Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)
Minh N. Tran1,2, Gyorgy Torok3, Timea Medveczki1,2, Akos Toth1,2, Tamas Lakat1,2, Illes Kovacs4,5, Attila J. Szabo2, Andrea Fekete1,2, Judit Hodrea1,2
1. MTA-SE Lendület “Momentum” Diabetes Research Group, Semmelweis University, Budapest
2. 1st Department of Pediatrics, MTA Centre of Excellence, Semmelweis University, Budapest
3. Department of Biophysics and Radiation Biology, Semmelweis University, Budapest
4. Department of Ophthalmology, Semmelweis University, Budapest
5. Department of Ophthalmology, Weill Cornell Medical College, New York, NY5.
Lowering intraocular pressure (IOP) is currently the only treatment strategy to slow the progression of glaucoma. The increased IOP is attributed to abnormally elevated trabecular aqueous outflow resistance that can be caused by fibrosis of the trabecular meshwork (TM). We recently found that the specific sigma-1 receptor (S1R) agonist fluvoxamine (FLU) effectively reduces profibrotic factor-induced cytoskeletal rearrangement and cell proliferation of TM cells in vitro, therefore we propose that FLU may prevent TM fibrosis in vivo and thus can reduce IOP.
To investigate the role of S1R on Dexamethasone-induced elevated IOP in mice
To induce IOP C57BL/6J wild type (WT) and S1R knock-out (KO) mice were weekly injected (n=8-12/group) with vehicle or Dexamethasone Acetate (Dex) through periocular conjunctival fornix to both eyes. FLU eye drops (30mM) were given bilaterally twice daily after 1 week of Dex. IOP was measured with Icare Tonolab weekly. After 4 weeks, the eyes were enucleated and bisected just posterior to the limbus. The retina, choroid, vitreous, and lens were removed and the remaining anterior segments were frozen for further investigations. For S1R labeling fluorescent beads were injected intracamerally and TM regions with engulfed beads were imaged with confocal microscope.
Dex increased the IOP in 7 month old WT mice after three weeks from baseline 17.26±1.46 to 18.61±1.05 mmHg (+7.82%; p<0.05) and two weeks of FLU eye drop treatment lowered IOP to 16.90±1.19 mmHg (-9.18%; p<0.05) compared to Dex group. In younger (2 to 5 month) WT mice IOP was elevated from baseline 17.66±1.01 mmHg to 19.65±2.00 mmHg (+11.27%; p<0.05) which is more pronounced than in aged mice. In KO mice the IOP increased from 16.81±1.41 to 18.72±1.04 mmHg (+11.36%; p<0.05). Of note the increase of IOP started earlier in KO mice (1 week) than in WT (2 weeks). As novelty, confocal images showed that S1R present in the mouse TM region and preliminary PCR results revealed that the expression of key fibrosis elements (fibronectin and α-smooth muscle actin) were upregulated by Dex.
FLU treatment effectively prevented the increase in IOP in vivo. Thus S1R agonists could be potential candidates for the development of a novel IOP-lowering drug.
Funding: OTKA- K135398, LP2021-3/2021, TKP2021-EGA-24, Stipendium Hungaricum, TKP2020-6183169273