Myopia is a visual disorder affecting about one-half of the world's population. It is also a socio-economic-health problem of considerable proportions. Its prevalence shows a rising tendency and its incidence in school-age children is increasing markedly in many parts of the world, especially in Asian countries such as China,1,2 Japan,3,4 and Singapore.5,6 Besides widespread prevalence, myopia is also serious. High myopia is often accompanied by progressive lengthening of ocular axial length as well as retinal and choroidal degeneration, and can, therefore, give rise to a series of complications such as retinal detachment, macular hemorrhage, and even blindness.7,8 Therefore, a drug treatment that can either prevent myopia or limit its progression is needed. At present, there is no generally accepted and approved method or drug for preventing myopia.
Animal models of myopia, including chick, tree shrew, monkey, and guinea pig, provide a means of developing pharmacological interventions to control axial elongation of the eye. Dopaminergic agonists have been the focus of much research. Intravitreal injection of the non-selective dopamine agonists apomorphine9 or 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) in chicks10,11 or the topical administration of apomorphine by eyedrops in monkeys12 has been shown to retard the development of form-deprivation myopia. Because dopamine receptors (both D1 and D2 subtypes) widely present on the retinal pigment epithelium, photoreceptors, subpopulations of amacrine and horizontal cells,13–16 there are many potential sites of action for these antimyopia effects of the dopaminergic agonists. In chicks retina, D2 receptor was localized to the photoreceptor inner segments, outer and inner plexiform layer, ganglion cell layer, and the basal region of the retinal pigment epithelium.17 Rohrer et al.18 reported that apomorphine blocked form-deprivation myopia in chicks by a dopamine D2-receptor mechanism acting in retina or pigmented epithelium. Subsequently, Ashby et al.11 found that when ADTN was injected intravitreally in chickens, the down-regulation of the immediate early gene ZENK in retina caused by form deprivation was reversed, suggesting that dopamine agonists acts early in the signal cascade controlling eye growth, possibly within the retina itself. Consistent with these results, it has been shown that the visual deprivation leads to ocular enlargement and a myopic refractive error, and it also reduces the rates of synthesis of retinal dopamine and decreases its content in chicks.19–21 However, not all the available evidence is consistent with these results. For example, intravitreal injection of reserpine, which depleted retinal dopamine and serotonin stores, blocked deprivation myopia very efficiently, whereas sulpiride (another D2 antagonist) could enhance myopia in chickens.22 In contrast, McCarthy et al.10 found that intravitreal injection of the D2-selective antagonist spiperone and a non-specific dopamine antagonist methylergonovine did not affect the increased axial elongation associated with form-deprivation myopia in chickens. So, we were also interested in the relationship between dopamine and the control of myopia.
3,4-dihydroxy-L-phenylalanine (levodopa, L-DOPA), a precursor of dopamine, can be converted into dopamine in the presence of aromatic L-amino acid decarboxylase (L-AAAD), and dopamine formed from exogenous L-DOPA has physiological activity and can in vivo activate dopamine receptors to realize corresponding physiological functions.23,24 It has been found that the molecular characteristics of dopaminergic neurons are expressed in Müller cells purified from developing chick and mouse retinas,25 amacrine cells of rat26 and guinea pig,27 and the inner segments of rat photoreceptor cells.26 L-AAAD activity in the rat retina is modulated in vivo by environmental light,28 and this modulation is associated with dopamine D1 receptors29 and alpha 2 adrenoceptor.30 It has been shown that exposure to light accelerates the formation of dopamine from exogenous L-DOPA in the rat retina.31 At present, it is unclear whether systemic application of L-DOPA is able to suppress the development of form-deprivation myopia.
Parkinson disease is a progressive neurodegenerative movement disorder, affecting mainly the elderly, and loss of nigrostriatal dopaminergic function is its basic underlying pathophysiology.32,33 It has been shown that levodopa can successfully treat Parkinson disease in humans, because exogenously applied L-DOPA can be converted into dopamine that can be released into the extracellular space in the striatum.34 Various experiments in children with amblyopia have shown that L-DOPA is well tolerated and produces a clinical short-term improvement of visual acuity with an increase in contrast sensitivity and decrease of the size of the fixation point scotoma.35–38 However, Leguire et al.39 found that amblyopic eyes showed similar amounts of regression of visual acuity between L-DOPA plus occlusion treatment and occlusion treatment only in the long-term follow-up test without side effects. In a word, L-DOPA is a safe, well-tolerated drug that clinically treats human disease.
The guinea pig is a suitable model for myopia in mammals because goggles can be readily applied, ocular development is rapid, and it is a precocial species born with a well-developed visual system.40–42 In the present study, we used the established guinea pig myopia to investigate the effect of intraperitoneal injection of L-DOPA on refractive state and retinal dopamine content in the form-deprived eyes to explore a potential new pharmacological intervention for myopia.
MATERIALS AND METHODS
All animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No.86-23, revised 1986). Sixty pigmented guinea pigs were obtained from the Animal Center of Xiang-ya Medical College and were randomly divided into six groups: (1) normal control, (2) L-DOPA group, (3) saline group, (4) deprived group, (5) deprived plus L-DOPA group, and (6) deprived plus saline group.
Induction of the Guinea Pig Myopia
Guinea pigs, at age of 4 weeks, were intraperitoneally injected with 30 mg/kg sodium pentobarbital (Huamai Biochemical Company, Luoyang, China). After anesthesia, self-made translucent eye shields were applied to occlude the right eye. Four stitches of suture were made to fix eye shields to the tissue surrounding the eye socket. The occluders made from milky white latex gloves, were opaque, soft, and elastic with the thickness of ∼0.06 mm. Light transmission through the latex material is 56% (measured by Humphrey system). It was observed that the occluders did not compromise the cornea, and the form-deprived eyes could freely blink behind the occluders. Animals were then reared under 12 h light/12 h darkness cycle (100 lux at eye level in the light).
Tropicamide 1%, widely used in human studies, was used for cycloplegia.43–45 Tens days after occlusion, guinea pigs were intraperitoneally injected with 30 mg/kg sodium pentobarbital. After the occluders were removed, cycloplegia and dilation of pupil was induced by 2 drops of 1% tropicamide, and 30 min later ocular biometric examination was performed. Its corneal radius of curvature was measured with a keratometer (Topcon, OM-4, Japan), and ocular refraction was measured with a streak retinoscope. Type-A ultrasonic examination (Cinescan A/B, Quantel Medical, French) was conducted to determine the axial dimensions. The ultrasound frequency was 11 MHz. Peaks were selected for the front of the cornea, the front of the crystalline lens, the back of the crystalline lens, and the vitreous-retinal interface. In the text, figures, and tables, the term “axial length” refers to the distance from the corneal apex to the vitreo-retinal interface, the term “anterior segment depth” refers to the distance from the corneal apex to the front surface of the lens, and the term “vitreous chamber depth” refers to the distance from the back of the crystalline lens to the vitreous-retinal interface. Each animal was measured three times and the mean value was used for the following analysis.
Drug Delivery Methods
L-DOPA (Sigma, St. Louis, MO) solution (10 mg/ml) was freshly prepared by dissolving into physiological saline solution. From the first day of occlusion, guinea pigs in the L-DOPA group and the deprived plus L-DOPA group were intraperitoneally injected with L-DOPA solution (10 mg/kg), once daily at 10 a.m. The intraperitoneal injections were made without anesthesia. As a control, physiological saline solution (vehicle) was injected in the same way. In this study, daily L-DOPA (10 mg/kg) was chosen on the basis of previous work, which showed that the L-DOPA application was safe without side effect in rats and caused the increase of dopamine content in striatum.46
Dopamine Content in the Guinea Pig Retinas
Retinal dopamine content was detected by the high-performance liquid chromatography (HPLC) and was plotted as nanogram dopamine per milligram retina. After the measurements of corneal curvature, refraction, and axial length, preparation of the retina for HPLC measurements was performed immediately. Because it is known that retinal dopamine levels are light dependent47,48 and undergo diurnal variations,49 all preparations were performed at noon. Guinea pigs were killed by intraperitoneal injection of an overdose of sodium pentobarbital. Eyeballs were then excised. Retinal samples were dissected out without pigment epithelium within a few minutes, and each retina was collected in an ice-cooled homogenizer containing 1 ml of eluens with 10 ng of the internal standard dihydroxybenzylamine. The samples were then homogenized and centrifuged for 2 min at 14,000 rpm (not refrigerated). The supernatant was filtered and stored at −70°C until use. Before the analysis, the samples were centrifuged again and then loaded into the manual injector of the HPLC set-up. Chromatographic conditions were as follows: Hypersil ODS2 column (5 μm, 250 × 4.6 mm), mobile phase consisting of 20 mmol/L sodium citrate and methanol (90:7, v/v), flow rate at 1.0 ml/min, column temperature at 35°C, working voltage at 750 mV, injection volume of 20 μl. Dopamine content (ng) of per milligram retina was then calculated.
Values are expressed as means ± SEM. All data were analyzed by one-way analysis of variance and Student-Newman-Keuls t test. The correlation in axial length, refraction, and retinal dopamine was analyzed by the regression of an inverse function. Probability values <0.05 were accepted as statistically significant.
The Effect L-DOPA on Refraction in Form Deprived and Control Guinea Pig Eyes
The eyes of untreated 38-day-old guinea pigs showed mild hyperopia. No statistically significant difference in the degree of refraction was observed between their right and left eyes. After the right eyes were occluded for 10 days, the deprived eyes became myopic, which showed statistically significant difference when compared with the fellow control eyes and age-matched normal control eyes (p < 0.001). Daily intraperitoneal injection of L-DOPA significantly reduced the degree of myopia in the deprived eyes (from −3.62 ± 0.98 D to −1.50 ± 0.38 D, p < 0.001; Table 1, Fig. 1). However, myopia development in the deprived eyes was not suppressed completely by L-DOPA treatment (10 mg/kg), because its refraction showed statistically significant difference when compared with fellow control eyes (p < 0.001) and normal control eyes (p < 0.001). In contrast, intraperitoneal injection of physiological saline solution (vehicle) caused no statistically significant effect on the refraction in the deprived eyes. In undeprived age-matched animals, there was no statistically significant difference between the ocular refraction of L-DOPA treatment and normal control. No statistically significant difference was observed in the degree of refraction of left eyes in different treatment groups. The ocular refraction changes correlated highly with retinal dopamine content in the normal control eyes, deprived eyes, and L-DOPA-treated deprived eyes (y = 2.37−3.77/x, R2 = 0.78, F1, 28 = 96.80, p < 0.001) (Table 1, Fig. 2).
The Effect L-DOPA on Ocular Dimensions in Form Deprived and Control Guinea Pig Eyes
There was no statistically significant difference in anterior segment depth, lens thickness, vitreous chamber depth, and axial length between the right and left eyes in normal controls. Ten days of form deprivation induced a significant increase in vitreous chamber depth and axial length of the deprived eyes when compared with the within-animal control eyes (p < 0.001) and age-matched normal control eyes (p < 0.001). Daily intraperitoneal injection of L-DOPA significantly retarded the increase of vitreous chamber depth (from 3.85 ± 0.05 mm to 3.74 ± 0.04 mm, p < 0.001; Table 1, Fig. 3) and axial length (from 8.42 ± 0.06 mm to 8.33 ± 0.04 mm, p < 0.001; Table 1, Fig. 4) in the deprived eyes. However, the increase of vitreous chamber depth and axial length in the deprived eyes was not suppressed completely by L-DOPA treatment (10 mg/kg), because its vitreous chamber depth and axial length showed statistically significant difference when compared with fellow control eyes and normal control eyes. In contrast, intraperitoneal injection of physiological saline solution (vehicle) caused no statistically significant effect on vitreous chamber depth and axial length in the deprived eyes. In undeprived age-matched animals, there was no statistically significant difference in the vitreous chamber depth and axial length between L-DOPA treatment and normal control. No statistically significant difference was observed in anterior segment depth, lens thickness, vitreous chamber depth, and axial length of left eyes in different treatment groups. There was no statistically significant difference in anterior segment depth and lens thickness of right eyes in different treatment groups. The axial length and retinal dopamine changes were well correlated in the normal control eyes, deprived eyes, and L-DOPA-treated deprived eyes (y = 8.21 + 0.13/x, R2 = 0.61, F1, 28 = 43.11, p < 0.001) (Table 1, Fig. 5).
The Effect L-DOPA on Corneal Curvature in Form Deprived and Control Guinea Pig Eyes
There was no statistically significant difference in corneal radius of curvature between the right and left eyes in normal control. Ten days of form deprivation induced no significant change in corneal radius of curvature of the deprived eyes when compared with fellow control eyes and age-matched normal control eyes. Intraperitoneal injection of L-DOPA caused no statistically significant effect on corneal radius of curvature in the deprived eyes. In undeprived age-matched animals, there was no statistically significant difference between the corneal radius of curvature of L-DOPA treatment and normal control. No statistically significant difference was observed in corneal radius of curvature of left eyes in different treatment groups (Table 1).
The Effect L-DOPA on Retinal Dopamine Content in Form Deprived and Control Guinea Pig Eyes
There was no statistically significant difference in dopamine content per milligram of the retina between the right and left eyes in normal control. Ten days of form deprivation induced a significant decrease in retinal dopamine content of the deprived eyes when compared with fellow control eyes (p < 0.001) and age-matched normal control eyes (p < 0.001). Daily intraperitoneal injection of L-DOPA significantly raised the retinal dopamine content in the deprived eyes (from 0.65 ± 0.10 ng to 1.33 ± 0.23 ng, p < 0.001). However, retinal dopamine content in the deprived eyes in the deprived plus L-DOPA group still displayed a declining tendency but showed no statistically significant difference when compared with those in fellow control eyes and normal control eyes. In contrast, intraperitoneal injection of physiological saline solution (vehicle) caused no statistically significant effect on retinal dopamine content in the deprived eyes. In undeprived age-matched animals, there was no statistically significant difference between the retinal dopamine content of L-DOPA treatment and normal control. No statistically significant difference was observed in retinal dopamine content of left eyes in different treatment groups (Table 1, Fig. 6).
In this study, our data showed that the intraperitoneal injection of L-DOPA could cause an increase in retinal dopamine content and effectively retard the myopic development in the form-deprived guinea pig eyes, which may be associated with the likelihood that exogenous L-DOPA was converted into dopamine to compensate for its deficiency in the retina of the deprived eyes. Our findings also suggested an involvement of retinal dopaminergic function in the development of form-deprivation myopia in guinea pigs.
Strong evidence from clinical and experimental studies indicates that the sclera is not a static container of the eye but rather is a dynamic tissue, capable of altering extracellular matrix composition and its biomechanical properties in response to changes in the visual environment to regulate ocular size and refraction.50,51 It has been found that the development of experimental myopia results from retina-controlled active remodeling of the sclera.50,51 The regulatory roles of the retina during this process are achieved through some myopia-related signal factors (such as dopamine,19–21 nitric oxide,52 retinoic acid53) in retina. However, it is not clear how to transmit myopic signal from retina to sclera through retinal pigment epithelial barrier and choroid. Dopamine, as a member of the catecholamine family, is one of the major neurotransmitters in the retina and is involved in the signal transmission in the visual system. In the retinal inner nuclear layer of the majority of species, a dopaminergic neuronal network has been visualized in amacrine cells.54,55 It has been shown that the retinal dopamine was involved in the regulation of electrical coupling between horizontal cells56 and the retinomotor movement of photoreceptors.54 Ohngemach et al.57 found that the retina in chicks was the major source of dopamine release with a steep gradient both to the vitreal and choroidal side, whereas vitreal content was about one tenth, choroidal content about one third, and scleral content about one twentieth of that of the retina. Visual deprivation leads to ocular enlargement and a myopic refractive error, and it also reduces the retinal concentration of dopamine and its metabolites.19–21,57 However, choroidal and scleral dopamine levels were not affected by form deprivation in chicks, indicating that other messengers may relay the myopic information to the sclera. It has been shown that the synthesis and release of dopamine are light dependent and are affected by flicker or temporal contrast, and the decrease of retinal dopamine might be related with loss of contrast sensitivity and high spatial frequency in the deprived chicken eyes.47,48 Changes in chicken retinal dopamine content displayed a circadian rhythm, showing a downtrend during the night, and form deprivation mainly led to a decline in retinal dopamine content during the day.49,58 By the same token, the level of retinal dopamine and its metabolite was also reduced in lens-induced myopic chick eyes.59 Therefore, retinal dopamine may participate in the development of experimental myopia, including form-deprivation myopia and lens-induced myopia, in chicks. Similar to the result of these studies, Gao et al.60 reported that repeated intravitreal injections of dopamine fully prevented the myopic shift, elongation of the vitreous chamber and axial elongation due to lid suture in rabbits, which may be associated with the increase of retinal dopamine by direct intravitreal dopamine injection. Therefore, it is feasible to seek drugs that can effectively treat myopia through supplementing retinal dopamine.
At present, L-DOPA is widely applied in clinical practice, such as Parkinson disease. In this study, we found that daily intraperitoneal injection of L-DOPA (10 mg/kg) showed a significant inhibitory effect on deprivation-induced myopia in guinea pigs. At the same time, it was also observed that systemic L-DOPA could significantly raise the retinal dopamine content in the deprived eyes. L-AAAD, a key-enzyme for converting L-DOPA to dopamine, is distributed in guinea pig retina.27 So, the inhibitory effect of L-DOPA on form-deprivation myopia may be associated with the fact that retinal L-AAAD can convert L-DOPA into dopamine to compensate for its deficiency in the retina of the deprived eyes.
After intraperitoneal injection of L-DOPA in the undeprived animals, their refraction, axial length, and corneal radius of curvature showed no significant changes, indicating that systemic L-DOPA had no effect on the normal refractive development in guinea pigs. However, intraperitoneal injection of L-DOPA (10 mg/kg) could not completely suppress the development of form-deprivation myopia, suggesting that the dose of L-DOPA may be too low to elicit complete suppression of myopia. Another reason may be associated with the fact that the development of myopia is a complex process involving multiple factors, of which retinal dopamine is only one important factor.
In summary, intraperitoneal injection of L-DOPA was effectively able to suppress the development of form-deprivation myopia in guinea pigs. However, the optimal dose and side-effect of L-DOPA treatment require further investigation. It has been suggested that the systemic use of L-DOPA might be a therapeutic strategy for study in modifying the development of human myopia.
We thank Xiaohua Li for his technical assistance and Heping Xu for critical reading of the manuscript.
Central South University
Xiang-ya Road 87
Changsha, Hunan 410008, China
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