The Sigma-1 Receptor Agonist Fluvoxamine is a Novel Treatment for Ocular Hypertension in Glaucoma

Abstract

Purpose : Elevated intraocular pressure (IOP) is the single modifiable risk factor of glaucoma. It occurs as a result of the impeded outflow of aqueous humor, partially due to the fibrosis of the trabecular meshwork (TM). We recently reported that Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) effectively reduces fibrotic processes in primary TM cells. To further prove the applicability of Sigma-1 receptor as a novel anti-glaucoma drug target in this in vivo study we investigated the tolerability, IOP lowering and antifibrotic effects of a FLU containing eyedrop in a mouse model of glaucoma.

Methods : Toxicity and tolerability investigations of FLU containing eye drops (100 mM) were performed on C57BL/6J wild-type (WT) mice using fluorescein test. IOP increase was induced in 3.5- 4-month-old WT and S1R knock-out (KO) mice (n=8-12/group) by periocular injection of Dexamethasone acetate (Dex, 10 mg/mL). FLU eye drops were administered bilaterally, twice daily after 2 weeks of Dex. IOP was measured weekly with the Icare Tonolab and after 4 weeks, anterior segment tissues were collected, markers of fibrosis were assessed by Western blot.

Results : FLU eye drop is non-toxic and non-irritating. After two weeks, Dex increased IOP both in WT and S1R KO mice by 14.21%, p<0.001 and 14.91%, p<0.001 respectively. Of note, IOP elevation started one week earlier in KO mice than in the WT. Two weeks of FLU treatment lowered IOP in WT mice almost back to control levels, reducing it by 11.58% (16.49±0.9 mmHg, p<0.001) compared to the Dex group. However, in KO mice FLU eyedrop did not have any effect on IOP. S1R is present in the anterior segment of mice, and its level is elevated after Dex. Increased levels of fibrotic elements such as TGFb2 and fibronectin were also detected, which were lowered by FLU eyedrop. In parallel, FLU increased the protein level of brain-derived neurotrophic (BDNF) factor, which has already been shown to have protective effects in the retina.

Conclusions : S1R activation prevents Dex-induced IOP elevation. S1R agonist FLU eyedrop treatment is well-tolerated, non-toxic and effective in reducing increased IOP as well as the fibrosis components in the anterior segment. Therefore, Sigma-1 receptor agonists could be new treatment options to lower IOP and for other fibrosis-associated eye disorders.
Grants: OTKA- K135398, LP2021-3/2021, TKP2021-EGA-24

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.