Bruce A Berkowitz1, Bryce X Bredell2, Christopher Davis2, Marijana Samardzija3, Christian Grimm3, Robin Roberts2. 1. Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States. 2. Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States. 3. Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Switzerland.
Abstract
PURPOSE: Excessive and continuously produced free radicals in the outer retina are implicated in retinal aging and the pathogenesis of sight-threatening retinopathies, yet measuring outer retinal oxidative stress in vivo remains a challenge. Here, we test the hypothesis that continuously produced paramagnetic free radicals from the outer retina can be measured in vivo using high-resolution (22-μm axial resolution) 1/T1magnetic resonance imaging (MRI) without and with a confirmatory quench (quench-assisted MRI). METHODS: Low-dose sodium iodate-treated and diabetic C57Bl6/J mice (and their controls), and rod-dominated (129S6) or cone-only R91W;Nrl-/- mice were studied. In dark-adapted groups, 1/T1 was mapped transretinally in vivo without or with (1) the antioxidant combination of methylene blue (MB) and α-lipoic acid (LPA), or (2) light exposure; in subgroups, retinal superoxide production was measured ex vivo (lucigenin). RESULTS: In the sodium iodate model, retinal superoxide production and outer retina-specific 1/T1 values were both significantly greater than normal and corrected to baseline with MB+LPA therapy. Nondiabetic mice at two ages and 1.2-month diabetic mice (before the appearance of oxidative stress) had similar transretinal 1/T1 profiles. By 2.3 months of diabetes, only outer retinal 1/T1 values were significantly greater than normal and were corrected to baseline with MB+LPA therapy. In mice with healthy photoreceptors, a light quench caused 1/T1 of rods, but not cones, to significantly decrease from their values in the dark. CONCLUSIONS: Quench-assisted MRI is a feasible method for noninvasively measuring normal and pathologic production of free radicals in photoreceptors/RPE in vivo.
PURPOSE: Excessive and continuously produced free radicals in the outer retina are implicated in retinal aging and the pathogenesis of sight-threatening retinopathies, yet measuring outer retinal oxidative stress in vivo remains a challenge. Here, we test the hypothesis that continuously produced paramagnetic free radicals from the outer retina can be measured in vivo using high-resolution (22-μm axial resolution) 1/T1magnetic resonance imaging (MRI) without and with a confirmatory quench (quench-assisted MRI). METHODS: Low-dose sodium iodate-treated and diabetic C57Bl6/J mice (and their controls), and rod-dominated (129S6) or cone-only R91W;Nrl-/- mice were studied. In dark-adapted groups, 1/T1 was mapped transretinally in vivo without or with (1) the antioxidant combination of methylene blue (MB) and α-lipoic acid (LPA), or (2) light exposure; in subgroups, retinal superoxide production was measured ex vivo (lucigenin). RESULTS: In the sodium iodate model, retinal superoxide production and outer retina-specific 1/T1 values were both significantly greater than normal and corrected to baseline with MB+LPA therapy. Nondiabeticmice at two ages and 1.2-month diabeticmice (before the appearance of oxidative stress) had similar transretinal 1/T1 profiles. By 2.3 months of diabetes, only outer retinal 1/T1 values were significantly greater than normal and were corrected to baseline with MB+LPA therapy. In mice with healthy photoreceptors, a light quench caused 1/T1 of rods, but not cones, to significantly decrease from their values in the dark. CONCLUSIONS: Quench-assisted MRI is a feasible method for noninvasively measuring normal and pathologic production of free radicals in photoreceptors/RPE in vivo.
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