Metformin prevents glucocorticoid-induced trabecular meshwork damage and intraocular pressure elevation via activating mitophagy

Purpose: We investigated the preventive effects of metformin (MET) on glucocorticoid-induced intraocular pressure (IOP) elevation in mice and cellular damage to human trabecular meshwork cells (HTMC). Methods: Male C57BL/6J mice received a 9-day preventive treatment of phosphate-buffered saline (PBS) or MET, followed by synchronous dexamethasone sodium phosphate (DEX) treatment for 19 days. A PBS group served as the negative control. MET's preventive effect on DEX-induced ocular hypertension in C57BL/6J mice was examined, focusing on IOP, fibrosis, and trabecular aqueous humor outflow (AHO) ultrastructure. HTMC were pre-stimulated with MET for 24 h, then exposed to DEX with MET for five days. Immunofluorescence and western blotting analyzed protein expression in the trabecular meshwork, and flow cytometry analyzed reactive oxygen species content. Results: DEX significantly increased IOP from the 5 ^th day until the 4 ^th week's end (all p <0.05) in the PBS+DEX group, whereas MET partially neutralized this elevated IOP. The PBS+DEX group exhibited upregulated fibrotic markers in the AHO, which MET+DEX mitigated in trabecular tissues. DEX disrupted the HTMC cytoskeleton, whereas MET facilitated its recovery, induced more autophagosomes, and promoted biological activities of mitophagy and mitochondrial fusion. Conclusion: MET prevents glucocorticoid-induced trabecular meshwork damage by inducing mitophagy, hinting at potential benefits for primary open-angle glaucoma.