Neuroprotective Effects of Transferrin in Experimental Glaucoma Models

Abstract

Iron is essential for retinal metabolism, but an excess of ferrous iron causes oxidative stress. In glaucomatous eyes, retinal ganglion cell (RGC) death has been associated with dysregulation of iron homeostasis. Transferrin (TF) is an endogenous iron transporter that controls ocular iron levels. Intraocular administration of TF is neuroprotective in various models of retinal degeneration, preventing iron overload and reducing iron-induced oxidative stress. Herein, we assessed the protective effects of TF on RGC survival, using ex vivo rat retinal explants exposed to iron, NMDA-induced excitotoxicity, or CoCl2-induced hypoxia, and an in vivo rat model of ocular hypertension (OHT). TF significantly preserved RGCs against FeSO4-induced toxicity, NMDA-induced excitotoxicity, and CoCl2-induced hypoxia. TF protected RGCs from apoptosis, ferroptosis, and necrosis. In OHT rats, TF reduced RGC loss by about 70% compared to vehicle-treated animals and preserved about 47% of the axons. Finally, increased iron staining was shown in the retina of a glaucoma patient’s eye as compared to non-glaucomatous eyes. These results indicate that TF can interfere with different cell-death mechanisms involved in glaucoma pathogenesis and demonstrate the ability of TF to protect RGCs exposed to elevated IOP. Altogether, these results suggest that TF is a promising treatment against glaucoma neuropathy.

Evaluation of serum iron status indicators in patients with primary open angle glaucoma

“…A recent article includes all publications measuring iron indicators in the serum, aqueous humor, and tears of patients with glaucoma and in the retinal tissue layers of primates. 21 In addition to studies reporting increased ferritin and transferrin levels in the retinas of monkeys with glaucoma and humans with glaucoma, 22,23 there are several studies reporting increased levels of transferrin in the aqueous humors of people with PAAG, 24 and increased iron levels in the tears of people with glaucoma. 25 Also, when human aqueous humor iron levels were examined, it was determined that they were low in pseudo-exfoliating glaucoma and high in POAG.…”

Research progress of iron metabolism in retinal diseases

“…Compared with healthy individuals, glaucoma patients have a different distribution of iron in the retina, with iron overload around Müller cells, RGCs, and optic nerve axons and reduced iron in cones. 54 In the retina of glaucoma patients and monkeys, the mRNA and protein expression levels of iron regulatory proteins Tf, Cp and Ft were increased. 55 Iron metabolism plays an important role in the pathogenesis of glaucomatous neuropathy through cell death, oxidative stress, inflammation, mitochondrial dysfunction, and gene mutations.…”

“… 60 Tf can interfere with different cell death mechanisms such as apoptosis and iron death in the pathogenesis of glaucoma and has a protective effect on RGCs exposed to ocular hypertension. 54 …”

“…Tf has shown therapeutic potential in diseases such as AMD and RP. 47 , 54 , 79 It should be noted that the long-term therapeutic effect of iron chelators remains to be seen. In the future, iron chelator drugs should be able to cross the BRB, target iron-overloaded tissues and have a sufficiently long half-life and rapid elimination pathways.…”

Advancements in Nanogels for Enhanced Ocular Drug Delivery: Cutting-Edge Strategies to Overcome Eye Barriers

“…Transferrin is an iron transfer protein in the body, and studies have shown that transferrin receptors on retinal pigment epithelial cells are upregulated in diseases of the eye’s posterior segment, such as vitreoretinopathy, glaucomatous neuropathy, and age-related macular degeneration. As a result, retinal-targeted drug delivery using the reaction between the transferrin receptor and transferrin present on the cell surface is being studied [ 118 , 119 , 120 , 121 ]. When transferrin binds to its receptor on the cell surface, the complex containing transferrin is internalized and can easily enter the cell.…”