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Veluchamy A. Barathi, J L. Kwan, Q S. Tan, S R. Weon, W S. Lee, L Tong, S E. Iismaa, J Wess, R W. Beuerman; Muscarinic Receptor Specific Blockers Down Regulates Transglutaminase-2 in Experimental Myopia: Target for Myopia Treatment. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3919.
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To determine the novel or target drug for myopia and also to investigate the interaction of muscarinic receptors (mAChR) and transglutaminases (TGase) during myopia development.
Experimental myopia was induced for 6 weeks in M1-M5 knock-out (KO), TGase-2 KO and wild-type mice (30 mice from each strain) by wearing of -25D spectacle lens or diffusers over the right eyes. Left eyes were used as controls. Eye biometry was measured via AC-Master and refraction error measured by infrared photo-refraction. Murine and human scleral derived fibroblasts were cultured to passage 2 and treated to exogenous atropine or carbachol, pirenzepine, AFDX-116, himbacine, 4-DAMP, darifenacin and tropicamide at baseline, 0.1, 1, 10 and 100 µM for 5 days. The TGase-2 transamidase activity was measured after 5 days. Following 5 days of treatment, the total RNA and protein was extracted from these cells and RT-qPCR performed to determine transcript levels of TGM2 and western blot performed to determine protein levels of TGase-2.
M1, M4 and M5 KO axial growth was significantly 270 µm longer than the M2 and TGM-2 KO; 310 µm longer than the M3 KO. Wild-type mice axial growth was not significantly different. The refraction measurements for TGM-2, M1-M5 KO were +6.4D, -6.2 D, +6D, +6.5D, -6.5D, -6.25D respectively. The transamidase activity of endogenous cellular TGase-2 activity was reduced by antagonists’ treatment in a concentration-dependent manner in human and mouse SFs. Moreover TGase-2 activity was most significantly reduced with himbacine treatment in both cells and also with darifenacin at low concentrations. In addition, we found that in himbacine treated murine myopic eyes, TGase-2 transcript and protein were significantly reduced in sclera tissue compared to untreated eyes.
These findings suggest that mAChR2, mAChR3, TGase-2 mediates myopia formation in mice and these blockers are the potential drugs for the reduction of myopia progression. Based on these results we hypothesize that TGase-2 and muscarinic receptors interaction could be involved in the sclaral remodeling or myopia development.
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