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Jenny Youale, Thara Javorsky, Karine Bigot, Thierry Bordet, Emilie Picard, Francine F Behar-Cohen; Human apo-Transferrin confers neuroprotection in ex vivo glaucoma rat models. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2371.
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Even though iron is essential for retinal homeostasis, its overload is involved in most of pathogenic mechanisms associated with many retinal diseases1. In glaucoma, progressive retinal ganglion cell (RGC) death has been associated with dysregulation of iron homeostasis. Apo-Transferrin (apo-TF) is an endogenous iron transporter that neutralizes free toxic iron (III) in biological fluids and also delivers iron to cells by binding to its receptors. In various models of retinal degeneration, we previously demonstrated that local administration of apo-TF is neuroprotective, controlling iron-induced oxidative stress and regulating other iron unrelated pathways without undesirable side-effects unlike chemicals iron chelators1. The purpose of this study was to evaluate the effects of apo-TF on RGCs death induced by various stresses that mimic glaucoma pathogenesis.
Retinas from adult rats were harvested and placed on polycarbonate membrane with RGCs facing up. Retinal explants were then subjected for 24 hours to hypoxia (CoCl2 100-500 µM) or excitotoxicity (NMDA 100-500 µM). Apo-TF (50 mg/mL) was added to the medium during the 24-hour stress induction period. RGC survival was quantified by Brn3a immunolabeling on flat-mounted retinas and quantification of LDH release at 24 to 96 hours post exposure. Markers for necrosis (RIP3) or apoptosis (Cas-8, Apaf-1, Cas-3, Bcl2) were evaluated by western blot at 6 to 96 hours post exposure..
Both CoCl2 and NMDA induced a dose-dependent reduction in RGCs density with LD50 around 100 µM. CoCl2 induced a gradual increase of Apaf-1- and activated caspases along with a parallel reduction in Bcl2 and a necrosis activation peak at 24 hours. Conversely, NMDA induced a rapid increased in RIP3 and Apaf-1 in the very first hours of intoxication followed by a delayed activation of Cas-8 and Cas-3 with maximal activation at 72 hours. Incubation with apo-TF prevented CoCl2-induced RGC hypoxia (+109% RGCs; -33% LDH release) reducing Cas-3 activation. Similarly, apo-TF partly preserved RGCs against NMDA-induced excitotoxicity (+35% RGCs; -26% LDH release) reducing levels of necrotic and apoptotic markers to normal.
These results indicate that apo-TF can promote RGC survival by interfering with cell death mechanisms involved in glaucoma pathogenesis.1. Picard, E. et al. From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology. Cells 9, 705 (2020).
This is a 2021 ARVO Annual Meeting abstract.
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