Biomarkers and special features of oxidative stress in the anterior segment of the eye linked to lens cataract and the trabecular meshwork injury in primary open‐angle glaucoma: challenges of dual combination therapy with N‐acetylcarnosine lubricant eye drops and oral formulation of nonhydrolyzed carnosine

Abstract

The implication of oxidative stress associated with increased oxidant production in mammalian and human cells characterized by the release of free radicals, resulting in cellular degeneration, is involved in many ocular diseases, such as age-related macular degeneration, retinopathy of prematurity, retinal light damage, primary open-angle glaucoma (POAG), and cataract. Cataract is the leading cause of blindness, accounting for 50% of blindness worldwide. Glaucoma, the leading cause of irreversible blindness, is considered as a progressive optic neuropathy often caused by elevated intraocular pressure (IOP) consequent to abnormally high resistance to aqueous humor (AH) drainage via the trabecular meshwork (TM) and Schlemm's canal. Morphological and biochemical analyses of the TM of patients with POAG revealed the loss of cells, increased accumulation of extracellular matrix proteins (ECM), changes in the cytoskeleton, cellular senescence, and the process of subclinical inflammation. The TM is the target tissue of glaucoma in the anterior chamber, and the development and progression of glaucoma are accompanied by the accumulation of oxidative damage in this tissue. The separate studies were conducted to comparatively evaluate the sensitivity to oxidative stress and lipid peroxidation (LPO) of anterior chamber tissues including TM. Accumulation of the primary, secondary, and end products of LPO (diene and triene conjugates, Schiff's bases) was noted in the studied extracts. Significant differences in the levels of all mentioned LPO products in comparison with the control were observed. The data may be considered as an evidence of LPO participation in the destruction of the trabecule and Schlemm's canal in POAG. Treatment of TM cells with oxidative stress induced POAG-typical changes such as ECM accumulation, cell death, disarrangement of the cytoskeleton, advanced senescence, and the release of inflammatory markers. By pretreatment with antioxidants, prostaglandin analogs, beta-blockers, or local carbonic anhydrase inhibitors, these effects were markedly reduced. Oxidative stress can induce characteristic glaucomatous TM changes, and these oxidative stress-induced TM changes can be minimized by the use of antioxidants and IOP-lowering substances. It is tempting to speculate that the prevention of oxidative stress exposure to the TM may help to reduce the progression of POAG. The author's laboratory has developed and patented the dual combination therapy with N-acetylcarnosine lubricant eye drops and oral formulation of nonhydrolyzed carnosine in ripe cataracts and POAG. The specific regimen for the treatment in each stage of age-related ophthalmic disease has been taken up. In the treatment of POAG, this dual therapy can be combined with conventional antiglaucoma therapy with beta-blocking and/or adrenergic agonist medicines providing the significant IOP-lowering effect and significant increase in outflow facility. The developed therapy is a prominent management care of the glaucomatous neurodegeneration.

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…For this reason, the enzymatic hydrolysis of Lcarnosine is the main limitation for their possible effective pharmacological applications. Still, some authors put forward interesting hypotheses that lubricant drug delivery and perfume toilet water formulations [129], or lubricant eye drops and oral formulation [145], all based on non-hydrolyzed Lcarnosine, should be explored for their therapeutic potential in olfactory dysfunction, Alzheimer's disease and other neurodegenerative disorders.…”

Pharmacotherapy of Glaucoma

“…24 Another mechanism that is related to loss of cells, increased accumulation of extracellular matrix proteins, changes in the cytoskeleton, cellular senescence, and the process of subclinical inflammation in the trabecular meshwork is oxidative stress. 25 It has also been speculated that a hypoxic environment in glaucoma may induce aberrant epigenetic mechanisms that contribute to extracellular matrix change in the trabecular meshwork. 26 Vascular aspects.…”

Oxidative stress and potential applications of free radical scavengers in glaucoma

“…101 The combination therapy with N-acetylcarnosine lubricant eye drops and oral formulation of non-hydrolysed carnosine has been developed and studied in primary open-angle glaucoma. 102 In the treatment of primary open-angle glaucoma this dual therapy was combined with the conventional antiglaucoma therapy with beta-blocking and/or adrenergic agonist medicines providing the significant IOP-lowering effect and significant increase in outflow facility. 102 Potential applications of free radical scavengers in glaucomatous neurodegeneration are shown in Table 1.…”