The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action
The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action
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DOI：
10.1111/j.1475-1313.2011.00841.x
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发表时间：
2011-09-01
影响因子：
2.9
通讯作者：
Sahebjada, Srujana
中科院分区：
文献类型：
--
作者：
McBrien, Neville A.;Arumugam, Baskar;Sahebjada, Srujana
目的：已充分确定，宽带毒蕈碱拮抗剂阿托品可有效抑制近视的进展，并通过防止眼睛玻璃体腔的延长来实现。然而，这种作用是否通过受体机制发生，以及如果是，哪种毒蕈碱受体亚型介导这种作用，仍存在不确定性。先前在鸟类和哺乳动物近视模型中的研究表明，M1和M4受体是潜在的靶点。目前的研究使用生理相关浓度的高选择性毒蕈碱拮抗剂（MT-3和MT-7），以进一步验证M4受体的作用，在控制近视的小鸡模型的屈光development.Methods：9组周龄的小鸡进行了5天的单眼剥夺，与半透明的封堵器，诱导近视。这些动物没有注射、用针进行巩膜穿刺或每天玻璃体内注射MT-3（M4-选择性）、MT-7（M1-选择性）或媒介物。递送三种浓度的每种拮抗剂（250 nm、2.5 μ m和10 μ m）。结果：与赋形剂治疗相比，MT-3治疗在相对近视（治疗的对照眼）中产生了显著的剂量依赖性降低（赋形剂-10.1 +/-1.1D对10 μ mMT-3 -4.0 +/-1.5D，p < 0.01）。这种作用的大部分是由于药物治疗眼中相对玻璃体腔伸长的减少（溶剂+0.26 +/- 0.04 mm，10 μ m MT-3 +0.08 +/- 0.07 mm，p < 0.05）。相比之下，MT-7对近视的发展没有显著影响（MT-7 10 μ m：近视，-12.1 +/-0.8 D和玻璃体腔深度，+0.23 +/-0.07 mm）。计算表明，抑制50%近视发展所需的眼内受体处的MT-3实验达到的浓度（在5和50 nm之间）与公开的M4受体的体外亲和力常数一致，并且低于M1受体的亲和力常数。组织学表明，MT-3在所使用的剂量对视网膜没有明显的影响，表明无毒的作用模式。结论：在鸡，它缺乏同源的哺乳动物M1受体，上述研究结果代表令人信服的证据表明，毒蕈碱拮抗剂通过M4受体介导的机制，最有可能位于视网膜预防近视进展。
Purpose: It is well established that the broad-band muscarinic antagonist, atropine is effective at inhibiting the progression of myopia and does so by preventing the elongation of the vitreous chamber of the eye. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which muscarinic receptor subtype mediates this effect. Previous work, in avian and mammalian models of myopia, implicates the M1 and M4 receptors as potential targets. The current study used physiologically relevant concentrations of highly selective muscarinic antagonists (MT-3 and MT-7) to further characterise the role of the M4 receptor in the control of myopia in the chick model of refractive development.Methods: Nine groups of week-old chicks underwent 5 days of monocular deprivation, with a translucent occluder, to induce myopia. These animals had either no injection, scleral puncture with a needle, or daily intravitreal injections of MT-3 (M4-selective), MT-7 (M1-selective) or vehicle. Three concentrations of each antagonist were delivered (250 nm, 2.5 mu m and 10 mu m). After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry.Results: MT-3 treatment produced a significant dose-dependent reduction in relative myopia (treated) control eye) compared to vehicle treatment (vehicle -10.1 +/- 1.1 D vs 10 mu m MT-3 -4.0 +/- 1.5 D, p < 0.01). The majority of this effect was due to reduced relative vitreous chamber elongation in drug treated eyes (vehicle +0.26 +/- 0.04 mm, 10 mu m MT-3 +0.08 +/- 0.07 mm, p < 0.05). In contrast, MT-7 had no significant effect on the development of myopia (MT-7 10 mu m: myopia, -12.1 +/- 0.8 D and vitreous chamber depth, +0.23 +/- 0.07 mm). Calculations indicate that the experimentally achieved concentrations of MT-3 at intraocular receptors necessary to inhibit 50% of myopia development (between 5 and 50 nm) were consistent with published in vitro affinity constants for the M4 receptor and below those for the M1 receptor. Histology demonstrated that MT-3 at the doses used had no gross effects on the retina, indicating a non-toxic mode of action.Conclusions: In the chick, which lacks a homologue of the mammalian M1 receptor, the above findings represent compelling evidence that muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina.