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other·ophthalmology, retina, preclinical research, antioxidants, biomedical research·PMC10514139

Preserving Retinal Structure and Function with the Novel Nitroxide Antioxidant, DCTEIO

Neurochemical Research · 4 authors, 4 centres

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Retinal function was assessed by electroretinography (ERG) measuring a-wave, b-wave, isolated-cone, and oscillatory potential amplitudes, and structural integrity was evaluated by histology.

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Retinal function was assessed by electroretinography (ERG) measuring a-wave, b-wave, isolated-cone, and oscillatory potential amplitudes, and structural integrity was evaluated by histology. DCTEIO at 20 mg/kg did not affect normal retinal function over 8 days, indicating no retinal toxicity at this concentration. Following ischemia-reperfusion injury, DCTEIO maintained retinal function at normal pre-injury levels for at least 8 days and preserved the inner and outer nuclear layers. DCTEIO also significantly reduced GFAP upregulation, a marker of Müller cell activation and retinal stress, and significantly reduced microglial activation and infiltration into the outer retina. An in vitro assay using the ME-TRN probe in cultured photoreceptor cells confirmed the antioxidant capacity of DCTEIO, though higher concentrations were needed compared to lutein, likely due to reduced lipophilicity.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10514139

Preserving Retinal Structure and Function with the Novel Nitroxide Antioxidant, DCTEIO

Neurochemical Research

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ABSTRACT

Abstract Oxidative stress is a major contributor to progressive neurodegenerative disease and may be a key target for the development of novel preventative and therapeutic strategies. Nitroxides have been successfully utilised to study changes in redox status (biological probes) and modulate radical-induced oxidative stress. This study investigates the efficacy of DCTEIO (5,6-dicarboxy-1,1,3,3-tetraethyllisoindolin-2-yloxyl), a stable, kinetically-persistent, nitroxide-based antioxidant, as a retinal neuroprotectant. The preservation of retinal function following an acute ischaemic/reperfusion (I/R) insult in the presence of DCTEIO was quantified by electroretinography (ERG). Inflammatory responses in retinal glia were analysed by GFAP and IBA-1 immunohistochemistry, and retinal integrity assessed by histology. A nitroxide probe combined with flow cytometry provided a rapid technique to assess oxidative stress and the mitigation offered by antioxidant compounds in cultured 661W photoreceptor cells. DCTEIO protected the retina from I/R-induced damage, maintaining retinal function. Histological analysis showed preservation of retinal integrity with reduced disruption and disorganisation of the inner and outer nuclear layers. I/R injury upregulated GFAP expression, indicative of retinal stress, which was significantly blunted by DCTEIO. The number of ‘activated’ microglia, particularly in the outer retina, in response to cellular stress was also significantly reduced by DCTEIO, potentially suggesting reduced inflammasome activation and cell death. DCTEIO mitigated oxidative stress in 661W retinal cell cultures, in a dose-dependent fashion. Together these findings demonstrate the potential of DCTEIO as a neuroprotective therapeutic for degenerative diseases of the CNS that involve an ROS-mediated component, including those of the retina e.g. age-related macular degeneration and glaucoma. Keywords: Oxidative stress, Ischemia, Neuroprotection, Retina, Nitroxide, Antioxidant

CITATION EXPORT

Cassie L Rayner, Steven E Bottle, Alexander P Martyn et al.. Preserving Retinal Structure and Function with the Novel Nitroxide Antioxidant, DCTEIO. Neurochemical Research. (2023). https://doi.org/10.1007/s11064-023-03978-w

AUTHORS

4 · 4 CENTRES

Cassie L Rayner, Steven E Bottle, Alexander P Martyn, Nigel L Barnett

1Clem Jones Centre for Regenerative Medicine, Faculty of Health Sciences and Medicine, Bond University, 14 University Drive, Robina, Gold Coast, QLD 4226 Australia
2Queensland Eye Institute, South Brisbane, QLD 4101 Australia
3School of Physical and Chemical Sciences, Queensland University of Technology, Brisbane, QLD 4000 Australia
4Cancer and Ageing Research Program (CARP), Princess Alexandra Hospital, Brisbane, QLD 4102 Australia

Cassie L Rayner, Steven E Bottle, Alexander P Martyn et al.. Preserving Retinal Structure and Function with the Novel Nitroxide Antioxidant, DCTEIO. Neurochemical Research. (2023). https://doi.org/10.1007/s11064-023-03978-w