Potential Treatment for Glaucoma: NAD+ Precursor NR
Introduction
Glaucoma is regarded as the second dominant cause of blindness across the world. With the amounting number and proportion of elderly people, it is estimated that 111.8 million people will have glaucoma by 2040. Nicotinamide riboside (NR) has been attested to protect retinal ganglion cells from the stress of elevated intraocular pressure and optic nerve crush. Glaucoma patients can protect their optic nerves by oral administration of NR at a dose of 300 mg (approximately 1.18 mM). The abovementioned protective effects of NR may be achieved by its antioxidant and antifibrotic properties.
About glaucoma
Glaucoma is a typical ocular disease characterized by atrophy and depression of the optic nerve head, visual field defects, and diminution of vision. The pathologically increased intraocular pressure and insufficient blood supply to the optic nerve are deemed as the primary risk factors for the development of the disease. In addition to those with family history of glaucoma, people with severe myopia/hyperopia, hypertension, hyperlipidemia, hyperglycemia and long-term use of corticosteroid medications, especially eye drops, are at high risk for glaucoma.
Extraordinary role of NR in protecting HTMs against oxidative stress
In glaucoma, oxidative stress can trigger TM degeneration, thereby resulting in intraocular hypertension. Herein, an oxidative damage model is established in vitro by incubation of human trabecular meshwork (HTM) cells with 200 μM H2O2 for 24 h. As expected, NR hampers H2O2-induced apoptosis in HTM cells, as evidenced by the upregulation of the anti-apoptotic protein Bcl-2 and downregulation of apoptotic protein Bax. Conversely, NR boosts the viability of oxidative-damaged HTM cells.
In addition, NR can shield HTM cells from oxidative stress by lowering ROS and superoxide anion levels. Apart from this, NR overtly improves the H2O2-induced decrease in the mitochondrial membrane potential (MMP) in HTM cells, hinting its antioxidant effect possibly achieved by maintaining mitochondrial homeostasis.
In addition, NR can shield HTM cells from oxidative stress by lowering ROS and superoxide anion levels. Apart from this, NR overtly improves the H2O2-induced decrease in the mitochondrial membrane potential (MMP) in HTM cells, hinting its antioxidant effect possibly achieved by maintaining mitochondrial homeostasis.
Underlying mechanism regarding the antioxidant role of NR in HTM cells
MAPK and JAK2/Stat3 pathways are related to NR-alleviated HTM cell apoptosis during oxidative stress. In the MAPK pathway, H2O2 leads to the downregulation of p-P38/P38 ratio and upregulation of p-ERK1/2 protein expression, which are offset by intervention with NR. In the JAK2/Stat3 pathway, H2O2 induces downregulation of p-JAK2 protein expression, while NR runs oppositely.
Potential antifibrotic role of NR in HTM cells
Considering that transforming growth factor-beta 2 (TGF-β2), a profibrotic cytokine, is also a major contributor to glaucomatous HTM dysfunction, an HTM cell model of fibrosis is constructed by induction of TGF-β2 at 10 ng/mL for 48 h. Remarkably, NR prevents TGF-β2-induced fibrosis by reducing extracellular matrix (ECM) deposition in HTM cells. Concretely, the mRNA and protein levels of fibronectin (FN) are elevated in the TGF-β2-treated HTM cells, which however are counteracted by NR.
Conclusion
NR can boost the viability, proliferation and MMP oxidative damage in H2O2-induced HTM cells, and hamper TGF-β2-induced fibrosis, which is linked to the MAPK and JAK2/Stat3 pathways. NR may be a potential therapeutic agent for glaucoma by inhibiting oxidative damage and fibrosis in HTM cells.
Reference
Zeng Y, Lin Y, Yang J, et al. The Role and Mechanism of Nicotinamide Riboside in Oxidative Damage and a Fibrosis Model of Trabecular Meshwork Cells. Transl Vis Sci Technol. 2024;13(3):24. doi:10.1167/tvst.13.3.24
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