Role of M1 and M4 Receptors in Development of Myopia: Study With Muscarinic Receptor Antagonists and Muscarinic Toxins

Abstract

Abstract: : Purpose: Muscarinic receptor antagonists have been proven effective in preventing development of myopia. However, it is not known which of the five muscarinic receptor subtypes mediate this effect. Such an investigation was hindered in the past by the lack of sufficiently subtype–selective drugs. To investigate the involvement of M₁– and/or M₄–receptors in the modulation of axial eye growth we have now tested a preferential M₁–antagonist and muscarinic toxins (MTs), the most subtype–selective muscarinic receptor ligands known to date. Effects of telenzepine (preferential M₁), MT7 (M₁–selective) and MT3 (M₄–selective) were determined in lens–induced myopia (LIM) in chicks. Methods: Unilateral intravitreal injections of 12.5 µl solution (treated eye), containing either vehicle (control) or different doses of telenzepine, MT7 or MT3, were performed daily for a period of 4 successive days. The contralateral eye received the vehicle. Following the initial injection at day 8 post–hatching, chickens were fitted with –7D lenses over the treated eye. After 4 days, refractive error (RE) was measured by infrared photoretinoscopy. Groups (7–9 animals) were tested for significant differences using Dunnett’s test. Results:All three compounds tested inhibited LIM. However, their potency and efficacy clearly differed. Whereas telenzepine caused complete suppression of the lens–induced myopic shift, both MT7 and MT3 were only partially effective (interocular differences given in mean RE±SEM: Control (0 µg): –6.5±0.7D; telenzepine: 2.5 µg: –4.3±1.0D, 25 µg: –4.6±0.7D, 250 µg: –2.7±0.6D**, 750 µg: +1.1±0.7D***, 1500 µg: +0.5±0.6D***; MT7: 0.1 µg: –4.0±0.5D*, 1µg: –3.6±0.3D**, 10 µg: –3.2±0.6D***, 25 µg: –4.7±0.6D; MT3: 0.1 µg: –4.2±0.6D*, 1µg: –3.9±0.5D**; 10 µg: –2.0±0.5D***, 25 µg: –2.8±0.5D***; significant differences compared to the control group are in bold: *p<0.05, **p<0.01, ***p<0.001). Moreover, for MT7 a bell–shaped dose–response curve was observed. Finally, MT3 was slightly more effective than MT7. Conclusions: We show here that the muscarinic receptor antagonist telenzepine and the muscarinic toxins MT7 and MT3 inhibit LIM development in chickens. The data suggest that both M₁– and M₄–receptors are involved in modulation of axial eye growth. Blockade of a single muscarinic receptor subtype is not sufficient to fully prevent development of myopia.

Keywords: myopia • pharmacology • drug toxicity/drug effects