Measuring In Vivo Free Radical Production by the Outer Retina

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2015 Dec 17

PMID 26670830

Citations 27

Authors

Bruce A Berkowitz

Bryce X Bredell

Christopher Davis

Marijana Samardzija

Christian Grimm

Robin Roberts

Affiliations

Soon will be listed here.

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.

Citing Articles

Acetazolamide Challenge Changes Outer Retina Bioenergy-Linked and Anatomical OCT Biomarkers Depending on Mouse Strain.

Berkowitz B, Paruchuri A, Stanek J, Podolsky R, Childers K, Roberts R Invest Ophthalmol Vis Sci. 2024; 65(3):21.

PMID: 38488413 PMC: 10946704. DOI: 10.1167/iovs.65.3.21.

Polyunsaturated Lipids in the Light-Exposed and Prooxidant Retinal Environment.

Longoni B, Demontis G Antioxidants (Basel). 2023; 12(3).

PMID: 36978865 PMC: 10044808. DOI: 10.3390/antiox12030617.

CCR2-positive monocytes contribute to the pathogenesis of early diabetic retinopathy in mice.

Saadane A, Veenstra A, Minns M, Tang J, Du Y, Abubakr Elghazali F Diabetologia. 2023; 66(3):590-602.

PMID: 36698021 PMC: 9892100. DOI: 10.1007/s00125-022-05860-w.

Transducin-Deficient Rod Photoreceptors Evaluated With Optical Coherence Tomography and Oxygen Consumption Rate Energy Biomarkers.

Berkowitz B, Podolsky R, Childers K, Roberts R, Katz R, Waseem R Invest Ophthalmol Vis Sci. 2022; 63(13):22.

PMID: 36576748 PMC: 9804021. DOI: 10.1167/iovs.63.13.22.

Functional Changes Within the Rod Inner Segment Ellipsoid in Wildtype Mice: An Optical Coherence Tomography and Electron Microscopy Study.

Berkowitz B, Podolsky R, Childers K, Burgoyne T, De Rossi G, Qian H Invest Ophthalmol Vis Sci. 2022; 63(8):8.

PMID: 35816042 PMC: 9284466. DOI: 10.1167/iovs.63.8.8.

References

Zheng L, Du Y, Miller C, Gubitosi-Klug R, Kern T, Ball S . Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia. 2007; 50(9):1987-1996. DOI: 10.1007/s00125-007-0734-9. View

Wangsa-Wirawan N, Linsenmeier R . Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 2003; 121(4):547-57. DOI: 10.1001/archopht.121.4.547. View

Du Y, Cramer M, Lee C, Tang J, Muthusamy A, Antonetti D . Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability. FASEB J. 2015; 29(5):2194-204. PMC: 4415023. DOI: 10.1096/fj.14-269431. View

Rohrer B, Pinto F, Hulse K, Lohr H, Zhang L, Almeida J . Multidestructive pathways triggered in photoreceptor cell death of the rd mouse as determined through gene expression profiling. J Biol Chem. 2004; 279(40):41903-10. DOI: 10.1074/jbc.M405085200. View

Linsenmeier R, Braun R . Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia. J Gen Physiol. 1992; 99(2):177-97. PMC: 2216610. DOI: 10.1085/jgp.99.2.177. View

Yu D, Cringle S . Oxygen distribution in the mouse retina. Invest Ophthalmol Vis Sci. 2006; 47(3):1109-12. DOI: 10.1167/iovs.05-1118. View

Usui S, Komeima K, Lee S, Jo Y, Ueno S, Rogers B . Increased expression of catalase and superoxide dismutase 2 reduces cone cell death in retinitis pigmentosa. Mol Ther. 2009; 17(5):778-86. PMC: 2803613. DOI: 10.1038/mt.2009.47. View

Perkins G, Ellisman M, Fox D . Three-dimensional analysis of mouse rod and cone mitochondrial cristae architecture: bioenergetic and functional implications. Mol Vis. 2003; 9:60-73. View

Komeima K, Rogers B, Lu L, Campochiaro P . Antioxidants reduce cone cell death in a model of retinitis pigmentosa. Proc Natl Acad Sci U S A. 2006; 103(30):11300-5. PMC: 1544081. DOI: 10.1073/pnas.0604056103. View

10.

Berkowitz B, Grady E, Khetarpal N, Patel A, Roberts R . Oxidative stress and light-evoked responses of the posterior segment in a mouse model of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2015; 56(1):606-15. PMC: 4309313. DOI: 10.1167/iovs.14-15687. View

11.

Berkowitz B, Roberts R, Goebel D, Luan H . Noninvasive and simultaneous imaging of layer-specific retinal functional adaptation by manganese-enhanced MRI. Invest Ophthalmol Vis Sci. 2006; 47(6):2668-74. DOI: 10.1167/iovs.05-1588. View

12.

Berkowitz B, Roberts R, Stemmler A, Luan H, Gradianu M . Impaired apparent ion demand in experimental diabetic retinopathy: correction by lipoic Acid. Invest Ophthalmol Vis Sci. 2007; 48(10):4753-8. DOI: 10.1167/iovs.07-0433. View

13.

Fuchsjager-Mayrl G, Polska E, Malec M, Schmetterer L . Unilateral light-dark transitions affect choroidal blood flow in both eyes. Vision Res. 2001; 41(22):2919-24. DOI: 10.1016/s0042-6989(01)00171-7. View

14.

Vallet P, Van Haverbeke Y, Bonnet P, Subra G, Chapat J, Muller R . Relaxivity enhancement of low molecular weight nitroxide stable free radicals: importance of structure and medium. Magn Reson Med. 1994; 32(1):11-5. DOI: 10.1002/mrm.1910320103. View

15.

Fitzgerald M, Gamlin P, Zagvazdin Y, Reiner A . Central neural circuits for the light-mediated reflexive control of choroidal blood flow in the pigeon eye: a laser Doppler study. Vis Neurosci. 1996; 13(4):655-69. DOI: 10.1017/s0952523800008555. View

16.

Campochiaro P, Strauss R, Lu L, Hafiz G, Wolfson Y, Shah S . Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa?. Antioxid Redox Signal. 2015; 23(7):643-8. PMC: 4554553. DOI: 10.1089/ars.2015.6327. View

17.

Enzmann V, Row B, Yamauchi Y, Kheirandish L, Gozal D, Kaplan H . Behavioral and anatomical abnormalities in a sodium iodate-induced model of retinal pigment epithelium degeneration. Exp Eye Res. 2005; 82(3):441-8. DOI: 10.1016/j.exer.2005.08.002. View

18.

Zhang X, Rojas J, Gonzalez-Lima F . Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res. 2006; 9(1):47-57. DOI: 10.1007/BF03033307. View

19.

Ekanger L, Allen M . Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging. Metallomics. 2015; 7(3):405-21. PMC: 4357574. DOI: 10.1039/c4mt00289j. View

20.

Roberts R, Luan H, Berkowitz B . alpha-lipoic acid corrects late-phase supernormal retinal oxygenation response in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci. 2006; 47(9):4077-82. DOI: 10.1167/iovs.06-0464. View