Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming.

Abstract

Purpose:

To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE).

Methods:

The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine.

Results:

In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells.

Conclusions:

Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.

• Authors: Ji Yeon Do, Juhee Kim, Mi-Jin Kim, Jung Yi Lee, So-Young Park, Ryoji Yanai, In-Kyu Lee, Sungmi Park, Dong Ho Park
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 61 Issue 12 Pg. 24 (10 01 2020) ISSN: 1552-5783 [Electronic] United States
• PMID: 33107903 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Interleukin-6
• Interleukin-8
• Lipopolysaccharides
• interleukin-6, mouse
• Fursultiamin
• Vitamin B Complex

Topics

• Animals
• Blotting, Western
• Capillary Permeability (drug effects)
• Cell Line
• Cellular Reprogramming Techniques
• Chemokine CCL2 (metabolism)
• Choroidal Neovascularization (metabolism, prevention & control)
• Choroiditis (drug therapy, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Fursultiamin (therapeutic use)
• Inflammation (drug therapy, metabolism)
• Interleukin-6 (metabolism)
• Interleukin-8 (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Real-Time Polymerase Chain Reaction
• Retinal Pigment Epithelium (drug effects, metabolism)
• Vitamin B Complex (therapeutic use)