Senescent Phenotype of Trabecular Meshwork Cells Displays Biomarkers in Primary Open-Angle Glaucoma

M.A.      Babizhayev; Y.E.      Yegorov

Abstract

Glaucoma is a major cause of irreversible blindness, affecting more than 70 million individuals worldwide. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma and in the progression of glaucomatous damage. High IOP usually occurs as a result of an increase in aqueous humor outflow resistance in trabecular meshwork (TM). Primary open angle glaucoma (POAG) is characterized by quantifiable parameters including the IOP, the aqueous outflow facility, and geometric measurements of the optic disc and visual defects.

Morphological and biochemical analyses of the TM of POAG patients revealed loss of cells, increased accumulation of extracellular matrix (ECM), changes in the cytoskeleton, cellular senescence and the process of subclinical inflammation. Various biochemical and molecular biology biomarkers of TM cells senescence are considered in the article. Oxidative stress is becoming an important factor more likely to be involved in the pathogenesis of POAG. Treatment of TM cells with oxidative stress induced POAG-typical changes like ECM accumulation, cell death, disarrangement of the cytoskeleton, advanced senescence and the release of inflammatory markers. Oxidative stress is able to induce characteristic glaucomatous TM changes and these oxidative stress-induced TM changes can be minimized by the use of antioxidants, such as carnosine -related analogues and IOP-lowering substances. There is evidence demonstrating that carnosine related analogues may have antioxidative capacities, can prevent cellular senescence and the attrition of telomeres during the action of oxidative stress.

Prevention of oxidative stress exposure to the TM with N-acetylcarnosine ophthalmic prodrug of carnosine and oral formulation of non-hydrolized carnosine may help to reduce the progression of POAG. The previous work has demonstrated that carnosine is able to reach the TM directly via the transcorneal and systemic pathways of administration with N-acetylcarnosine ophthalmic prodrug and oral formulation of non-hydrolized carnosine. We suggest in this article that dual therapy with N-acetylcarnosine lubricant eye drops, oral formulation of nonhydrolized carnosine combined with anti-glaucoma adrenergic drug may become the first-line therapy in glaucoma due to their efficiency in reducing IOP, prevention and reversal of oxidative stress-induced damages in TM and the low rate of severe side effects during combined treatment.

Keywords: Primary open-angle glaucoma, an increased outflow resistance and elevated intraocular pressure, trabecular meshwork endothelium cells, accelerated senescence and telomere attrition of trabecular meshwork cells, oxidative stress-induced damages of trabecular meshwork, loss of trabecular meshwork cells, biomarkers, accumulation of extracellular matrix, carnosine related compounds, primary open-angle glaucoma therapy, aqueous humor outflow resistance, optic disc, visual defects, blindness, retinal ganglion cells