2026
Pharmaceuticals

The Sigma-1 Receptor Agonist Fluvoxamine Is Protective in Hyperglycaemia-Induced Dysfunction of Trabecular Meshwork Cells

Authors:

Alexandra Rozsahegyi, Marcell Cserhalmi, Timea Medveczki, Zsuzsanna Buzogany, Eva Ruisanchez, Andras Budai, Balazs Besztercei, Attila J. Szabo, Judit Hodrea, Andrea Fekete

Keywords:

Sigma-1 receptor; trabecular meshwork; fibrosis; diabetes mellitus; hyperglycaemia; oxidative stress; fluvoxamine; Wistar rat; db/db mice; HTM5

Abstract:

Background/Objectives: Diabetes mellitus (DM) is associated with a doubled prevalence of elevated intraocular pressure (IOP) caused by trabecular meshwork (TM) dysfunction. Chronic hyperglycaemia leads to oxidative stress and fibrotic remodeling of the TM. We previously identified the Sigma-1 receptor (S1R) as a novel anti-fibrotic target by demonstrating that its agonist, fluvoxamine (FLU), is protective in diabetes-related renal fibrosis. Here, we investigate its potential to mitigate ocular fibrosis.

Methods: First, we wanted to verify in different in vivo models (high-fat diet/streptozotocin (HFD/STZ) rats, db/db mice) that type 2 DM (T2DM) leads to fibrotic remodeling of the TM. Then, in vitro, we assessed the effect of FLU (15 µM) on hyperglycaemia-induced (HG, 25 µM) fibrosis, oxidative stress and endogenous nitric oxide (NO) production.

Results: In T2DM models, excessive accumulation of collagen, α-smooth muscle actin (αSMA), fibronectin (Fn) and F-actin was observed in the eyes. Ocular fibrosis was accompanied by IOP elevation (13.7 vs. 18.7 mmHg) in db/db mice. In human TM cells (HTM5), FLU decreased HG-induced cell proliferation (14% vs. 24%) and upregulated S1R protein expression. Furthermore, FLU suppressed the expressions of key fibrotic elements, including transforming growth factor-β2 (TGF-β2) by 37%, Fn by 49%, collagen type 1 (COL1A1) and type 4 (COL4A1) by 24% and 45%, respectively. FLU also reversed HG-induced F-actin accumulation by 39% and enhanced intracellular NO levels by 34%. Crucially, FLU decreased ROS generation by half, demonstrating its protective effect against HG-induced oxidative stress.

Conclusions: These findings highlight the potential of S1R activation as a promising therapeutic target to alleviate hyperglycaemia-induced injury to the TM by modulating multiple molecular pathways.