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Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment.

ABSTRACT: PURPOSE: To investigate the effect of atropine on the development of spectacle lens induced myopia in the mouse and to determine if the level of mRNAs for the muscarinic receptor subtypes (M(1) - M(5)) is affected by atropine treatment. METHODS: Experimental myopia was developed in Balb/CJ (BJ) mice by placing -10 diopter spectacle lens on post-natal day 10 over the right eyes of 150 mice (n=10 in each group, 5 repetitions) for six weeks. After 2 weeks of lens wearing, the atropine group received a daily sub-conjunctival injection (10 µl) of 1% atropine sulfate and the saline group received daily 10 µl of 0.9% normal saline for 4 weeks. In addition, myopia was developed in C57BL/6 (B6) mice by placing -10 D spectacle lens on post-natal day 10 over the right eyes of 60 mice (n=10 in each group, 2 repetitions) for six weeks with and without atropine treatment. Refraction and axial length was measured at 2, 4, and 6 weeks after treatments. RT-PCR and northern blots were performed using specific primers for M(1)-M(5), and products sequenced. Real-time PCR was used to quantify message levels. RESULTS: Axial length of myopic eyes was 111% of their controls without atropine treatment and 103% of controls after atropine (p<0.01). Refraction shifted from myopic to emmetropic after atropine was administered in both pigmented and non-pigmented eyes. Corneal thickness, anterior chamber depth, corneal curvature and retinal thickness were not significantly different with and without atropine treatment (p=0.14). The lens thickness and vitreous chamber depth were significantly reduced after receiving atropine (p<0.05). Real-time PCR showed that message levels for M(1), M(3), and M(4) were upregulated in myopic sclera after atropine treatment, but M(2) and M(5) showed little change. CONCLUSIONS: The present study shows that 1% atropine reduces myopia progression in both pigmented and non-pigmented mice eyes. Axial length and vitreous chamber depth appear to be the main morphological parameters related to myopia. The results suggest that atropine may act on one or more muscarinic receptors to differentially regulate expression levels of specific receptors.

SUBMITTER: Barathi VA

PROVIDER: S-EPMC3056126 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment.

Barathi V A VA Beuerman Roger W RW

Molecular vision 20110309

<h4>Purpose</h4>To investigate the effect of atropine on the development of spectacle lens induced myopia in the mouse and to determine if the level of mRNAs for the muscarinic receptor subtypes (M(1) - M(5)) is affected by atropine treatment.<h4>Methods</h4>Experimental myopia was developed in Balb/CJ (BJ) mice by placing -10 diopter spectacle lens on post-natal day 10 over the right eyes of 150 mice (n=10 in each group, 5 repetitions) for six weeks. After 2 weeks of lens wearing, the atropine ...[more]

PMID: 21403852

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Project description:SIGNIFICANCE:The Bifocal & Atropine in Myopia (BAM) study aims to determine whether combining 0.01% atropine and +2.50-diopter add center-distance soft bifocal contact lenses (SBCL) slows myopia progression more than SBCL alone. The results could provide significant information on the myopia control effect of combining optical and pharmacological treatments. PURPOSE:This article describes the subject characteristics at baseline, the study methods, and the short-term effects of this combination treatment on visual acuity (VA) and vision-related outcomes. METHODS:Subjects from the BAM study who met the baseline eligibility criteria were dispensed the combination treatment for 2 weeks to determine final eligibility. Outcome measures included VA at near and distance (Bailey-Lovie logMAR charts), near phoria (modified Thorington), accommodative lag (Grand Seiko WAM-5500), and pupil size (NeurOptics VIP-200 Pupillometer). Compliance was monitored using surveys. Two subgroups in the Bifocal Lenses In Nearsighted Kids study, single-vision contact lens wearers and those who wore +2.50-diopter add SBCL, will serve as the age-matched historical controls for BAM study. RESULTS:Forty-nine BAM subjects (9.6 ± 1.4 years) were enrolled; mean spherical equivalent cycloplegic autorefraction was -2.33 ± 1.03 diopters. After 2 weeks of treatment, the best-corrected low-contrast (10% Michelson) distance VA was reduced (pre-treatment, +0.09 ± 0.07; post-treatment, +0.16 ± 0.08; P < .0001), but the high-contrast VA at near or distance was unaffected. Near phoria increased by approximately 2 in the exo direction (P = .01), but the accommodative lag was unchanged. The pupil size was not significantly different between pre-treatment and post-treatment of either the photopic or mesopic condition. Surveys indicated that the subjects wore SBCL 77 ± 22% of waking hours and used atropine 6.4 ± 0.7 days per week. CONCLUSIONS:Two weeks of combination treatment reduced low-contrast distance VA and increased near exophoria slightly, but the subjects were compliant and tolerated the treatment well.

Project description:ImportanceSome uncertainty about the clinical value and dosing of atropine for the treatment of myopia in children remains.ObjectiveTo evaluate the efficacy vs the adverse effects of various doses of atropine in the therapy for myopia in children.Data sourcesData were obtained from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception to April 30, 2016. The reference lists of published reviews and clinicaltrials.gov were searched for additional relevant studies. Key search terms included myopia, refractive errors, and atropine. Only studies published in English were included.Study selectionRandomized clinical trials and cohort studies that enrolled patients younger than 18 years with myopia who received atropine in at least 1 treatment arm and that reported the annual rate of myopia progression and/or any adverse effects of atropine therapy were included in the analysis.Data extraction and synthesisTwo reviewers independently abstracted the data. Heterogeneity was statistically quantified by Q, H, and I2 statistics, and a meta-analysis was performed using the random-effects model. The Cochrane Collaboration 6 aspects of bias and the Newcastle-Ottawa Scale were used to assess the risk for bias.Main outcomes and measuresThe primary outcome was a difference in efficacy and the presence of adverse effects at different doses of atropine vs control conditions. The secondary outcomes included the differences in adverse effects between Asian and white patients.ResultsNineteen unique studies involving 3137 unique children were included in the analysis. The weighted mean differences between the atropine and control groups in myopia progression were 0.50 diopters (D) per year (95% CI, 0.24-0.76 D per year) for low-dose atropine, 0.57 D per year (95% CI, 0.43-0.71 D per year) for moderate-dose atropine, and 0.62 D per year (95% CI, 0.45-0.79 D per year) for high-dose atropine (P < .001), which translated to a high effect size (Cohen d, 0.97, 1.76, and 1.94, respectively). All doses of atropine, therefore, were equally beneficial with respect to myopia progression (P = .15). High-dose atropine were associated with more adverse effects, such as the 43.1% incidence of photophobia compared with 6.3% for low-dose atropine and 17.8% for moderate-dose atropine (χ22 = 7.05; P = .03). In addition, differences in the incidence of adverse effects between Asian and white patients were not identified (χ21 = 0.81; P = .37 for photophobia).Conclusions and relevanceThis meta-analysis suggests that the efficacy of atropine is dose independent within this range, whereas the adverse effects are dose dependent.

Project description:PurposeThe purpose of this study was to describe the cellular architecture of normal human peripapillary sclera (PPS) and evaluate surface topography's role in fibroblast behavior.MethodsPPS cryosections from nonglaucomatous eyes were labelled for nuclei, fibrillar actin (FA), and alpha smooth muscle actin (αSMA) and imaged. Collagen fibrils were imaged using second harmonic generation. Nuclear density and aspect ratio of the internal PPS (iPPS), outer PPS (oPPS), and peripheral sclera were determined. FA and αSMA fibril alignment with collagen extracellular matrix (ECM) was determined. PPS fibroblasts were cultured on smooth or patterned membranes under mechanical strain and in the presence of TGFβ1 and 2.ResultsThe iPPS (7.1 ± 2.0 × 10-4, P < 0.0001) and oPPS (5.3 ± 1.4 × 10-4, P = 0.0013) had greater nuclei density (nuclei/µm2) than peripheral sclera (2.5 ± 0.8 × 10-4). The iPPS (2.0 ± 0.3, P = 0.002) but not oPPS (2.4 ± 0.4, P = 0.45) nuclei had smaller aspect ratios than peripheral (2.7 ± 0.5) nuclei. FA was present throughout the scleral stroma and was more aligned with oPPS collagen (9.6 ± 1.9 degrees) than in the peripheral sclera (15.9 ± 3.9 degrees, P =0.002). The αSMA fibers in the peripheral sclera were less aligned with collagen fibrils (26.4 ± 4.8 degrees) than were FA (15.9 ± 3.9 degrees, P = 0.0002). PPS fibroblasts cultured on smooth membranes shifted to an orientation perpendicular to the direction of cyclic uniaxial strain (1 Hz, 5% strain, 42.2 ± 7.1 degrees versus 62.0 ± 8.5 degrees, P < 0.0001), whereas aligned fibroblasts on patterned membranes were resistant to strain-induced reorientation (5.9 ± 1.4 degrees versus 10 ± 3.3 degrees, P = 0.21). Resistance to re-orientation was reduced by TGFβ treatment (10 ± 3.3 degrees without TGFβ1 compared to 23.1 ± 4.5 degrees with TGFβ1, P < 0.0001).ConclusionsRegions of the posterior sclera differ in cellular density and nuclear morphology. Topography alters the cellular response to mechanical strain.

Dataset Information

Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment.

Publications

Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment.

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