Sigma − 1 receptor activation as a new option for the treatment of glaucoma in preclinical models

Abstract

AbstractIntroduction: Trabecular meshwork (TM) is the main pathway for aqueous humour drainage. The fibrotic‐like remodelling of the actin cytoskeleton in TM cells results in accumulation of extracellular matrix proteins leading to altered stiffness and impaired outflow. These are the primary cause of increased intraocular pressure (IOP) and glaucoma. Our group owns a world‐wide patent for various Sigma‐1 receptor (S1R) agonists as novel antifibrotic compounds. Fluvoxamine (FLU), a potent S1R agonist, decreases the levels of key elements of fibrosis in the kidney and in the lung, and preserves organ function.Aim: Here in vitro (1) we identified the presence and localization of S1R in the eye, (2) studied S1R activation on cytoskeletal rearrangement and (3) investigated the IOP lowering‐effect of FLU in the in vivo mice‐model of glaucoma.Methods: S1R was detected on HTM5 and on primary MsTM cells. Cells were treated platelet‐derived growth factor (PDGF, 24 h, 20 ng/ml) combined with 10 μM of FLU. Cell proliferation and migration were measured band F‐actin formation was visualized by phalloidin staining. To induce IOP C57BL/6J mice were weekly injected (n = 8–12/group) with vehicle or Dexamethasone Acetate (Dex) through periocular conjunctival fornix to both eyes. FLU eye drops (30 mM) were given bilaterally twice daily after 1 week of Dex. IOP was measured with Icare Tonolab weekly.Results: S1R was present both in TM cells and is localized in the endoplasmic reticulum. PDGF‐induced cell proliferation, migration and cytoskeletal rearrangement were ameliorated or even prevented by FLU treatment. Dex increased the IOP in WT mice after 3 weeks from baseline 17.26 ± 1.46 to 18.61 ± 1.05 mmHg (+7.82%; p < 0.05). Two‐week treatment of FLU‐containing eye drop was not harmful to the eyes and lowered IOP to 16.90 ± 1.19 mmHg (−9.18%; p < 0.05) compared to Dex group.Conclusions: FLU is non‐toxic and reduces profibrotic factor‐induced cytoskeletal rearrangement and cell proliferation of TM cells. FLU treatment effectively prevents the increase in IOP. Thus Sigma‐1 receptor agonists could be potential candidates for the development of a novel drug candidate for glaucoma.Grants: OTKA‐ K135398, LP2021‐3/2021, TKP2021‐EGA‐24.