The Sigma-1 Receptor Agonist Fluvoxamine prevents Dexamethasone-induced Ocular Hypertension in vivo.

Abstract

Purpose : 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.

Methods : 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 carefully 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.

Results : 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 is 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.

Conclusions : Fluvoxamine treatment effectively reduced the steroid-induced fibrosis and cytoskeletal rearrangement of trabecular meshwork tissue and prevented the increase in intraocular pressure in vivo. Thus Sigma-1 receptor agonists could be potential candidates for the development of a novel IOP-lowering drug.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.