n-acetylcarnosine and Glaucoma--Open-Angle

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

Topics: Administration, Ophthalmic; Administration, Oral; Animals; Biomarkers; Blindness; Carnosine; Cataract; Glaucoma, Open-Angle; Humans; Ophthalmic Solutions; Oxidative Stress; Trabecular Meshwork

Elevated levels of transforming-growth-factor (TGF)-β2 in the trabecular meshwork (TM) and aqueous humor are associated with primary open-angle glaucoma (POAG). The underlying mechanism includes alteration of extracellular matrix homeostasis through Smad-dependent and independent signaling. Smad4, an essential co-Smad, upregulates hepcidin, the master regulator of iron homeostasis. Here, we explored whether TGF-β2 upregulates hepcidin, implicating iron in the pathogenesis of POAG.. Primary human TM cells and human and bovine ex vivo anterior segment organ cultures were exposed to bioactive TGF-β2, hepcidin, heparin (a hepcidin antagonist), or N-acetyl carnosine (an antioxidant), and the change in the expression of hepcidin, ferroportin, ferritin, and TGF-β2 was evaluated by semiquantitative RT-PCR, Western blotting, and immunohistochemistry. Increase in reactive oxygen species (ROS) was quantified with dihydroethidium, an ROS-sensitive dye.. Primary human TM cells and bovine TM tissue synthesize hepcidin locally, which is upregulated by bioactive TGF-β2. Hepcidin downregulates ferroportin, its downstream target, increasing ferritin and iron-catalyzed ROS. This causes reciprocal upregulation of TGF-β2 at the transcriptional and translational levels. Heparin downregulates hepcidin, and reduces TGF-β2-mediated increase in ferritin and ROS. Notably, both heparin and N-acetyl carnosine reduce TGF-β2-mediated reciprocal upregulation of TGF-β2.. The above observations suggest that TGF-β2 and hepcidin form a self-sustained feed-forward loop through iron-catalyzed ROS. This loop is partially disrupted by a hepcidin antagonist and an anti-oxidant, implicating iron and ROS in TGF-β2-mediated POAG. We propose that modification of currently available hepcidin antagonists for ocular use may prove beneficial for the therapeutic management of TGF-β2-associated POAG.

Topics: Adult; Aged; Aged, 80 and over; Animals; Blotting, Western; Carnosine; Cation Transport Proteins; Cattle; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Female; Ferritins; Glaucoma, Open-Angle; Heparin; Hepcidins; Humans; Immunohistochemistry; Iron; Male; Middle Aged; Organ Culture Techniques; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Tissue Donors; Trabecular Meshwork; Transforming Growth Factor beta2; Up-Regulation

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 non-hydrolized 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.

Topics: Antioxidants; Aqueous Humor; Biomarkers; Carnosine; Cellular Senescence; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Ophthalmic Solutions; Oxidative Stress; Phenotype; Trabecular Meshwork