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

Area of Science:

• Ophthalmology
• Endocrinology
• Pharmacology

Background:

• Diabetes mellitus (DM) doubles the risk of elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction.
• Chronic hyperglycemia in DM causes oxidative stress and fibrotic remodeling of the TM.
• Sigma-1 receptor (S1R) agonists, like fluvoxamine (FLU), show anti-fibrotic potential in renal fibrosis.

Purpose of the Study:

• Investigate S1R activation's potential to mitigate ocular fibrosis in diabetes.
• Assess FLU's effects on hyperglycemia-induced fibrosis, oxidative stress, and nitric oxide (NO) production in TM cells.
• Verify if type 2 DM (T2DM) models exhibit TM fibrotic remodeling and IOP elevation.

Main Methods:

• Evaluated TM fibrotic remodeling in HFD/STZ rats and db/db mice with T2DM.
• Assessed FLU's impact on hyperglycemia-induced fibrosis, oxidative stress, and NO production in human TM cells (HTM5) in vitro.
• Measured IOP, collagen, αSMA, fibronectin, F-actin, TGF-β2, and reactive oxygen species (ROS) levels.

Main Results:

• T2DM models showed increased ocular collagen, αSMA, fibronectin, and F-actin, with elevated IOP in db/db mice.
• In HTM5 cells, FLU reduced hyperglycemia-induced proliferation, upregulated S1R, and suppressed fibrotic markers (TGF-β2, Fn, COL1A1, COL4A1).
• FLU reversed F-actin accumulation, enhanced NO production, and halved ROS generation, indicating protection against oxidative stress.

Conclusions:

• S1R activation, via fluvoxamine, effectively mitigates hyperglycemia-induced ocular fibrosis and oxidative stress.
• These findings suggest S1R is a promising therapeutic target for managing diabetes-related TM injury and IOP elevation.
• Modulating S1R offers a potential strategy to prevent vision loss in diabetic patients.