Ebselen by modulating oxidative stress improves hypoxia-induced macroglial Müller cell and vascular injury in the retina.
Oxidative stress is an important contributor to glial and vascular cell damage in ischemic retinopathies. We hypothesized that ebselen via its ability to reduce reactive oxygen species (ROS) and augment nuclear factor-like 2 (Nrf2) anti-oxidants would attenuate hypoxia-induced damage to macroglial Müller cells and also lessen retinal vasculopathy. Primary cultures of rat Müller cells were exposed to normoxia (21% O2), hypoxia (0.5% O2) and ebselen (2.5 μM) for up to 72 h. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice while control mice were housed in room air. Mice received vehicle (saline, 5% dimethyl sulfoxide) or ebselen (10 mg/kg) each day between postnatal days 6-18. In cultured Müller cells, flow cytometry for dihydroethidium revealed that ebselen reduced the hypoxia-induced increase in ROS levels, whilst increasing the expression of Nrf2-regulated anti-oxidant genes, heme oxygenase 1, glutathione peroxidase-1, NAD(P)H dehydrogenase quinone oxidoreductase 1 and glutamate-cysteine ligase. Moreover, in Müller cells, ebselen reduced the hypoxia-induced increase in protein levels of pro-angiogenic and pro-inflammatory factors including vascular endothelial growth factor, interleukin-6, monocyte chemoattractant-protein 1 and intercellular adhesion molecule-1, and the mRNA levels of glial fibrillary acidic protein (GFAP), a marker of Müller cell injury. Ebselen improved OIR by attenuating capillary vaso-obliteration and neovascularization and a concomitant reduction in Müller cell gliosis and GFAP. We conclude that ebselen protects against hypoxia-induced injury of retinal Müller cells and the microvasculature, which is linked to its ability to reduce oxidative stress, vascular damaging factors and inflammation. Agents such as ebselen may be potential treatments for retinopathies that feature oxidative stress-mediated damage to glia and the microvasculature.
Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Sih Min
SM
Tan
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Devy
D
Deliyanti
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
William A
WA
Figgett
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Dean M
DM
Talia
Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia. Electronic address: judy.dehaan@bakeridi.edu.au.
Judy B
JB
de Haan
Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Jennifer L
JL
Wilkinson-Berka
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein; D005911:Gliosis / Q000188:drug therapy* / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D054833:Isoindoles; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism / Q000517:prevention & control*; D015861:Retinal Neovascularization / Q000378:metabolism / Q000517:prevention & control; D012171:Retinal Vessels / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D057772:Vascular System Injuries / Q000517:prevention & control
D000975:Antioxidants; D001393:Azoles; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D054833:Isoindoles; D009419:Nerve Tissue Proteins; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C528900:glial fibrillary astrocytic protein, mouse; D013481:Superoxides; C042986:ebselen
Ebselen; Glia; Oxidative stress; Reactive oxygen species; Retinopathy; Vasculature