Myopia was measured as a myopic shift, or the difference in refractive error between the form-deprived and contralateral eyes. We found that Opn4−/− mice had altered normal refractive development compared to Opn4+/+ wildtype mice, starting ∼4D more myopic but developing ∼2D greater hyperopia by 16 weeks of age. Consistent with hyperopia at older ages, 16 week-old Opn4−/− mice also had shorter eyes compared to Opn4+/+ mice (3.34 vs 3.42 mm). Opn4DTA/DTA mice, however, were more hyperopic than both Opn4+/+ and Opn4−/− mice across development ending with even shorter axial lengths. Despite these differences, both Opn4−/− and Opn4DTA/DTA mice had ∼2D greater myopic shifts in response to form-deprivation compared to Opn4+/+ mice. Furthermore, when vision was intact, dopamine and DOPAC levels were similar between Opn4−/− and Opn4+/+ mice, but higher in Opn4DTA/DTA mice, which differed with age. However, form-deprivation reduced retinal dopamine and DOAPC by ∼20% in Opn4−/− compared to Opn4+/+ mice but did not affect retinal dopamine and DOPAC in Opn4DTA/DTA mice. Lastly, systemically treating Opn4−/− mice with the dopamine precursor L-DOPA reduced their form-deprivation myopia by half compared to non-treated mice. Collectively our findings show that disruption of retinal melanopsin signaling alters the rate and magnitude of normal refractive development, yields greater susceptibility to form-deprivation myopia, and changes dopamine signaling. Our results suggest that mRGCs participate in the eye's response to myopigenic stimuli, acting partly through dopaminergic mechanisms, and provide a potential therapeutic target underling myopia progression. We conclude that proper mRGC function is necessary for correct refractive development and protection from myopia progression.
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Purpose: Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via peribulbar, intravitreal, or intraperitoneal injections is not clinically viable, we sought to evaluate ocular penetration and safety of the topically applied dopaminergic prodrug etilevodopa. Methods: The ocular penetration of dopamine and dopaminergic prodrugs (levodopa and etilevodopa) were quantified using an enzyme-linked immunosorbent assay in enucleated porcine eyes after a single topical administration. The pharmacokinetic profile of the etilevodopa was then assessed in rats. A four-week once-daily application of etilevodopa as a topical eye drop was conducted to establish its safety profile. Results: At 24 hours, the studied prodrugs showed increased dopaminergic derivatives in the vitreous of porcine eyes. Dopamine 0.5% (P = 0.0123) and etilevodopa 10% (p = 0.370) achieved significant vitreous concentrations. Etilevodopa 10% was able to enter the posterior segment of the eye after topical administration in rats with an intravitreal half-life of eight hours after single topical administration. Monthly application of topical etilevodopa showed no alterations in retinal ocular coherence tomography, electroretinography, caspase staining, or TUNEL staining. Conclusions: At similar concentrations, no difference in ocular penetration of levodopa and etilevodopa was observed. However, etilevodopa was highly soluble and able to be applied at higher topical concentrations. Dopamine exhibited both high solubility and enhanced penetration into the vitreous as compared to other dopaminergic prodrugs. Translational relevance: These findings indicate the potential of topical etilevodopa and dopamine for further study as a therapeutic treatment for myopia.
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To increase our understanding of the mechanisms that remodel the sclera during the development of lens-induced myopia, when the sclera responds to putative "go" signals of retinal origin, and during recovery from lens-induced myopia, when the sclera responds to retinally-derived "stop" signals. Seven groups of tree shrews were used to examine mRNA levels during minus lens compensation and recovery. Starting 24 days after eye opening (days of visual experience [VE]) lens compensation animals wore a monocular -5D lens for 1, 4, or 11 days. Recovery animals wore the -5D lens for 11 days, which was then removed for 1 or 4 days. Normal animals were examined at 24 and 38 days of VE. All groups contained 8 animals. Scleral mRNA levels were examined in the treated and contralateral control eyes with quantitative real-time polymerase chain reaction (qPCR) for 27 genes divided into four categories: 1) signaling molecules, 2) matricellular proteins, 3) metalloproteinases (MPs) and tissue inhibitors of metalloproteinases (TIMPs), and 4) cell adhesion and other proteins. Four groups (n=5 per group) were used to examine protein levels. One group wore a -5D lens for 4 days. A second group recovered for 4 days after 11 days of -5D lens treatment. Two groups were used to examine age-matched normal protein levels at 28 and 39 days of VE. The levels of six scleral proteins that showed differential mRNA expression were examined with quantitative western blots. Nineteen of the genes showed differential (treated eye versus control eye) expression of mRNA levels in at least one group of animals. Which genes showed differential expression differed after 1 and 4 days of compensation and after 1 or 4 days of recovery. The mRNA level for one gene, a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), was upregulated in the treated eyes after 1 day of compensation. After 4 days, transforming growth factor beta receptor 3 (TGFBR3), transforming growth factor-beta-induced protein ig-h3 (TGFBI), and matrix metalloproteinase 14 (MMP14) mRNA levels were upregulated. Downregulated were mRNA levels for transforming growth factor beta-1 (TGFB1), transforming growth factor beta-2 (TGFB2), thrombospondin 1 (THBS1), tenascin (TNC), osteonectin (SPARC), osteopontin (SPP1), tissue inhibitor of metalloproteinases 3 (TIMP3), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). After 11 days of lens wear, there was no differential expression. During recovery, after 1 day, treated-eye mRNA downregulation was found for TGFB2, TGFBR1, TGFBR2, TGFBR3, SPARC, ADAMTS1, ADAMTS5, syndecan 4 (SDC4), and collagen type VI, alpha 1 (COL6A1). After 4 days, TGFB1, TGFB2, TGFB3, THBS2, and TIMP3 mRNA levels were upregulated in the recovering eye. Significant downregulation, relative to normal eyes, was found in both the control and treated eyes for most genes after 1 day of compensation; a similar decrease was found, compared to lens-compensated eyes, after one day of recovery. Protein levels for THBS1 showed positive correlation with the differential mRNA levels and TGFBR3 showed a negative correlation. No differential protein expression was found for TGFB2, TGFBI, MMP14, and TIMP3. The different patterns of differential mRNA expression during minus lens compensation (hyperopia) and recovery (myopia) show that scleral fibroblasts distinguish between "go" and "stop" conditions. There is evidence of binocular global downregulation of genes at the start of both lens wear and recovery. As additional information accumulates about changes in gene expression that occur during compensation and recovery the "signature" of differential changes may help us to understand in more detail how the sclera responds in "go" and "stop" conditions.
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This study investigated whether adolescent guinea pigs can develop myopia induced by negative lenses, and whether they can recover from the induced myopia. Forty-nine pigmented guinea pigs (age of 3 weeks) were randomly assigned to 4 groups: 2-week defocus (n = 16), 4-week defocus (n = 9), 2-week control (n = 15) and 4-week control (n = 9). A −4.00 D lens was worn in the defocus groups and a plano lens worn in the control groups monocularly. The lenses were worn from 3 weeks to 5 weeks of age in the 2-week treatment groups with the biometry measured at 2, 4, 6, 10 and 14 days of lens wear. The lenses were worn from 3 weeks to 7 weeks of age in the 4-week treatment groups with the biometry measured immediately and at 2, 4, 6, 10 and 14 days after lens removal. Refractions in the defocused eyes developed towards myopia rapidly within 2 days of lens wear, followed by a slower development. The defocused eyes were at least 3.00 D more myopic with a greater increase in vitreous length by 0.08 mm compared to the fellow eyes at 14 days (p < 0.05). The estimated choroidal thickness of the defocused eyes decreased rapidly within 2 days of lens wear, followed by a slower decrease over the next 4 days. Relative myopia induced by 4 weeks of negative-lens treatment declined rapidly following lens removal. A complete recovery occurred 14 days after lens removal when compared to the fellow controls. The refractive changes during the recovery corresponded to a slower vitreous lengthening and a rapid thickening of the choroid. The plano-lens wearing eyes showed a slight but significant myopic shift (<−0.80 D) with no associated biometrical changes. Guinea pigs aged 3 weeks can still develop negative lens induced myopia and this myopia is reversible after removal of the lens. The myopia and recovery are mainly due to changes in vitreous length and choroidal thickness.
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Form-deprivation myopia (FDM) in the chick is a popular model for studying the postnatal regulation of ocular growth. Using this model, we have shown previously that dopamine and FGF-2 can counteract the effects of form-deprivation, thereby producing emmetropia. In the present study, we tested the hypothesis that the emmetropizing effects of flickering light and intraocular injections of FGF-2 in the chick are mediated by the activity of dopaminergic retinal amacrine cells. We have assessed the rate of dopamine synthesis 3n the retina by measuring the accumulation of 3,4-dihydroxyphenylalanine (DOPA). We found that form-deprivation reduces the rate of dopamine synthesis in the light-adapted retina, and that the normal rate of dopamine synthesis in the light can be restored by stroboscopic illumination at freqeuncies around 10 Hz. By labeling cells immunocytochemically we have shown that the synthesis of c- fos, a putative transcriptional regulator of the tyrosine hydroxylase gene, is induced in dopaminergic amacrine cells by stroboscopic illumination at around 10 Hz. These observations are consistent with a critical role for dopaminergic amacrine cells in the regulation of ocular growth by intermittent illumination. We have found also that intraocular injections of FGF-2 cause emmetropization without altering levels of expression of c-fos, amounts of tyrosine hydroxylase, or rates of dopamine synthesis with respect to vehicle-injected controls. We conclude that FGF acts either in parallel to or downstream from the dopaminergic amacrine cells, rather than through them. We observed that intravitreal injection per se induces high levels of c-fos expression in both form-deprived and non-deprived retinas, and causes partial emmetropization in form-deprived eyes, while inhibiting dopamine synthesis in non-deprived retinas. It is likely, therefore, that injection stimulates the production and/ or release of unknown factors whose diverse effects on ocular growth and dopamine metabolism are mediated by complex pathways. Taken together, our results are consistent with the view that the retinal circuitry that controls postnatal ocular growth in the chick involves multiple messengers and pathways.
Article
The dopaminergic system has been implicated in ocular growth regulation in chicks and monkeys. In both, dopamine D2 agonists inhibit the development of myopia in response to form deprivation, and in chicks, to negative lenses as well. Because there is mounting evidence that the choroidal response to defocus plays a role in ocular growth regulation, we asked whether the effective agonists also elicit transient thickening of the choroid concomitant with the growth inhibition. Negative lenses mounted on velcro rings were worn on one eye starting at age 8-12 days. Intravitreal injections (20 μl; dose = 10 nmole) of the agonist (dissolved in saline) or saline, were given through the superior temporal sclera using a 30G needle. Eyes were injected daily at noon, for 4 days, and the lenses immediately replaced. Agonists used were apomorphine (non-specific; n = 17), quinpirole (D2; n = 10), SKF-38393 (D1; n = 9), and saline controls (n = 22). For the antagonists, the same protocol was used, but on each day, the lenses were removed for 2 h. Immediately prior to lens-removal, the antagonist was injected (20 μl; dose = 5 nmole). Antagonists used were methylergonovine (non-specific; n = 12), spiperone (D2; n = 20), SCH-23390 (D1; n = 6) and saline controls (n = 27). Comparisons to saline (continuous lens wear) controls were from the agonist experiment. Axial dimensions were measured using high frequency A-scan ultrasonography at the start of lens wear, and on day 4 prior to the injections, and then again 3 h later. Refractive errors were measured using a Hartinger's refractometer at the end of the experiment. Apomorphine and quinpirole inhibited the refractive response to the hyperopic defocus induced by the negative lenses (drug vs saline controls: -1.3 and 1.2 D vs -5.6 D; p < 0.005 for both). This effect was axial: both drugs prevented the excessive ocular elongation (change in axial length: 233 and 205 μm vs 417 μm; p < 0.01 for both). Both drugs were also associated with a transient thickening of the choroid over 3 h (41 and 32 μm vs -1 μm; p < 0.01; p = 0.059 respectively) that did not summate: choroids thinned significantly over the 4 day period in all lens-wearing eyes. Two daily hours of unrestricted vision during negative lens wear normally prevents the development of myopia. Spiperone and SCH-23390 inhibited the ameliorating effects of periods of vision on lens-induced refractive error (-2.9 and -2.8 D vs 0.6 D; p < 0.0001), however, the effects on neither axial length nor choroidal thickness were significant. These data support a role for both D1 and D2 receptors in the ocular growth responses.
Article
To investigate the distributions and changes in dopamine transporters (DATs) using Tc-TRODAT-1 ([Tc-(2((2-(((3-(4-chlorophenyl)-8-methyl-8-azabicyclo(3,2,1)-oct-2-yl)-methyl)(2-mercaptoethyl)amino)ethyl)amino)ethane-thiolato(3-)-N2,N2',S2,S2)oxo-(1R-(exo-exo)))]) in form deprivation myopia retina. Pigmented guinea pigs aged 3 weeks were randomly assigned into two groups: form-deprivation myopia and normal control group. The test group wore a translucent goggle covering randomly for 4 weeks, and both groups underwent biometric measurement before and after the experiment. Both Micro-single-photon emission computed tomography (SPECT) imaging and ex-vivo autoradiography were performed with the injection of Tc-TRODAT-1 on the 4th week for all the guinea pigs. The retinas were clearly resolved with Tc-TRODAT-1 in both Micro-SPECT imaging and ex-vivo autoradiography. In Micro-SPECT imaging, the ratio of Tc-TRODAT-1 uptake in the myopic retinas (11.55+/-2.80) was 3.64+/-1.40 lower than that in the normal control eyes (15.20+/-1.98, P=0.026, F=2.94, t=2.605), and 2.35+/-1.05 lower than that in the fellow eyes (13.90+/-2.04, P=0.003, t=5.476). In ex-vivo autoradiography, the ratio of Tc-TRODAT-1 uptake in the myopic retina (95.52+/-12.04) was 18.54+/-5.86 lower than in the normal control eyes (114.06+/-7.81, P=0.01, F=0.331, t=3.164), and was 16.95+/-5.78 lower than in the fellow eyes (112.47+/-15.67, P=0.001, t=7.179). Tc-TRODAT-1 can be used to trace the distributions and changes in DAT in the retina. DATs in the myopic retinas were lower than that in the fellow and normal control eyes. Radionuclide tracing may provide a new approach in vivo for further studies on the dopamine system in myopia.
Article
To evaluate the efficacy of 0.025% atropine solution for prevention of myopic shift and myopia onset in premyopic children. This study was designed as a retrospective cohort study. Six- to 12-year-old children with spherical equivalent refraction of <+1 diopter (D) (defined as premyopia), with cylindrical refraction of <-1 D, without amblyopia, and who received 0.025% atropine eye drops at bedtime every night or no treatment after follow-up for at least 12 months were enrolled. Fast myopic shift is defined as a myopic shift >-0.5 D per year. Fifty children were enrolled in the study. Twenty-four children (average age 7.6 years old) were in the 0.025% atropine group, and 26 children (average age: 8.2 years old) were in the control group. The mean spherical refraction myopic shift in the 0.025% atropine group was -0.14 +/- 0.24 D/year, significantly lower than that in the control group, -0.58 +/- 0.34 D/year (P < 0.0001). In multiple linear regression analysis, 0.025% atropine treatment was the only independent variable in preventing myopia shift. There were statistically significant differences between the 0.025% atropine group and the control group in myopia onset and fast myopic shift (21% vs. 54%, P = 0.016; 8% vs. 58%, P = 0.0002, respectively). There was no difference between the 2 groups with regard to the symptom of photophobia (16% vs. 8%, P = 0.409). None of the children in either group complained of near-blurred vision. Regular topical administration of 0.025% atropine eye drops can prevent myopia onset and myopic shift in premyopic schoolchildren for a 1-year period.
Article
It has been shown that sunlight or bright indoor light can inhibit the development of deprivation myopia in chicks. It remains unclear whether light merely acts on deprivation myopia or, more generally, modulates the rate of emmetropization and its set point. This study was conducted to test how bright light interacts with compensation for imposed optical defocus. Furthermore, a dopamine antagonist was applied to test whether the protective effect of light is mediated by dopamine. Experiment A: Chicks monocularly wore either -7 or +7 D lenses for a period of 5 days, either under normal laboratory illuminance (500 lux, n = 12 and 16, respectively) or under high ambient illuminance (15,000 lux, n = 12 and 16). Experiment B: Chicks wore diffusers for a period of 4 days, either under normal laboratory illuminance (500 lux, n = 9) or high ambient illuminance (15,000 lux), with the bright-light group intravitreally injected daily with either the dopamine D(2) antagonist spiperone (500 μM, n = 9) or a vehicle solution (0.1% ascorbic acid, n = 9), with an untreated group serving as the control (n = 6). Axial length and refraction were measured at the commencement and cessation of all treatments. Exposure to high illuminances (15,000 lux) for 5 hours per day significantly slowed compensation for negative lenses, compared with that seen under 500 lux, although full compensation was still achieved. Compensation for positive lenses was accelerated by exposure to high illuminances but, again, the end point refraction was unchanged, compared with that of the 500-lux group. High illuminance also reduced deprivation myopia by roughly 60%, compared with that seen under 500 lux. This protective effect was abolished, however, by the daily injection of spiperone, but was unaffected by the injection of a vehicle solution. High illuminance levels reduce the rate of compensation for negative lenses and enhance the rate for positive lenses, but do not change the set point of emmetropization (target refraction). The retardation of myopia development by light is partially mediated by dopamine, as the injection of a dopamine antagonist abolishes the protective effect of light, at least in the case of deprivation myopia.
Article
Levodopa is the mainstay of symptomatic treatment for Parkinson's disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs. Medline literature search (from 1973 to date). A perspective on the evolution of PD pharmacological treatment. Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy.
Article
It has been shown that visual deprivation leads to a myopic refractive error and also reduces the retinal concentration of dopamine. Exogenously 3,4-dihydroxy-L-phenylalanine (levodopa, L-DOPA) can be converted into dopamine in vivo, which safely and effectively treats Parkinson disease. Moreover, L-DOPA was also used in the treatment of amblyopia in clinical studies. However, the effect of L-DOPA on the development of myopia has not been studied. The aim of this study was to investigate whether intraperitoneal injection of L-DOPA could inhibit form-deprivation myopia in guinea pigs and to explore a new strategy for drug treatment of myopia. Sixty guinea pigs, at age of 4 weeks, were randomly divided into six groups: normal control, L-DOPA group, saline group, deprived group, deprived plus L-DOPA group, and deprived plus saline group. Form deprivation was induced with translucent eye shields on the right eye and lasted for 10 days. L-DOPA was injected intraperitoneally into the guinea pig once a day. The corneal radius of curvature, refraction, and axial length were measured in all animals. Subsequently, retinal dopamine content was evaluated by high-performance liquid chromatography with electrochemical detection. Ten days of eye occlusion caused the form-deprived eyes to elongate and become myopic, and retinal dopamine content to decrease, but the corneal radius of curvature was not affected. Repeated intraperitoneal injection of L-DOPA could inhibit the myopic shift (from -3.62 +/- 0.98 D to -1.50 +/- 0.38 D; p < 0.001) due to goggles occluding and compensate retinal dopamine (from 0.65 +/- 0.10 ng to 1.33 +/- 0.23 ng; p < 0.001). Administration of L-DOPA to the unoccluded animals had no effect on its ocular refraction. There was no effect of intraperitoneal saline on the ocular refractive state and retinal dopamine. Systemic L-DOPA was partly effective in this guinea pig model and, therefore, is worth testing for effectiveness in progressing human myopes.