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Inhibition of experimental myopia by a dopamine agonist: Different effectiveness between form deprivation and hyperopic defocus in guinea pigs
Abstract and Figures
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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... Dopamine, one of the most studied neurotransmitters in animal models of myopia, has been associated with a potent control of emmetropization [14,15]. Subsequent data from multiple experiments in different species suggest that dopamine acts as a "stop" signal in axial eye growth, with a decrease in dopamine levels in response to form-deprivation (FD), which then recover when the diffuser is removed [14,[16][17][18][19]. Activation of retinal dopamine D1 receptor has been shown to suppress myopia development in various animal models, including mice and chicks, while antagonists enhanced it [20,21]. ...
... Experimental studies have been conducted in various species to investigate the potential of increasing dopamine levels or enhancing dopamine receptor activity to inhibit myopic growth in FD myopia models [16,19,[29][30][31][32]. Nevertheless, no studies have been conducted on the topical instillation of dopamine in FD myopia models with a light diffuser in mammals. ...
... Since Stone et al. [8] demonstrated that dopamine levels are reduced in FD myopia, it has been shown that dopamine or levodopa injected directly into the eye can prevent FD myopia in rabbits [32] and guinea pigs [31]. In addition, the dopamine receptor agonist, such as apomorphine, has also been shown to prevent FD myopia in a variety of species, including chickens [40], guinea pigs [19], monkeys [9] and mice [41]. Recent studies, not only animal studies but also clinical evidence, showing a strong correlation between time spent outdoors and light intensity with myopia suppression, support the hypothesis that retinal dopamine, which is synthesized and released by light stimulation, plays a role in myopia control [22,[42][43][44][45]. ...
Background/Objectives: This study aimed to investigate the efficacy of topical dopamine administration in inhibiting form deprivation (FD) myopia in a rabbit model. Methods: A total of 16 neonatal New Zealand white rabbits were randomly assigned to two groups: a control group and a dopamine treatment group. FD myopia was induced in both groups by applying a light diffuser to one eye. The dopamine group received daily topical instillations of 4% dopamine in the eye with FD myopia, while the control group received normal saline instillations over a four-week period. Axial length measurements were taken to assess the degree of myopia, and histological analysis was performed to evaluate retinal safety and structural integrity. Results: The results indicated that dopamine treatment significantly inhibited axial elongation of the FD eyes compared to the control group, with measurements of 15.07 ± 0.34 mm for the dopamine group versus 15.63 ± 0.33 mm for the control group (p = 0.015). Histological analysis showed no evidence of structural alterations or apoptosis in the retina, confirming the safety of topical dopamine. Conclusions: Topical dopamine appears to be a promising therapeutic approach for controlling the progression of myopia in a rabbit model, demonstrating significant efficacy in reducing axial elongation without inducing ocular toxicity. These findings highlight the potential of dopamine in managing myopia and warrant further investigation in clinical settings.
... Apomorphine, a nonselective dopamine receptor agonist, has been studied in this context. Dong et al. [70] found that apomorphine effectively inhibits the development of form deprivation myopia in animal models, though it does not affect defocus myopia. Despite its potential, there are few studies on apomorphine, and further research is needed to assess its feasibility, safety, and clinical indications for treating myopia. ...
... Furthermore, we investigated whether vitreous dopamine in rabbit eyes exhibited similar changes in other animal models of myopia. 15,16 The findings contribute to the possibility of integrating additional research on myopia and fundus disease. ...
Purpose:
This study assessed the characteristics of refractive development and choroidal vasculature in the form-deprivation (FD) pigmented rabbit model.
Methods:
Monocular FD was performed in three-week-old pigmented rabbits (n = 18 for FD, n = 12 for control). Throughout the eight-week rearing period, refractive errors, corneal curvature radius (CCR), ocular biometric parameters, retinal thickness (RT), and choroidal thickness (ChT) were measured every two weeks using cycloplegic retinoscopy, keratometer, A-scan ultrasonography, and optical coherence tomography (OCT). The choroidal vascularity index (CVI) was calculated from OCT images by measuring the total choroidal area (TCA), stromal area (SA), and luminal area (LA). At the end of the form deprivation, the vitreous dopamine level was measured using an enzyme-linked immunosorbent assay kit.
Results:
Relatively myopic refraction was induced in FD eyes after two, four, six, and eight weeks (interocular differences: -1.48 ± 0.88, -1.92 ± 0.90, -1.95 ± 0.80, and -2.00 ± 0.83 diopter; P < 0.001). Furthermore, FD eyes showed significantly longer axial length (AL) and vitreous chamber depth after eight weeks, with mean differences of 0.32 ± 0.03 and 0.32 ± 0.05 mm, respectively (P < 0.001). There were no significant differences in anterior chamber depth, lens thickness, CCR, and RT among the three groups through the intervention (all P > 0.05). After eight weeks, the average ChT of FD eyes was thinner than contralateral eyes (-19.37 ± 7.01 µm; P < 0.001). Additionally, the TCA, SA, and LA in FD eyes were smaller after four, six, and eight weeks (all P < 0.05, week 8: 0.3697 ± 0.0639 vs. 0.4272 ± 0.0968, 0.1047 ± 0.0221 vs. 0.1233 ± 0.0328, and 0.2650 ± 0.0459 vs. 0.3039 ± 0.0659 mm2, respectively). However, the CVI showed no significant difference among the three groups (P > 0.05). Finally, the concentration of vitreous dopamine was lower in the FD eyes, compared with contralateral and control eyes: 0.18 ± 0.20, 0.40 ± 0.67, and 0.33 ± 0.06 ng/mL, respectively (P < 0.05).
Conclusions:
Form deprivation led to a relatively myopic shift in pigmented rabbits and a decrease in vitreous dopamine levels. In addition, with the lengthening of AL, the choroid thinned, but CVI remained unchanged.
Translational relevance:
Our study offered data about the refractive characteristics of pigmented rabbits to investigate myopia mechanisms. The modified method imaged the choroid of the inferior species more clearly, achieving in exploring the changes of choroidal vasculature in vivo.
... DA and 3, 4-dihydroxyphenylacetic acid (DOPAC) levels have been found to be reduced in models of form deprivation and lens defocus in chickens, guinea pigs and monkeys [66][67][68][69]. In an experiment, intravitreal-injected atropine (250 µg or 360 nMol), atropine combined with the dopamine antagonist aspirin (500 µMol), or aspirin alone induced changes in retinal DA release and choroidal thickness in chickens tracked by optical coherence tomography (OCT), correlation analysis showed that the higher the retinal dopamine level release, the thicker the choroid [45]. ...
Myopia is one of the dominant causes of visual impairment in the world. Pathological myopia could even lead to other serious eye diseases. Researchers have reached a consensus that myopia could be caused by both environmental and genetic risk factors. Exploring the pathological mechanism of myopia can provide a scientific basis for developing measures to delay the progression of myopia or even treat it. Recent advances highlight that scleral hypoxia could be an important factor in promoting myopia. In this review, we summarized the role of scleral hypoxia in the pathology of myopia and also provided interventions for myopia that target scleral hypoxia directly or indirectly. We hope this review will aid in the development of novel therapeutic strategies and drugs for myopia.
... Activation of DA signaling attenuates induced myopia in animal models 17,[65][66][67][68][69][70] , depletion of DA signaling can lead to spontaneous myopia in mice 71 , and DA or DOAPC is reduced in myopic eyes 23,[72][73][74][75][76][77] (though see [78][79][80][81] showing no effect in mice). In contrast, administration of atRA induces myopic eye growth 26,53,82 , inhibition of atRA signaling protects against myopia development 54,83 , (which was not certified by peer review) is the author/funder. ...
Purpose
Ambient light exposure is linked to myopia development in children and affects myopia susceptibility in animal models. Currently, it is unclear which signals mediate the effects of light on myopia. All- trans retinoic acid (atRA) and dopamine (DA) oppositely influence experimental myopia and may be involved in the retino-scleral signaling cascade underlying myopic eye growth. However, how ocular atRA responds to different lighting and whether atRA and DA interact remains unknown.
Methods
Dark-adapted C57BL/6J mice (29-31 days old) were exposed to Dim (1 lux), Mid (59 lux), or Bright (12,000 lux) ambient lighting for 5-60 minutes. Some mice were also systemically administered the DA precursor, LDOPA, or atRA prior to light exposure. After exposure, the retina and the back-of-the-eye (BOE) were collected and analyzed for levels of atRA, DA, and the DA metabolite, DOPAC.
Results
DA turnover (DOPAC/DA ratio) in the retina increased in magnitude after only five minutes of exposure to higher ambient luminance but was minimal in the BOE. In contrast, atRA levels in the retina and BOE significantly decreased with higher ambient luminance and longer duration exposure. Intriguingly, LDOPA-treated mice had a transient reduction in retinal atRA compared to saline-treated mice, whereas atRA treatment had no effect on ocular DA.
Conclusions
Ocular atRA was affected by the duration of exposure to different ambient lighting and retinal atRA levels decreased with increased DA. Overall, these data suggest specific interactions between ambient lighting, atRA, and DA that could have implications for the retino-scleral signaling cascade underlying myopic eye growth.
SIGNIFICANCE
Atropine is effective at slowing myopia progression in children, but the mechanism of action by which it controls myopia remains unclear. This article is an evidenced-based review of potential receptor-based mechanisms by which atropine may act to slow the progression of myopia.
The rising number of individuals with myopia worldwide and the association between myopia and vision-threatening ocular pathologies have made myopia control treatments one of the fastest growing areas of ophthalmic research. High-concentration atropine (1%) is the most effective treatment for slowing myopia progression to date; low concentrations of atropine (≤0.05%) appear partially effective and are currently being used to slow myopia progression in children. While significant progress has been made in the past few decades in understanding fundamental mechanisms by which atropine may control myopia, the precise characterization of how atropine works for myopia control remains incomplete. It is plausible that atropine slows myopia via its affinity to muscarinic receptors and influence on accommodation, but animal studies suggest that this is likely not the case. Other studies have shown that, in addition to muscarinic receptors, atropine can also bind, or affect the action of, dopamine, alpha-2-adrenergic, gamma-aminobutyric acid, and cytokine receptors in slowing myopia progression. This review summarizes atropine’s effects on different receptor pathways of ocular tissues and discusses how these effects may or may not contribute to slowing myopia progression. Given the relatively broad array of receptor-based mechanisms implicated in atropine control of myopia, a single mode of action of atropine is unlikely; rather atropine may be exerting its myopia control effects directly or indirectly via several mechanisms at multiple levels of ocular tissues, all of which likely trigger the response in the same direction to inhibit eye growth and myopia progression.
Purpose:
Ambient light exposure is linked to myopia development in children and affects myopia susceptibility in animal models. Currently, it is unclear which signals mediate the effects of light on myopia. All-trans retinoic acid (atRA) and dopamine (DA) oppositely influence experimental myopia and may be involved in the retinoscleral signaling cascade underlying myopic eye growth. However, how ocular atRA responds to different lighting and whether atRA and DA interact remains unknown.
Methods:
Dark-adapted C57BL/6J mice (29-31 days old) were exposed to dim (1 lux), mid (59 lux), or bright (12,000 lux) ambient lighting for 5 to 60 minutes. Some mice were also systemically administered the DA precursor, LDOPA, or atRA before light exposure. After exposure, the retina and the back of the eye (BOE) were collected and analyzed for levels of atRA, DA, and the DA metabolite, DOPAC.
Results:
DA turnover (DOPAC/DA ratio) in the retina increased in magnitude after only 5 minutes of exposure to higher ambient luminance, but was minimal in the BOE. In contrast, atRA levels in the retina and BOE significantly decreased with higher ambient luminance and longer duration exposure. Intriguingly, LDOPA-treated mice had a transient reduction in retinal atRA compared with saline-treated mice, whereas atRA treatment had no effect on ocular DA.
Conclusions:
Ocular atRA was affected by the duration of exposure to different ambient lighting, and retinal atRA levels decreased with increased DA. Overall, these data suggest specific interactions between ambient lighting, atRA, and DA that could have implications for the retinoscleral signaling cascade underlying myopic eye growth.
Purpose:
While previously investigating the mechanism by which atropine inhibits ocular growth, we observed that stimulation of nicotinic receptors can inhibit experimental myopia. This study expands on that preliminary finding and investigates the safety and efficacy of nicotinic stimulation in the inhibition of ocular growth.
Methods:
Nicotine's ability to inhibit form-deprivation myopia (FDM), following intravitreal injection (9 chicks per group) or topical application (6 chicks per group), was investigated over three doses. The ability of nicotine to inhibit lens-induced myopia (LIM) was also tested (in 12 chicks). For ocular safety, following 4 weeks of topical treatment with nicotine (n = 10), pupillary reflex, intraocular pressure, corneal curvature/thickness, lens thickness, retinal health (retinal thickness/cell apoptosis), as well as retinal function (electroretinogram recordings) were assessed. We also examined the effects of nicotine on non-ocular autonomic functions in both chicks (n = 5) and mice (n = 5).
Results:
Nicotine was observed to significantly inhibit the development of FDM in chicks when administered as an intravitreal injection (P < 0.05) or topical eye drops (P < 0.05), albeit not in a dose-dependent manner. Nicotine also inhibited LIM (P < 0.05) to a similar degree to that seen for FDM. Although ocular health was (for the most part) unaffected by nicotine, the highest topical dose induced a temporary reduction in cardiorespiratory output (P < 0.05).
Conclusions:
Nicotine, administered as an intravitreal injection or topical eye drop, significantly inhibits the development of experimental myopia. Although the anti-myopic effects observed presently are interesting, the well-reported side effects (expanded on presently) and addictive properties of nicotine would preclude its clinical use.
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.
To investigate changes in protein profiles of posterior sclera in guinea pigs during development of form deprivation myopia and recovery.
Three groups of guinea pigs (developing form deprivation myopia, recovering from the myopia and normal control) were evaluated for protein profiles of the posterior sclera using two-dimensional gel electrophoresis. Protein spots with a different intensity of at least threefold among the 3 groups were further identified with mass spectrometry. Key proteins associated with ocular growth (crystallins) were examined at mRNA levels using RT-PCR.
Moderate myopia was induced at 7 weeks of monocular deprivation and then more gradually recovered toward the previous refractive status 4 days after re-exposure of the eye to normal visual conditions. The profile of all protein spots at the posterior sclera was similar for both the deprived and the recovery eyes but distinct between either of the 2 experimental eyes and the normal control eyes. Twenty-six and 33 protein spots were differentially expressed in the deprived and the recovery eyes, respectively, compared to the normal control eyes. In contrast, the number of proteins differentially expressed between the deprived and the recovery eyes was only 5. Among the different subtypes of crystallins, βB2-crystallin was down-regulated and βA4-crystallin was upregulated in the deprived eyes at both protein and mRNA levels compared to the normal control eyes. The trend of expression for βA3/A1-crystallin was also similar at both mRNA and protein levels for the deprived eyes. However, αA-crystallin mRNA in the recovery eyes was upregulated while αA-crystallin itself was down-regulated. A similar inconsistency in expression of βA3/A1-, βA4-, and βB2-crystallins between the protein and mRNA levels also occurred in the recovery eyes.
Proteomic analysis provides a useful survey of the number of proteins whose levels change during form deprivation myopia and the subsequent recovery. In particular, the crystallins changed during the development of form deprivation myopia and recovery. The changes in crystallin protein levels were consistent with that in mRNA levels during the development stage of form-deprivation myopia (FDM). However, the changes of most crystallin protein levels were mismatched with mRNA levels during the recovery stage.
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.
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.
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.
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.
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.
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.
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.
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.