Optometry and Vision Sciences - Theses
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ItemStrategies to inhibit myopia: pharmacological and optical approaches( 2011)Aims: Myopia is a significant public health issue affecting around 30% of the world’s population and is a major cause of blindness because of the increased risk of pathology to the retina, choroid and sclera. Currently there is no effective treatment for myopia. The broadband muscarinic antagonist agent atropine and the M1/M4 receptor selective muscarinic antagonist pirenzepine are effective at slowing the progression of myopia in animals and humans. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which muscarinic receptor mediates this effect. An optical strategy that has been investigated in recent times is the effect of intermittent positive lens wear to reduce myopia progression. This thesis conducts a series of investigations on animal models of myopia to further assess both pharmacological and optical strategies to inhibit myopia. Methods: The animal models used for these investigations were chicks and tree shrews. Chicks underwent daily intravitreal injections with MT3 or MT7 or MT3 + spiperone for four consecutive days in the treated eye. The contralateral control eye was untreated and used for comparison. After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry. Tree shrews underwent daily intravitreal injections with MT3 or MT7 or saline vehicle for five consecutive days in the treated eye and form-deprivation. The contralateral control eyes underwent intravitreal injections of saline and were unoccluded for the same period. Two more of tree shrew groups underwent daily intravitreal injections with MT7 or saline vehicle for ten consecutive days in the treated eye combined with negative lens defocus. The control eye was injected with saline and wore plano lenses for 10 days. The optical and structural measurements were taken before the start of treatment and after the treatment. In a study to assess intermittent positive lens wear on experimentally induced myopia, tree shrews wore binocular -9.5D lenses. The negative lens defocus was either never interrupted or interrupted twice daily with binocular positive (+4.0D) or plano lens wear for twelve days. The optical and structural measurements were performed before the start of treatment, 5 and 12 days. Results: MT3 treatment produced a significant dose-dependent reduction in relative myopia in chicks compared to vehicle (treated – control eye; vehicle -10.1 ± 1.1D; 10µM MT3; -4.0 ± 1.5D; p<0.01). The majority of this effect was due the inhibition of vitreous chamber depth (treated – control eye; vehicle; 0.26 ± 0.04 mm vs 10µM MT3; 0.08 ± 0.07 mm, p<0.05). The relative combined retina + choroid thickness was significantly different between MT3 and vehicle groups (treated – control eye; vehicle; -0.19 ± 0.03 mm vs 10µM MT3; 0.02 ± 0.05 mm; p<0.01). MT7 had no significant effect on the development of myopia in chicks, relative to vehicle control. In tree shrew, both MT3 and MT7 prevented the form-deprivation myopia (treated – control eye; myopia; vehicle; -4.3 ± 0.6D vs MT3; -0.7 ± 0.2D and MT7; -0.7 ± 0.4D; p<0.001). The MT7 treatment was also effective in inhibiting the lens-induced myopia (treated – control eye; vehicle; -4.6 ± 0.5D vs MT7; 0.2 ± 0.2D; p<0.05) and elongation of vitreous chamber depth (treated – control eye; vehicle; 0.07 ± 0.01 mm and MT7; 0.01 ± 0.02 mm; p<0.05). The co-application of MT3 + the D2 antagonist spiperone prevented MT3 inhibition of myopia (treated – control eye; MT3 + spiperone; -11.2 ± 1.2D vs MT3; -4.7 ± 1.2D; p<0.001). Intermittent binocular positive lens wear was significantly more effective in inhibiting negative lens induced myopia than binocular plano lens wear following 12 days (-9.5D / 0D (2); 6.8 ± 0.6D vs -9.5D / +4.0D (2); 9.5 ± 0.6D, p<0.05). Conclusions: The M4 muscarinic antagonist MT3 was effective at reducing myopia in chicks. Based on changes in choroidal thickness, it is proposed the site of action for MT3 inhibition occurs in the retina or choroid. Both the M4 and M1 receptors are implicated in the muscarinic antagonist inhibition of myopia in tree shrews. Antagonism of the D2 receptor demonstrated that dopaminergic signalling is involved in M4 muscarinic antagonist control of myopia in chicks. Intermittent binocular transient positive lens wear for only 4% of the day was more effective in reducing the binocular negative lens-induced myopia than transient plano lens wear in a tree shrew.