Metabolic Profiling of Aqueous Humor from Glaucoma Patients Identifies Potential Therapeutic Target for Neuroprotection

Abstract

Purpose : Glaucoma is the second leading cause of blindness worldwide currently affecting 76 million people and is estimated to increase up to ~112 million by 2040. The current therapies for glaucoma mainly focused on either lowering the IOP or decreasing the aqueous humor production which decelerates but never halts the progression of RGC loss and visual impairment. Currently, there are no biomarkers or immunomodulatory therapy available to screen or prevent vision loss in glaucoma. In the current study, we performed metabolomics analysis using aqueous humor from glaucoma patients to investigate metabolic dysregulation and identify potential therapeutic targets.

Methods : Aqueous humor from glaucoma and non-glaucoma patients undergoing cataract or glaucoma surgeries was subjected to targeted metabolomics using LC-MS/MS. Metabolic changes were analyzed using Metaboanalyst. For in vivo therapeutic studies, a few significantly dysregulated metabolites (agmatine and thiamin) were injected intravitreally in C57BL/6 mouse eyes, and protective responses were measured using electroretinography and by assessing inflammatory response. In vitro neuroprotection studies were performed using mouse cone photoreceptor cell line, 661W, exposed to oxidative stress. Cell death was measured by using TUNEL assay.

Results : Targeted metabolomics approach identified dysregulation of ~31 metabolites in the aqueous humor of glaucoma patients. Among these metabolites, a putative neuromodulator and L-Arginine metabolite ‘agmatine’ and a vitamin ‘thiamin’ showed a significant reduction in glaucoma patients. Agmatine and thiamin treatment via the intravitreal route showed significant protection against neuroinflammatory damage in the mouse eyes. Agmatine and thiamin treatment also demonstrated significant protection in mouse neuronal photoreceptor cells from oxidative stress-induced damage

Conclusions : Our findings reveal several metabolic dysregulations in glaucoma. These metabolites could serve as potential biomarkers, and a neuroprotective or immunomodulatory therapy to treat and prevent vision loss in glaucoma.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.